SOCRA Practice 4

What criteria should IRBs strive to achieve in membership (4)

1) One member with scientific expertise 2) One member who is non-scientific 3) One member not affiliated with the institution 4) Both men and women

What 2 criteria must research in kids with > minimal risk and prospect of benefit meet to be IRB-approved?

1) Risk is justified by benefit 2) Relationship of risk to benefit is at least as favorable as any alternative

What 3 criteria must research in kids with > minimal risk and no benefit meet to be IRB-approved?

1) Risk is minor increase over minimal 2) Intervention experience is reasonably comparable to clinical care 3) Knowledge will be generalizeable

What 5 types of reports must be made from an investigator to a sponsor?

1) Safety occurrences 2) Protocol deviations 3) Progress reports 4) Final report 5) Financial disclosure report

What are the 4 types of blinding?

1) Triple blind: sponsor/investigator/subjects are blinded 2) Double blind: investigator/subjects blinded 3) Single blind: subjects blinded 4) Open label: no blinding

What 5 incidences must sponsors report to the FDA and/or investigators?

1) UADEs 2) Withdrawal of IRB approval 3) Withdrawal of FDA approval 4) Recall and device disposition 5) Significant risk device determination

Within how many days should a sponsor notify the FDA of the completion/termination of a SR device trial?

30 working days

Closed System

An environment in which system access is controlled by persons who are responsible for the content of electronic records that are on the system. (21 CFR, Sec. 11.3)

Controlled Study

An experiment or clinical trial that includes a comparison (control) group.

What 6 items should be recorded by investigator's to maintain adequate IP records

Dates, quantities, batch/serial numbers, expiration dates and code #s of: 1) Product delivery to site 2) Inventory at site 3) Dispensed IP 4) Usage by subject 5) Returned product 6) Disposed product

Class II Device

Medium risk, examples include powered wheelchairs, infusion pumps, surgical drapes

A primary purpose of the ICH is to:

Minimize the need for redundant research.

Ensure corrections on CRFs are initialed, dated and explained if necessary by PI or person authorized by PI to make changes to CRF - document authorization

Monitor

Ensures PI and Study Staff are adequately informed of trial

Monitor

Ensures PI is supplied with protocol, IB, docs and supplies to conduct trial

Monitor

Inform PI of any CRF entry error

Monitor

Reports subject recruitment rate

Monitor

Responsible for following sponsor's SOP for monitoring a specific trial

Monitor

Responsible for monitoring report to include summary of what was reviewed, findings, deviations, conclusions, actions taken or recommendations for compliance

Monitor

Submit report to sponsor after each site visit or trial-related communication

Monitor

Verifies CRF entries against source docs for accuracy

Monitor

Verifies IP are supplied at protocol specified dose

Monitor

Verifies IP only supplies to eligible subjects

Monitor

Verifies IP supplies are sufficient throughout trial

Monitor

Verifies PI are maintaining the Essential Documents

Monitor

Verifies PI comply with protocol

Monitor

Verifies PI is qualified and has appropriate resources

Monitor

Verifies PI submit all required reports, notifications, applications - also verify they are complete and timely

Monitor

Verifies signed ICF before subject participation

Monitor

Verifies source docs are accurate, complete, kept up to date and maintained

Monitor

Verifies study site dispose of unused IP in accordance to applicable regulatory requirements

Monitor

Verifies study site documents IP's receipt, use and return

Monitor

Verifies subjects were provided instructions on how to use, handle, tore and return IP

Monitor

Verifies that IP's storage times and conditions are acceptable

Monitor

How is QC done during a trial?

Monitoring by a study monitor

5-121 When must termination of an investigation due to unanticipated adverse device effects occur?

No later than 5 working days after the sponsor makes the determination that the device effect presents an unreasonable risk to subjects, and not later that 15 working days after the sponsor first received notice of the effect.

When is expedited IRB review allowed?

No more than minimal risk Minor or administrative changes Requires proper documentation and guidelines FDA can decide expedited review is not allowed for a particular institution

What are historical controls?

Prior data from similar patients with the disease to be studied, or data from same patient in crossover study

What does an investigator attest to when signing an Investigator's Agreement? (3)

Qualification Commitment to conduct study following regulations Supervision of trial

What must a sponsor do if the FDA requests more information about an IND safety report for drug studies?

Respond no more than 15 calendar days from receipt of request

What is Source Data Review (SDR)

Review of source documentation to check quality, and review and ensure protocol compliance

5-98: If a sponsor fails to inform the FDA of all serious and unexpected adverse experiences, what is the most significant action the FDA may take relative to the IND?

Termination of the IND. 21 CFR 312.44

All unused investigational agents are expected to be returned to the sponsor at the:

Termination site visit.

15-142 Which records must be maintained by investigators for investigational drug supplies? 21 CFR 312.62

The correct answer is: Records of drug disposition that include dates, quantities, and use by study subjects.

15-142 What are records that must be maintained by investigators for investigational drug supplies?

The correct answer is: Records of drug disposition to include dates, quantities, and use by study subjects. 21 CFR 312.62

15-57: For purposes of filing an IND safety reports with the FDA, what is the definition of a "life-threatening event?"

The correct answer is: The patient was at immediate risk of death from the reaction as it occurred.

15-87: FDA may place a Phase 2 or Phase 3 clinical trial on clinical hold if the study design is deficient in design to meet the stated objectives. True or False?

The correct answer is: True 21 CFR 312.42

5-93: Unless patients are exposed to immediate and serious risk the FDA will attempt to satisfactorily resolve deficiencies with sponsors prior to issuing a clinical hold order. True or False?

True 21 CFR 312.42

5-99: Sponsor failure to comply with any IND requirement of 21 CFR parts 312, 50 or 56 may result in FDA termination of the IND. True or False?

True 21 CFR 312.44

When must a sponsor submit a brief report of investigation progress to FDA for drug trials?

Within 60 days of anniversary date that IND went into effect

5-63: What is the time frame in which a sponsor must file an IND annual report?

Within 60 days of the anniversary date that the IND went into effect.

Office of Human Research Protection (OHRP)

federal government office that issues assurances and overseas complicance

Phase II

most rigidly controlled @ 200 subjects, see if effective and further evaluate safety, maximum effective dose (efficacy)

what is beneficence according to the belmont report?

ratio/risk, doing no harm, maximizing benefits while minimizing risks

Nuremburg Code

set of standards proclaimed following the trial of Nazi doctors in 1947

OHRP

2000

1. Research 2. Risks 3. Benefits 4. Alternatives to treatment 5. Confidential 6. Compensation 7. Contact Person 8. Voluntary

8 required elements of informed consent

How many days does an IRB have to report a change in registration information due to a change in chairperson or contact?

90 days

Adverse Drug Reaction (ADR)

All noxious and unintended responses to a medicinal product related to any dose. (ICH GCP E6 1.1)

Documentation

All records, in any form, that describe or record the methods, conduct and or results of a trial, the factors affecting the trial and the actions taken. (ICH GCP E6 1.22)

Quality Assurance (QA)

All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented, and reported in compliance with Good Clinical Practices and the applicable regulatory requirements. (ICH GCP E6 1.46)

What regulation dictates that investigators and staff should be adequately trained?

ICH GCP 5.18.4

What regulations dictate QA and QC definitions?

ICH GCP Guideline 1.46 and 1.47

What regulatory body offers more guidance on protocol structure/contents?

ICH GCP guideline

What regulations dictate how investigators should complete CRFs?

ICH GCP guideline section 4.9

What regulations describe the essential documents to be kept in trial conduct?

ICH GCP guideline, section 8

4 topics Efficacy Safety Quality Multidisciplinary

ICH guidelines are divided into how many categories and what are the categories?

21 CFR 812

IDE

The name and address of the SPONSOR A report of prior investigations Methods, facilities, controls, etc Example of agreements with investigators Proof that all investigators have signed the agreements, a list of investigators participating IRB reviewer information Institutional information Sale and cost information A claim for exclusion under other chapters Labeling and forms "Additional information"

IDE Applications require:

What are 2 potential phases of Phase III trials and their purposes?

IIIa: safety and efficacy IIIb: additional disease indications or marketing claims

21 CFR 312

IND

5-104: End-of-Phase 2 meetings between the FDA and a sponsor are generally reserved for what type of IND?

INDs involving new molecular entities or major new uses of marketed drugs. 21 CFR 312.47

21 CFR 56

IRB

Part 56

IRB

Who determines whether consent is needed from child, mom and/or dad?

IRB

Who ultimately approves an ICF?

IRB - sponsor can provide sample form

If device meets even 1 of the criteria for exemption, what is the regulatory process?

IRB review and approval - no FDA notification required

45 CFR Part E

IRBs

Submit summary of trial outcome to IRB and regulatory authorities - FDA at the completion of the trial

Investigator

Sufficient time to conduct trial

Investigator

Supply additional info to sponsor and IRB if reported Death

Investigator

Understand why subject withdraws

Investigator

Who has ultimate responsibility for an investigational product?

Investigator

What is the device study equivalent of an FDA 1572?

Investigator Agreement

What is the FDA requirement for investigator retention of records?

Investigator retains for 2 years after date a marketing application is approved for indication for which it was investigated or for 2 yrs after an investigator was discontinued and FDA notified (312.62(c))

What does the FDA regulation state regarding investigator provision of access to records for audits?

Investigator shall permit an FDA officer or employee to have access to, copy and verify any records or report made by the investigator; investigator is not required to divulge subject names unless records of certain individuals require a more detailed case study, the records may not represent actual case studies or don't represent actual results obtained

What relationships are considered when reporting a financial disclosure?

Investigator, spouse and dependent children

Explain correct use of IP to subjects

Investigator/Designee

Fully inform subjects of all aspects of trial

Investigator/Designee

The ICH E6 GCP describes standards that apply to:

Investigators, sponsors, and IRBs.

21 CFR 50

Protection of Human Subjects

45 CFR 46

Protection of Human Subjects

Part 50

Protection of Human Subjects

21 CFR 50

Protection of Human Subjets/Informed Consent

5-43 Results of pre-clinical studies on abuse potential and drug dependence are required in the original IND application for which classes of drugs?

Psychotropic substances or any other drug with abuse potential.

May use statistically controlled sampling to select data to be verified

Sponsor

Obtain IRB info from PI

Sponsor

Obtain updated IRB approved documents from PI

Sponsor

Provide insurance or indemnify PI against claims arising from the trial - via legal and financial coverage EXCEPT when negligence is involved

Sponsor

Provide protocol and IB for PI's consideration before entering into an agreement

Sponsor

Provide written instructions for the handling and storage of IP to PI

Sponsor

Report any transfer of data to regulatory authorities

Sponsor

Responsible for PI and coordinating PI (multicenter) selection

Sponsor

Responsible for appointing individuals independent of the trial/system to conduct audit

Sponsor

Responsible for expediting report of ADR that is both serious and unexpected to PI, IRB and Regulatory Authorities

Sponsor

Responsible for ongoing safety evaluation of IP

Sponsor

Responsible for providing audit certificate

Sponsor

Responsible for submitting all safety updates and periodic updates to Regulatory Authorities

Sponsor

Responsible to assess whether significant formulation changes to IP would significantly alter the pharmacokinetic profile of the IP before using the new formulation

Sponsor

Responsible to ensure audit is carried out according to the sponsor's SOP on: 1) What to audit 2) How to audit 3) Audit frequency 4) Form and content of audit reports

Sponsor

Responsible to perform audit to evaulate trial conduct and compliance with the protocol, SOP and GCP as part of quality assurance

Sponsor

Responsible to select/appoint monitors

Sponsor

Retain samples until data analysis is completed or longer

Sponsor

Retain sponsor-specific Essential Documents for at least 2 year

Sponsor

Secure and document agreement from all parties

Sponsor

Submit applications to regulatory authorities for permission to begin trial

Sponsor

Submit clinical trial report to Regulatory Authorities at study completion or termination

Sponsor

Supply and ensure timely delivery of IP to institute only after all required docs are obtained

Sponsor

Takes immediate action to secure compliance from study site if non-compliance is found in audit or monitoring report

Sponsor

Terminate study site and notify Regulatory Authorities if non-compliance of study site is persistent

Sponsor

Use unambiguous subject codes

Sponsor

Who is ultimately responsible for a clinical trial being conducted according to regulations?

Sponsor or sponsor-investigator via Clinical Trial Monitor or CRA

What does ICH GCP 5.18.3 state regarding monitoring of investigators by sponsors?

Sponsor should ensure trials are adequately monitored. Sponsor determines appropriate extent and nature of monitoring. There is usually a need for on-site monitoring before, during and after a trial. Sometimes, sponsor may determine central monitoring + investigators meeting and training is sufficient

Agree to comply with: 1. GCP 2. Protocol 3. Obtain IRB approval 4. Permit monitoring 5. Permit auditing 6. Retain trial Essential Documents for specified period

Sponsor's basic agreement with Investigator

Who determines whether a device trial is SR, NSR or exempt?

Sponsor/investigator makes suggestion > IRB makes decision > FDA confirms

Who is responsible for ensuring investigators are compliant with GCP requirements?

Sponsors - obtain signed FDA 1572 or Investigator's Agreement stating investigator will comply with GCP, so usually require training

What does ICH GCP 5.1.1 dictate regarding SOPs?

Sponsors are responsible for implementing and maintaining QA/QC systems with written SOPs

5-111: If a sponsor desires to transfer some obligations to a contract research organization, what documentations must the sponsor prepare?

Sponsors must describe, in writing, the specific responsibilities being transferred unless all responsibilities are being transferred, in which case a general statement will suffice. Any obligation not described in writing is deemed no to have been transferred.

What do FDA regulations state about monitors?

Sponsors shall select monitors qualified by training and experience to monitor the progress of the investigation (21 CFR 312.53(d))

What is FDA Form 1572?

Statement of investigator

Form 1572

Statement of investigator for IND

Form 1572

Statement of the Investigator

Nature and extent of monitoring should be based on...

Study Design

Sponsor's Audit Plan should be guided by....

Study Design

Single blinding

Subject being unaware of their treatment assignement

Double blinding

Subject, investigator, and monitor unaware of treatment assignment

How do you document long form consent?

Subject/LAR signs long form consent

5-13: Sponsors are prohibited from unduly prolonging clinical investigations, once adequate data has been generated to support a marketing application. True or False?

TRUE

5-15: Charging a reasonable amount for investigational drugs under a treatment IND is permissible provided certain criteria are met and there is no commercialization or promotion involved. True or False?

TRUE

5-1: IND regulations typically do not apply to investigations with lawfully marketed drugs which are being studied for purposes other than supporting a change in labeling or a change in advertising, so long as the study complies with IRB and consent regulations and does not significantly increase risks or decrease acceptability of risks. True or False?

TRUE

5-2: Some clinical investigations involving an in vitro diagnostic biologic product may be exempt from the IND regulations if it used only to confirm a diagnosis made by another medically established diagnostic product or procedure. True or False?

TRUE

5-3: Clinical research on blood grouping serum, reagent red blood cells and anti human globulin are generally exempt from the FDA's IND regulation. True or False

TRUE

5-4: Clinical investigations involving placebos may be exempt from IND regulations if the investigation does not otherwise require the submission of an IND application. True or False?

TRUE

5-59: For marketed drugs, a sponsor is not required to file an IND safety report for events which are from non-clinical trial sources. True or False?

TRUE

5-5: Use of marketed drug or biologic product for an unlabeled indication in the practice of medicine is not subject to the IND regulations. True or False?

TRUE

5-6: Researchers planning an investigation may contact the FDA to obtain guidance on the applicability of the IND regulations to a particular study. True or False?

TRUE

5-71: "Treatment use" protocols are generally used once a drug's initial safety in Phase 2 trials has been demonstrated. True or False?

TRUE

Unless the FDA notifies a sponsor that investigations in an IND are subject to a clinical hold, how soon may the sponsor begin a clinical investigation after filing the IND?

Thirty days (30) after the FDA receives the IND submission.

5-101 If an investigator named in a treatment IDE is not specifically qualified to use an investigational device for the intended treatment use, approval of a controlled trial of device has been withdrawn by the FDA, or the sponsor is not pursuing marketing approval with due diligence, the FDA may deny or withdraw its approval of a treatment IDE. True or False?

True

5-105 The sponsor of a treatment IDE is responsible for submitting all other reports required by the IDE regulations, in 21 CFR 812.150, such as protocol deviations, unanticipated adverse device effects and withdrawal of IRB approval. True or False?

True

5-112: When a sponsor transfers some or all its obligations to a CRO, the CRO is required to comply with all regulations designated as sponsor requirements for the transferred obligations.

True

5-123: During the investigator selection process, sponsors are required to obtain a commitment from an investigator to provide financial disclosure statements before, during, and for one year after the completion of a study?

True

5-127: Even though the FDA Form 1572 is a contract between an investigator and the FDA, a sponsor may discontinue shipments of drug or terminate a study if the investigator fails to comply with the obligations on the signed for 1572 form. True or False?

True

5-16: The FDA may withdraw authorization to charge for an investigational drug.

True

5-17: Sponsors may request waivers of the IND requirements from the FDA

True

5-18: Filing an IND application with the FDA is required prior to commencing any clinical investigation with an investigational new drug

True

5-19: Filing a separate IND with the FDA is required if a sponsor elects to conduct investigations involving waiver of informed consent in emergency research.

True

5-20: A sponsor must receive written approval from the FDA, prior to beginning emergency research being conducted with waiver of consent.

True

5-34: The FDA Form 1571 contains a statement that an IRB that complies with the requirements of 21 CFR 56 will be responsible for review of all studies conducted under the IND

True

5-36: Foreign clinical experience with a drug must be submitted in an original IND application.

True

5-38 The Investigator Brochure is a required component of an original IND submission. True or False?

True

5-92 "Treatment use" of an investigational device includes the use of a device for diagnostic purposes. True of False?

True

5-97 A Licensed practitioner is considered an "investigator" under a treatment IDE when he/she receives an investigational device for treatment use and is responsible for complying with informed consent and IRB regulations. True or False?

True

A sponsor may withdraw an effective IND at anytime, without prejudice.

True

For treatment INDs, the investigator is responsible for reporting safety information directly to the FDA.

True

Serious or life-threatening diseases in patients for whom no alternative drug or comparable therapies are available may be evaluated outside of sponsor-planned clinical trials in a treatment protocol

True

The FDA Commissioner may deny requests for treatment-use of a drug for serious or life-threatening diseases if there is insufficient evidence to support its use.

True

The IND annual report should include an update description of the general investigational plan for the coming year.

True

When a licensed medical practitioner files a treatment IND with the FDA, the investigator becomes a sponsor-investigator, even though the sponsor may be supplying the drug

True

5-87: The FDA may place a Phase 2 or Phase 3 clinical trial on clinical hold if the study design is deficient in design to meet the stated objectives. True or False?

True 21 CFR 312.42

5-88: The FDA may place a treatment IND or treatment protocol on clinical hold if a comparable or satisfactory alternative therapy or drug becomes available for patients with conditions intended to be treated in the investigation. True or False?

True 21 CFR 312.42

5-89: The FDA may place a treatment IND on clinical hold if a sponsor is not pursuing marketing approval with due diligence. True or False?

True 21 CFR 312.42

research

systematic investigation designed to develop or contribute to generalizable knowledge

Who is responsible for the safety and well-being of all trial subjects?

the IRB

The review and follow up of monitoring reports with Sponsor should be documented by...

the Sponsor's Representative

therapeutic misconception

the belief that experimental treatment is for the benefit (treatment) of the individual patient

5-9: What statement must the label of all investigational drugs bear?

"Caution: New Drug--Limited by Federal [or United States] law to investigational use".

Significant device Risk

(1) Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; (2) Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject; (3) Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or (4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

The sponsor must submit an IND safety report to the FDA if an adverse event is (1) serious; (2) unexpected; AND:

(3) there is a reasonable possibility that the drug caused the event.

What 3 main sections should be included in the FDA progress report for drug studies?

1) Individual study information 2) Summary information 3) General investigational plan

21 CFR Part 312.310

*Individual patients, including for emergency use* (1) The physician must determine that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition; and (2) FDA must determine that the patient cannot obtain the drug under another IND or protocol.

21 CFR Part 312.315

*Intermediate-size patient populations* (1) Drug not being developed. The drug is not being developed, for example, because the disease or condition is so rare that the sponsor is unable to recruit patients for a clinical trial. (2) Drug being developed. The drug is being studied in a clinical trial, but patients requesting the drug for expanded access use are unable to participate in the trial. For example, patients may not be able to participate in the trial because they have a different disease or stage of disease than the one being studied or otherwise do not meet the enrollment criteria, because enrollment in the trial is closed, or because the trial site is not geographically accessible. (3) Approved or related drug. (i) The drug is an approved drug product that is no longer marketed for safety reasons or is unavailable through marketing due to failure to meet the conditions of the approved application, or (ii) The drug contains the same active moiety as an approved drug product that is unavailable through marketing due to failure to meet the conditions of the approved application or a drug shortage.

21 CFR part 312.305

*Requirements for all expanded access uses* (1) The patient or patients to be treated have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition; (2) The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated; and (3) Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.

Informed Consent MUST Contain:

- explanation of purpose of research - duration of participation - description of procedures to be followed - identification of any procedures which are experimental - any foreseeable risks or discomfort - statement about potential benefits to subjects - statement if no reasonable alternative procedures or treatments are available to subjects - for > minimal risk, a statement about compensation and if medical treatment is available for injuries - statement of who to contact in the event of research-related injury

21 CFR 312.320

*Treatment IND or treatment protocol* (1) Trial status. (i) The drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use, or (ii) All clinical trials of the drug have been completed; and (2) Marketing status. The sponsor is actively pursuing marketing approval of the drug for the expanded access use with due diligence; and (3) Evidence. (i) When the expanded access use is for a serious disease or condition, there is sufficient clinical evidence of safety and effectiveness to support the expanded access use. Such evidence would ordinarily consist of data from phase 3 trials, but could consist of compelling data from completed phase 2 trials; or (ii) When the expanded access use is for an immediately life-threatening disease or condition, the available scientific evidence, taken as a whole, provides a reasonable basis to conclude that the investigational drug may be effective for the expanded access use and would not expose patients to an unreasonable and significant risk of illness or injury.

21 CFR 812.36

*Treatment use of an investigational device* (1) The device is intended to treat or diagnose a serious or immediately life-threatening disease or condition; (2) There is no comparable or satisfactory alternative device or other therapy available to treat or diagnose that stage of the disease or condition in the intended patient population; (3) The device is under investigation in a controlled clinical trial for the same use under an approved IDE, or such clinical trials have been completed; and (4) The sponsor of the investigation is

What is the definition of a UADE?

- Any serious adverse effect on health/safety, or any life-threatening problem or death associated with a device (if the effect was not already identified in a pre-market application) - Any other unanticipated serious problem associated with device as related to welfare of subjects

How are AEs documented?

- In AE CRF for sponsor (or other study collection mechanism) - In medical record

21CFR56-B: What information is needed for IRB registration with DHHS?

- Information about the institution operating the IRB (ex. WUSTL info) - IRB information and contact information for the person submitting the registration - number of studies reviewed in the last 12 months - types of FDA regulated products reviewed

Which of the following are important for protecting computing devices and systems?

- Physical safeguards like a secure space protected by locked doors, etc. - Technical safeguards like passwords, encryption, and protective software. - Administrative safeguards like rules against sharing passwords.

21CFR56-A: What are 5 common exemptions to the IRB review requirement?

- Research approved prior to 7/27/81 - Emergency Use - Taste Tests - Food Quality - Consumer Acceptance

Which of the following is a good practice if one wishes to avoid "social engineering" attacks?

- Taking appropriate steps to confirm a person's (or site's) identity for any transaction that involves sensitive data. - Not opening attachments or clicking on links in messages, emails, or on websites unless absolutely sure of the source's authenticity. - Using strict procedures when it is necessary to exchange an authentication credential like a password, PIN, account number, or other personal data that is critical to establishing personal identity. - Being cautious any time someone asks for sensitive information, whether by phone, fax, email, or even in person. It could be a phishing scam.

When is father's consent not required for research involving neonates?

- When there is prospect of benefit to mom - When dad unavailable, incompetent or temporarily incapacitated - Rape/incest

What 5 classes of products do the informed consent regulations apply? (test articles)

- drugs - medical devices - biological products - electronic products - food (including dietary supplements and infant formulas) - color additives

Waiver of Signed Informed Consent

- if the only record linking the subject to the research would be the consent document and the principal risk would result from breach in confidentiality - the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the context of research

Private Information

- information about behavior which occurs in a context in which an individual can reasonably expect that no observation or recording is taking place - information which has been provided for a specified purpose by an individual and which the individual can reasonably expect will not be made public (e.g. medical record)

IRB membership requirements according to 45 CFR 46

- minimum of 5 members - IRB must be qualified through experience, expertise, diversity - diversity with respect to race, gender, cultural background - cannot consist of members of one profession - at least one member must have a primary concern in a scientific area and one in a non-scientific area - at least one member not affiliated with the institution

Types of federally-funded research that may be done using prisoners as subjects

- possible causes, effects, and processes of incarceration and criminal behavior - prisons as institutional structures or prisoners as incarcerated persons - conditions particularly affecting prisoners - practices aimed at improving the health or well-being of prisoners

Oral consent

- requires a witness - subject must sign short form only - witness must sign both short form and summary of what was said

Informed Consent ADDITIONAL Elements:

- risk to embyro or fetus - termination procedures - costs to study subjects - approximate number of study subjects - a statement of new findings when they may impact a subject's willingness to participate

Circumstances/conditions required for informed consent

- subject has had sufficient opportunity to consider whether to participate - the possibility of coercion or undue influence is minimized

What are the 5 phases of drug development?

0: PK/PD 1: Safety 2: Efficacy (proof of concept) 3: Pivotal 4: Post-marketing surveillance

What FDA regulations dictate AE/SAE reporting?

1) 21 CFR 312.32 2) 21 CFR 812.46

What 3 guidelines does ICH provide for completing CRFs?

1) Ensure accuracy, completeness, legibility and timeliness of data 2) Confirm data copied on the CRF from source match with original entry 3) Any change or correction to CRF is dated, initialed, explained and shouldn't obscure the original entry

What are an investigator's responsibilities regarding IP use and distribution? (7) - 21 CFR 312

1) Administer drug only to subjects under investigator's personal supervision or under supervision of sub-investigator 2) If IP is subject to Controlled Substances Act, investigator will take adequate precautions, including IP storage in secure location and limit access 3) Retain records for drug storage, tracking use, accounting, drug disposition (dates, quantity and use) 4) Reconcile IP received from sponsor 5) Train correct use of IP with each subject 6) Check subject is following instructions properly 7) Return unused supplies to drug sponsor or destroy drug on site should investigation be terminated, suspended or completed

What additional documents must be kept by both investigator and sponsor during a trial? (10)

1) Amendments to protocol, IB, CRFs and all pre-trial documents 2) IP destruction records 3) Communications 4) Completed CRFs and corrections 5) Safety reports 6) Screening log 7) Signature sheet (DOA) 8) Records of retained samples 9) IP accountability records 10) Clinical study report

What are the 3 components of an IND?

1) Animal pharmacology and toxicology studies 2) Manufacturing information 3) Clinical protocols and investigator information

What 5 items should be documented in IRB meeting minutes?

1) Attendance at meeting 2) Actions taken by IRB 3) Vote on actions, including # voting for, against or abstaining 4) Basis for requiring changes or disapproving research 5) Written summary of discussion of issues and resolution

What additional documents must be kept by the sponsor only during a trial? (3)

1) Audit certificate 2) Final close-out monitoring report 3) Treatment allocation and decoding documents

What are 2 methods used to reduce bias?

1) Blinding 2) Randomization

Protocol Amendment

1) Change in protocol (study design, increase in drug dosage/exposure, addition of new tests/procedures 2) New investigator (except when done for treatment IND/protocol)

What are the 4 types of INDs?

1) Commercial IND: sponsor 2) Investigator IND: sponsor/investigator 3) Emergency Use IND: emergency situations not allowing time for full IND 4) Treatment IND: for drug/biologic showing promise in testing for serious or immediately life-threatening conditions while final clinical testing and FDA review are taking place

What 5 scenarios require financial disclosure?

1) Compensation to PI affected by study outcome 2) Proprietary interest in tested product 3) Equity interest in sponsor of study whose value can't be determined during time or study or for 1 yr after 4) Stock in sponsor $50k+ held during study and for 1 yr after 5) Significant payments of $25k+ from sponsor to investigator during study and for 1 yr after

What 8 items does an investigator commit to when they sign a Form FDA 1572?

1) Conduct according to current protocol 2) Personally conduct/supervise the studies 3) Obtain informed consent 4) Report AEs 5) Properly train staff 6) Maintain adequate records 7) Ensure IRB complies with 21 CFR 56 8) Comply with all other requirements in 21 CFR 312

What are the responsibilities of an investigator per 21 CFR 312.60? (6)

1) Conduct investigation per signed investigator statement 2) Conduct investigation per investigational plan 3) Conduct investigation per applicable regulations 4) Protect rights, safety and welfare of subjects 5) Control IP 6) Obtain informed consent

Phase 1

1) Conducted in patients or normal volunteer subjects 2) Designed to determine metabolism and pharmacologic actions of the drug in humans and side effects of dose escalation 3) 20 to 80 total subjects 4) Closely monitored

IRBs must develop SOPs for which 6 items?

1) Conducting initial and continuing review 2) Reporting findings and actions to investigator and institution 3) Determining which project require more review 4) Ensuring prompt reporting of changes in research activity 5) Ensuring changes are not initiated without IRB approval 6) Ensuring prompt reporting to IRB, sponsor and FDA about UAPs, noncompliance, suspension and termination

What 3 items should be included in the Data Quality Assurance section of the protocol?

1) Data recording, handling and record keeping 2) Study monitoring 3) Auditing and direct access to source data/documents

What essential documents must also be kept with a 3rd party before a trial? (2)

1) Decoding procedure 2) Master randomization list

What 5 items should be present in an IB?

1) Description of drug and formulation, including structural formula 2) Pharmacological and toxicological effects of the drug 3) PK and biological disposition of drug 4) Safety and effectiveness in humans 5) Possible risks and side effects

What are an investigator's responsibilities regarding informed consent and recruitment? (7)

1) Develop ICFs that contain the basic and additional elements of informed consent per 21 CFR 50 2) Follow IRB requirements for consent, not necessarily sponsor's 3) ICF and recruitment materials approved by IRB prior to use per 21 CFR 56 4) Obtain legally effective informed consent 5) Provide subject sufficient opportunity to decide 6) Minimize possibility of coercion or undue influence 7) Avoid exculpatory language through which subject waives any legal rights regarding liability/negligence

What are an investigator's responsibilities regarding the protocol? (3)

1) Develop study protocol and content in compliance with ICH GCP (may also be sponsor) 2) Conduct trial in accordance with protocol per FDA 1572 3) Submit protocol changes to IRB prior to implementation

What 3 components of AE documentation should CRAs monitor?

1) Ensure AEs are recorded in study files and medical record 2) Make sure protocol procedures were followed 3) Check that responsible person assessed AE for seriousness, causality and expectedness

What are the 7 recommendations for electronic document systems described in ICH GCP 5.5.3?

1) Ensure eData processing systems conform to sponsor's established SOPs for completeness, accuracy, reliability and consistency 2) Maintain SOPs 3) Ensure systems document data changes and don't delete entered data 4) Maintain security system that prevents unauthorized access to data 5) Maintain list of individuals that can make data changes 6) Maintain backup of data 7) Safeguard blinding

What 6 requirements does ICH GCP state for sponsors regarding IP accountability?

1) Ensure timely delivery of IP to investigators 2) Maintain records of shipment, receipt, disposition, return and destruction 3) Maintain system for retrieving IP and documenting it 4) Maintain system for disposition of unused IP and documenting it 5) Take steps to ensure IP is stable over period of use 6) Maintain sufficient quantities of IP, record of batch sample analyses and characteristics, and retain samples as possible until analyses of trial data are complete

What 3 items should be included in the Administrative Considerations section of the protocol?

1) Ethical assurance 2) Publication rights 3) Financing and insurance

In what ways may sponsors provide investigator financial disclosures to the FDA? (3)

1) FDA Form 3454 - no financial interests 2) FDA Form 3455 - complete disclosure statement 3) FDA Form 3454/option 3 - no financial disclosure obtained after due diligence

What are 5 common issues the FDA finds during site inspection?

1) Failure to follow investigational plan and signed investigator agreement 2) Protocol deviations 3) Inadequate recordkeeping 4) Inadequate accountability for IP 5) Inadequate subject protection, including informed consent issues

What regulations must NSR studies follow? (3)

1) Follow abbreviated IDE regulations (21 CFR 812(b)) 2) Don't need IDE application approved by FDA 3) Sponsors/IRBs don't have to report to FDA prior to study start

What regulations must SR studies follow? (2)

1) Follow all IDE regulations in 21 CFR 812 2) Have IDE application approved by FDA prior to study start

What 8 items does an investigator commit to when signing an FDA 1572?

1) Follow protocol and make changes only after sponsor notification 2) Comply with FDA reqs 3) Personally conduct/supervise investigation 4) Inform subjects that drugs are investigational 5) Follow informed consent and IRB approval requirements (21 CFR 50 and 56) 6) Report AEs to sponsor 7) Read/understand info in IB 8) Ensure all staff are informed of their obligations

What are the 7 components of the summary information included in FDA progress report for drug studies?

1) Frequent and most serious adverse events 2) Summary of IND safety reports 3) List of subjects who died 4) List of subjects who dropped out due to AEs 5) New understandings of drug's actions 6) List of pre-clinical studies completed/in progress + findings 7) Significant manufacturing or microbiological changes

Phase 3

1) Gather additional information about efficacy and safety to evaluate overall benefit-risk relationship 2) Provide adequate basis for physician labeling 3) Expanded controlled and uncontrolled trials 4) Several hundred to several thousand subjects

What are the sections that ICH GCP recommends be included in a protocol? (6)

1) General information 2) Trial objective and purpose 3) Trial design 4) Selection and withdrawal of subjects 5) Treatment of subjects 6) Statistics

What criteria does the FDA require for Phase 1 protocols? (3)

1) General outline of planned investigation 2) Estimated duration of study 3) Maximum # of subjects involved

What 4 items must sponsors provide procedures/instructions to investigators about? (Per ICH GCP 5.14.3)

1) Handling/storage of IP 2) Receiving/dispensing of IP 3) Retrieval of unused IP 4) Return of unused IP to sponsor if authorized and in compliance

How might investigators assure the accuracy and completeness of information abstracted from source? (6)

1) Have a strategy of how and when to obtain information 2) Create/use standard procedure for abstraction and verification 3) Determine quality of source data prior to abstraction 4) Consider different methods of abstraction 5) Increase efficiency with methods like batching (getting one data point from multiple records at one time point) 6) Verify information (with second review or double data entry)

What essential documents must be kept by both an investigator and sponsor before a trial? (15)

1) IB 2) Protocol, amendments 3) CRFs 4) Financial agreement 5) Insurance (if applicable) 6) Agreements btw sponsor, investigator, CRO, etc. 7) IRB approval 8) IRB composition 9) Regulatory authority approval/notification 10) CVs for investigator and sub-Is 11) Lab normal ranges 12) Lab certification, CV 13) IP records 14) Decoding procedure 15) Trial monitoring report

What 5 considerations should be used for IRBs maintaining documentation electronically?

1) IRB records should be secure 2) Access should be limited with appropriate clearance 3) Paper/electronic back up should be stored clear from hazards 4) Written procedures for documentation and maintenance should be developed/implemented 5) Commercially available systems should meet above considerations

What are the 4 steps to creating a CAPA?

1) Identify issue/problem at root cause and persons involved 2) Determine solution - create plan with measurable actions 3) Set deadline for each action 4) Define how progress will be monitored

IVD studies don't need informed consent if they meet what 6 criteria?

1) If IDE submission unnecessary (NSR or exempt) 2) Leftover specimens used 3) Specimens not individually identifiable 4) Individual caring for patients is different from those conducting trial 5) Specimens provided to investigator without identifiers 6) Clinical trial overseen by IRB

What are the 7 options for exempt device studies?

1) In distribution before 5/1976 2) Device substantially equivalent to one meeting criteria 1 and is used following FDA labeling 3) Diagnostic device that meets 4 criteria (not invasive, introduce energy or used w/o confirmation by other diagnostic device) 4) Undergoing consumer testing, modification testing or combination testing if subjects not at risk 5) Veterinary use 6) Lab animal use 7) Custom device unless being tested for commercial distribution

What are the 4 criteria that define a significant risk device? (21 CFR 812.3(m))

1) Intended as an implant 2) Represented to be for use in supporting/sustaining life 3) Use is of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise preventing impairment of health - All of the above: and presents potential for serious risk to health, safety or welfare of subjects 4) Otherwise presents potential for serious risk to health, safety or welfare of subjects

Phase 2

1) Investigate the efficacy of the IP for particular indications 2) Determine short term side effects and risks 3) Well controlled and closely monitored 4) No more than a several hundred subjects

What are the core components of an FDA 1572? (7)

1) Investigator's name/address 2) Protocol name/code 3) Name of facilities 4) Name/address of lab 5) Name/address of IRB 6) Names of sub-Is 7) Commitment to regulations

What 3 items do statisticians consider to evaluate sample size?

1) Magnitude of IP effect expected between treatment arms (Effect size) 2) Variability of outcome 3) Probability of observing effect (Power)

What 8 guidelines does ICH GCP provide to investigators for maintaining essential study documents?

1) Maintain as required by regulations 2) Prevent accidental/premature destruction 3) Organize into sections 4) File chronologically 5) Explain missing documents or documents at another location 6) Avoid duplicate filing 7) Store in secure location with limited access 8) Document inventory of items archived

What are a monitor's responsibilities per ICH GCP 5.18? (16)

1) Maintain communication btw sponsor and investigator 2) Verify investigator qualifications and resources 3) Verify IP accountability 4) Verify protocol compliance 5) Verify informed consent obtained 6) Ensure investigator has current IB, documents and supplies 7) Ensure investigator and staff adequately trained/informed 8) Verify investigator/staff perform trial fxns according to protocol and appropriate delegation 9) Verify eligible subject enrollment 10) Report recruitment rate 11) Verify source documents 12) Verify investigator reporting is complete/accurate 13) Check CRF entries and errors 14) Accurate reporting of AEs 15) Ensure investigator retains essential documents 16) Communicate deviations from protocol, SOPs and regulations

IRBs must classify research involving children into what categories? (4)

1) Minimal risk only 2) Greater than minimal risk but may provide direct benefit 3) Greater than minimal risk with no potential benefit but generalizeable knowledge could be obtained 4) Presents opportunity to understand, prevent or alleviate a serious problem affecting health/welfare of kids, but not otherwise approvable

What 5 descriptive items should IRB members be documented by?

1) Name 2) Degrees 3) Representative capacity 4) Indication of experience (board certifications, etc.) 5) Employment or other relationship btw member and institution

What 5 items should be included in the "Treatment of Subjects" section of the protocol?

1) Name, dose, regimen, route of admin and treatment period for IP 2) Meds/treatments not permitted before and during trial 3) Procedures for monitoring subject compliance 4) IP storage and accountability 5) Return/destruction of IP

What 8 items should be included in the "Background Information" section of the protocol?

1) Name/desc of IP 2) Findings from nonclinical studies 3) Findings from clinical trials 4) Risks/benefits known 5) Route of admin, dosage, regimen and treatment period for IP 6) Statement of compliance with protocol, GCP and applicable requirements 7) Desc of population to be studied 8) References to relevant lit that provide background

In what 4 ways can an IND safety report be submitted for drug studies?

1) Narrative document 2) FDA Form 3500A 3) Electronic format that FDA can process, review, archive 4) Council for International Organziations of Medical Sciences Form (for foreign reactions)

What 3 criteria should IRB consider when determining assent requirements?

1) Nature of research 2) Child's age, status and condition 3) Whether all or some of children to be included will be capable of assenting

Information Amendment

1) New toxicology, chemistry, or other technical information 2) A report regarding the discontinuance of a clinical investigation.

Describe the 2 most important points to consider when consenting patients (per 21 CFR 50)

1) No person can participate without their or LAR consent (50.20) 2) Documentation of informed consent is required (50.27)

What are the 5 components of an FDA audit?

1) Notice of inspection and credentials 2) Opening interview 3) Records inventory and audit 4) Documentation of findings 5) Close-out discussion

What are the 3 FDA inspection classifications?

1) OAI: when significant objectionable conditions or practices were found and action is warranted 2) VAI: when objectionable conditions or practices were found that don't meet regulatory threshold 3) NAI: when no objectionable practices were found

Protocol Content

1) Objectives and purpose 2) Eligibility Criteria 3) Description of Study Design 4) Method for determining dose, planned maximum dose and duration of patient exposure 5) Observations and measurements to be documented 6) Clinical procedures, labs 7) IP Chemistry, manufacturing, and control information. 8) Pharmacology and toxicology 9) Previous human experience with IP

In what 3 ways does a sponsor ensure investigators obtain informed consent before starting a subject in trial?

1) Obtain signed FDA 1572 2) Provide sample ICF with all elements to investigator 3) Ensure appropriate monitoring

What 5 items should be available when making corrections to source documents?

1) Old value/text 2) New value/text 3) Date of correction 4) Name/initial of person making the correction 5) Reason for the change (as necessary)

What criteria does the FDA require of Phase 2 and 3 protocols? (7)

1) Outline of study protocol 2) Approximation of subject # treated vs controls 3) Clinical uses of treatment to be investigated 4) Characteristics of subjects by age, sex, condition 5) Clinical observations and lab tests to be conducted 6) Duration of study 7) Copies or description of CRFs to be used

What 2 study designs are most commonly used in clinical trials?

1) Parallel 2) Crossover

What are an investigator's responsibilities during study visits? (5)

1) Perform/oversee trial-related procedures 2) Provide medical decisions or ensure a qualified investigator does 3) Assess subject compliance 4) Evaluate subjects' response to treatment 5) Assess AEs and provide medical care

What are the 6 components of a Quality System?

1) Personnel roles/responsibilities 2) Training 3) Policies/procedures 4) QA/auditing 5) Document mgmt, record retention, reporting 6) CAPA

What are the phases of device trials?

1) Pilot 2) Pivotal

What are the 3 types of control groups used in trials?

1) Placebo 2) Standard of Care 3) Historical control

What 9 items does ICH GCP guideline recommend be included in Trial Design section?

1) Primary/secondary endpts 2) Type/design of trial 3) Measures to avoid bias 4) Treatments - dose, packaging, regimen 5) Duration of participation 6) Stopping rules 7) Accountability procedures for IP 8) Maintenance of randomization codes 9) Data to be recorded on CRFs/source data

What 3 items should be discussed in a DSMP?

1) Procedures for DSMB to oversee progress 2) Plans for DSMB to assure data accuracy and protocol compliance 3) How DSMB will review reporting of UAPs, AEs to sponsor, FDA and IRB

What 4 aspects of a trial should a sponsor focus on when monitoring for compliance per 21 CFR 312.56?

1) Progress of investigations under IND 2) Secure compliance or discontinue investigators that are not compliant and notify FDA 3) Review safety/effectiveness of drug and report safety issues to FDA + make annual reports or progress 4) Notify FDA, all IRBs and all investigators if drug presents unreasonable and significant risk to subjects - assure disposition of out-standing drug and provide full report to FDA

What 4 reports must investigators provide to a sponsor? (per 312.64)

1) Progress reports (annual report) 2) Safety reports (AEs/SAEs) 3) Final report 4) Financial disclosure report (during study and 1 yr after)

What are the 3 goals of the BIMO program?

1) Protect rights, safety and welfare of subject involved in FDA-regulated trials 2) Verify accuracy and reliability of clinical trial data submitted to the FDA 3) Assess compliance with FDA's regulations governing conduct of clinical trials

What are an investigator's responsibilities regarding follow up care? (2)

1) Provide or refer subject for medical care needed for intercurrent illnesses 2) Inform subject's PCP as needed

What are investigator's responsibilities regarding subject retention? (Not in FDA regulations) (4)

1) Provide subjects with complete understanding of treatment risks and procedures involved 2) Treat each subject with respect 3) Provide appropriate incentives for study completion without coercion 4) Utilize tools to enhance trial experience - Provide visit calendar and phone/email reminders - Allow flexibility in appt date/time within protocol limits - Train staff in customer service

What do FDA regulations mandate for sponsors regarding the IB? (2)

1) Provide to each participating clinical investigator before the investigation begins (21 CFR 312.23(a)(5)) 2) Keep investigators informed of new observations discovered by or reported to the sponsor regarding AEs and safe use (21 CFR 312.55(b))

What 11 components should IRB applications include?

1) Purpose of research 2) Scientific rationale 3) Research setting 4) Whether participants will be vulnerable to coercion/undue influence 5) Inc/exc criteria 6) Recruitment/enrollment procedures 7) Method of advertising 8) Time required to participate 9) Procedures 10) Payment amount and schedule 11) Risks/benefits

What are the 6 components of the general investigational plan included in FDA progress report for drug studies?

1) Rationale for study 2) Indications 3) General approach 4) Clinical trials to be conducted in 1st yr following submission 5) Estimated # of pts in trials 6) Risks anticipated on basis of animal data or previous studies

What are an investigator's responsibilities regarding safety reports for drug studies? (3)

1) Report SAEs, whether or not considered drug-related, to sponsor immediately after discovery (21 CFR 312) 2) Report SAEs to reviewing IRB promptly upon discovery (21 CFR 56 and 312) 3) Record and report non-serious adverse events to sponsor per protocol

What 2 additional protections are afforded child wards of the state?

1) Research > minimal risk w/ no benefit must be directly related to wards or conducted in setting where majority of kids aren't wards 2) Advocate must be appointed by IRB to give consent for study participation and protect child's interests

What 7 activities must IRBs maintain documentation of?

1) Research proposals and attachments 2) IRB meeting minutes 3) Continuing review 4) Correspondence btw IRB/investigators 5) IRB member list 6) Written IRB SOPs 7) Statements of significant new findings provided to subjects

What are the 3 principles in the Belmont Report?

1) Respect for Persons: informed consent required and individuals with diminished autonomy get special protections 2) Beneficence: maximize benefit to research while minimizing risk to subjects 3) Justice: one group of people shouldn't assume risks for the benefit of another (equality and diversity of participants)

What 4 items should be included in the Adverse Events section of the protocol?

1) Safety parameters 2) Methods/timing for assessing, recording and analyzing safety parameters 3) Procedures for reporting and recording AEs and illnesses 4) Type/duration of followup for AEs

What essential documents need only be kept by the sponsor before a trial? (4)

1) Sample of IP labels 2) Certificates of analysis for IP 3) Master randomization list 4) Pre-trial monitoring report

What 4 attachments to research proposals should IRBs maintain documentation of?

1) Scientific evaluations 2) Approved ICFs 3) Progress reports 4) Reports of subject injuries

What are the roles and responsibilities of a sponsor, per 21 CFR 312.50? (6)

1) Select qualified investigators 2) Provide investigators with information they need to conduct investigation 3) Ensure proper monitoring of the investigation 4) Ensure investigation is conducted in accordance with general plan/protocols in IND 5) Maintain IND 6) Ensure FDA and all investigators are informed of new AEs or risks

Sponsors must report what kind of serious events to the FDA within 15 calendar days? (4)

1) Serious and unexpected suspected adverse reactions 2) Findings from other studies that suggest a significant risk in humans 3) Findings from animal or in-vitro testing that suggest risks to humans 4) Increased rate of occurrence of serious suspected adverse reactions

What are the 4 types of incidences that require an IND safety report for drug studies?

1) Serious and unexpected suspected adverse reactions 2) Findings from other studies that suggest significant risk in humans 3) Findings from animal/in-vitro testing that suggest significant risk in humans 4) Increased rate of occurrence of serious suspected adverse reaction from previous protocol/IB

What are the 4 components of the consent process using a short form?

1) Short form consent document stating all elements of ICF have been presented orally to pt/LAR 2) Oral presentation of required elements 3) IRB-approved summary of what is said 4) Witness present during presentation

For what 3 reasons to sponsors conduct QA audit visits?

1) Show quality oversight 2) Identify potential issues and improvements 3) Identify potential regulatory risks that may jeaopardize product approval

As a sponsor, what information is needed from investigators prior to clinical trial participation?

1) Signed investigator agreement 2) CV 3) Signed protocol 4) Financial disclosure

What are the three types of medical device studies listed under IDE regulation (21 CFR 812)?

1) Significant risk 2) Non-significant risk 3) Exempt

What are 3 examples of SUSARs for drug studies?

1) Single occurrence of event that is known to be strongly associated with IP 2) 1+ occurrences of event not commonly associated with drug but otherwise uncommon in population 3) Aggregate analysis of events such as known consequences of disease that commonly occur in population but occur more frequently in IP treatment group

What 3 items should be documented when a subject is discontinued from a trial?

1) Source: whether discontinuation resulted from investigator decision or subject 2) Reason 3) Impact: whether withdrawal was from all components of the research or just primary intervention

What are the 7 items that should be included in the Statistics section of the protocol?

1) Stat methods + interim analyses 2) # of subjects to be enrolled 3) Level of significance 4) Criteria for termination 5) Procedure for accounting of missing, unused and spurious data 6) Reporting deviations from plan 7) Selection of subjects to be included in analysis

What are the additional elements of informed consent per FDA guidelines? (7)

1) Statement that treatment may involve unforseeable risks 2) Circumstances in which subject participation may be terminated 3) Additional costs to subject 4) Consequences of subject's decision to withdraw 5) Statement that new findings will be provided to subject 6) # of subjects in study 7) clinicaltrials.gov statement (as applicable)

What additional documents must be kept by the investigator only during a trial? (5)

1) Subject ID list 2) Subject enrollment list 3) Signed ICFs 4) Source documents 5) Final report to IRB

CRA should monitor what elements of consent process? (5)

1) Subject signed most recent version of form 2) Subject signature and name are both present 3) Subject dated themselves and date is correct 4) Errors were corrected adequately 5) All pages of ICF are present

How do you document short form consent?

1) Subject/LAR signs short form consent 2) Witness signs short form consent and summary 3) Person obtaining consent signs summary - Copy of short form consent and summary are given to subject/LAR

What are an investigator's responsibilities regarding continuing review? (2)

1) Submit progress reports to sponsor (21 CFR 312) - time and frequency not specified 2) Submit progress reports to IRB as defined by IRB approval

What additional sections are commonly used by sponsors in protocols? (8)

1) Table of contents 2) Study procedures 3) Data safety monitoring plan 4) Adverse events 5) Data quality assurance 6) Administrative considerations 7) References 8) Appendices

What 9 items should be included in the protocol "General Information" section

1) Title 2) Protocol # 3) Date 4) Name/address of sponsor and monitor 5) People authorized to sign protocol 6) Name/contact for medical expert 7) Name/contact for sites 8) Name/contact for physicians responsible for medical decisions 9) Name/contact for labs and other technical depts

What are the three components of individual study information included in FDA progress report for drug studies?

1) Title, protocol #, purpose, pt population and status 2) # subject planned, enrolled, completed, withdrawn by gender, age, race, etc. 3) Available interim results

What are the 10 points made in the Nuremberg Code?

1) Voluntary informed consent should be obtained 2) Research should yield benefit to society 3) Research should be based on animal work 4) Avoid unnecessary suffering 5) Don't do research resulting in death or disabling injury 6) Risks should be justified by benefits 7) Proper prep and adequate facilities should be used 8) Conducted by scientifically qualified people 9) Subject can withdraw whenever 10) Researchers can end the study if risks are too great

What 4 items should be included in a protocol to describe Withdrawal criteria?

1) When/how to withdraw subjects 2) Type/timing of data collection for withdrawn subjects 3) Whether subjects will be replaced 4) Follow up for subjects withdrawn from IP treatment

What requirements must be met to conduct research with pregnant women/fetuses?

1) With preclinical and clinical data on non-pregnant women assessing risk to pregnant women 2) Risk to fetus may result in direct benefit for woman or fetus, or risk is not greater than minimal + knowledge can't be obtained any other way 3) Risk is least possible 4) Consent obtained 5) Research benefitting fetus only requires mom+dad consent 6) Individuals providing consent understand impact on neonate 7) Assent + permission for pregnant children required 8) No inducements offered to terminate pregnancy 9) Researchers have no part in decisions to terminate pregnancy 10) Researchers have no part in determining viability of neonate

Generally, sponsors my request FDA comment and advice on which components of an IND submission?

1. Adequacy of technical data to support an investigational plan. 2. Design of a clinical trial. 3. A determination of whether proposed investigations are likely to produce the data and information needed for an NDA.

5-108: What is the proper sequence of actions a sponsor should take when attempting to resolve an administrative or procedural dispute with the FDA>

1. Attempt to resolve the dispute with the reviewing division of CDER or CBER, beginning with the assigned Consumer Safety Officer (CSO). 2. If the dispute is not resolved via the CSO, seek resolution via an ombudsman.

5-131: What records are sponsors required to retain regarding financial interests of its investigators?

1. Complete and accurate records showing any financial interest paid to investigators by the sponsor for the study. 2. Complete and accurate records concerning all other financial interests of the investigator in compliance with 21CFR part 54.

5- 109: What is the proper sequence of actions a sponsor should take when attempting to resolve a scientific or medical dispute with the FDA?

1. Discuss the matter directly with the responsible reviewing officials. 2. If unresolved, request a meeting with the reviewing officials and management representatives.

5-120 Name the two actions a sponsor must complete if unanticipated adverse device effects occur during an investigation.

1. Immediately conduct an evaluation. 2. Terminate the investigation if the unanticipated adverse device effect presents an unreasonable risk to subjects.

5-121: What actions must an investigator take to make changes in a study protocol?

1. Inform the sponsor, request the change, and obtain a protocol amendment, if required. 2 Inform the IRB as needed, and request review and approval of the amendment. 3. Modify the consent form, if required, and obtain IRB approval. 4. Inform study patients of the pertinent changes, and obtain new informed consent, if applicable.

5-45 Name the three categories of protocol amendments which require a sponsor to update the original IND application.

1. New protocols. 2. Changes in a protocol. 3. New investigators.

5-47 Give an example of the type of information required to be filed as an information amendment to an original IND application.

1. New technical information such as toxicology or chemistry. 2. Reports regarding discontinuation of a clinical investigation.

What are the criteria for involving children in minimal risk research? (2)

1. No greater than minimal risk 2. Assent from kid + consent from parent obtained

5-30: Name at least two factors that determine the amount of information that must be submitted in an IND.

1. Novelty of the drug. 2. Extent to which the drug has been previously studied. 3.Known or suspected risks. 4.Particular developmental phase.

5-40 List at least four required sections in a clinical protocol for a study conducted under an IND.

1. Objectives and purpose. 2. Name, address, and qualifications of investigators and of the reviewing IRB. 3. Inclusion/exclusion criteria. 4. Study Design. 5. Dosing information. 6. Planned observations and measurements. 7. Clinical procedures to evaluate safety.

5-33: FDA Form 1571 requires the names and titles of two persons with specific functions. Who are they?

1. Person responsible for monitoring the conduct and progress of the evaluation. 2. The person responsible for review and evaluation of safety information for the drug.

5-37 Name at least four elements required in the general investigational plan of an original IND application.

1. Rationale for the drug or study. 2. Indication (s). 3. General evaluation approach. 4. Types of trials to be conducted in the first year. 5. Estimated number of patients to be studied in the first year. 6. Any anticipated risks of particular severity or seriousness.

What are the criteria for involving children in greater than minimal risk research with prospect of benefit? (3)

1. Risks are justified by benefits 2. Relation of anticipated benefit is at least as favorable as that presented by alternative approaches 3. Assent + consent

What are the criteria for involving children in greater than minimal risk research with no direct benefit? (4)

1. Risks are minor increase over minimal risk 2. Intervention presents experiences that are reasonable commensurate with normal medical and living situations 3. Intervention is likely to yield generalizable knowledge that is vital 4. Assent + consent

What are the criteria for IRB approval of research? (7)

1. Risks to subjects are minimized 2. Risks are reasonable in relation to anticipated benefits 3. Selection of subjects is equitable 4. Informed consent will be sought from subjects or LARs 5. Informed consent will be documented 6. There is adequate provision of monitoring 7. There is adequate provision to protect the privacy of subjects

5-107 What report summaries or data will the FDA make publicly available upon request?

1. Safety and effectiveness information including any adverse health effects caused by the device. 2. Selected portions of safety and effectiveness data including clinical, animal or laboratory tests on a banned device or a device with a publicly-disclosed IDE for public consideration of a specific pending issue. 3. Reports of adverse effects related to its use can be disclosed to an individual on whom the investigational device has been used.

5-110: List at least three general responsibilities of sponsors?

1. Select qualified investigators, providing them with information to properly conduct the trial. 2. Ensure proper monitoring. 3. Ensure the study is conducted in compliance with the protocol. 4. Maintain an effective IND. 5. Ensure FDA and investigators are provided full safety information.

What are the 8 basic elements of informed consent per FDA guidelines?

1. Statement that the study involves research, purpose and expected duration, description of experimental procedures 2. Description of reasonably foreseeable risks 3. Benefits 4. Disclosure of alternative procedures or courses of treatment 5. Confidentiality measures 6. Compensation and treatments available if injury occurs 7. contact information 8. Participation is voluntary and subject may discontinue at any time

Name at least three elements required to be reported for each individual study reported in an IND annual report

1. Study title, indentifier and purpose description of patient population and completion status. 2. Total number of subjects a) initially planned for inclusion, b) entered to date, c) who completed as planned, d dropped for any reason 3. Brief description of any interim or final analysis results, if available.

5-106 Under what circumstances will the FDA disclose the existence of an IDE?

1. The IDE has been publicly disclosed or acknowledged. 2. The FDA approves an application for pre-market approval of the device subject to the IDE. 3. A notice of completion of a product development protocol for the device has become effective.

15-146 What types of reports is a investigator obligated to provide to the sponsor of a study?

15-146 The correct answer is: 1. Progress reports. 2. Safety reports. 3. A final report. 4. Financial disclosure reports.

5-99 The FDA may deny or withdraw approval of a treatment use IDE because the treatment use IDE does not contain the required information or any regulatory grounds for disapproval or withdrawal are present. Name two additional grounds for such an action by the FDA.

1. The device is intended for a serious disease or condition, but there is insufficient safety and effectiveness data to support its use. 2. The device is intended for an immediately life-threatening disease or condition, and the whole of the available scientific evidence fails to provide a reasonable basis for its potential effectiveness or safety.

5-117: Who must be specifically named on the FDA Form 1572?

1. The investigator 2. The institution where the investigation will be conducted. 3.The clinical laboratory to be used in the study. 4.The IRB responsible for review and approval . 5. Any sub- investigators who will assist the investigator.

5-104 The treatment IDE progress reports must contain what items?

1. The number of patients treated with the device. 2. All of the investigators participating in the treatment IDE. 3. Description of the sponsor's efforts to pursue marketing approval.

5-107: Name at least three major purposes for a Pre-NDA or Pre-BLA meeting between a sponsor and the FDA.

1. To uncover any major unresolved problems. 2. To identify studies on which the sponsor will rely to establish effectiveness. 3. To identify the status of ongoing or needed studies, to assess pediatric safety and effectiveness. 4. to acquaint FDA reviewers with technical content. 5. To discuss statistical analysis methods. 6. To determine the optimal approach for presenting and formatting of NDA data. 21 CFR 312.47

Name at least two grounds for FDA imposition of a clinical hold for a Phase 1,2, or 3 investigation.

1.Subjects would be exposed to unreasonable and significant risk or illness or injury. 2. Unqualified investigators. 3. Inadequate Investigator Brochure. 4. Gender bias on subject eligibility.

5-95 Describe the four criteria under which the FDA will consider the use of an investigational device under a treatment IDE.

1.The device is intended to treat or diagnose a serious or immediately life-threatening disease or condition. 2.There is no comparable or satisfactory alternative device or other therapy available in the intended patient population. 3. The device is under investigation in a controlled or completed clinical trial for the same use under an approved IDE. 4. The sponsor is actively pursuing marketing approval/clearance of the device with due diligence.

Investigators must submit Unanticipated Adverse Device Effects to the FDA within how many days?

10 working days (21 CFR 812.15)

Sponsors must submit Unanticipated Adverse Device Effects to the FDA within how many days?

10 working days (21 CFR 812.15)

Sponsors must report SAEs to the FDA within how many days of discovering the event?

15 calendar days (21 CFR 312.32)

15-132 How long must the sponsor retain records of clinical investigations?

15-132 The correct answer is: Two years after a marketing application is approved for the drug, or if an application is not approved for the drug, until two years after shipment and delivery of the drug for investigational use is discontinued and the FDA has been notified.

15-133 The sponsors are required to reserve samples of any test article and reference standards used in bioequivalence or bioavailability studies, yet are not required to release these samples to the FDA. True or False?

15-133 The correct answer is: False. The sponsor is requested to release these samples to the FDA, upon their request.

15-134 What authority does FDA have regarding inspection of sponsor records?

15-134 The correct answer is: The FDA may have access to, inspect, copy, and verify any records and reports relating to a clinical investigation at reasonable times.

15-143 Maintenance of adequate and accurate case histories for study subjects includes documentation that informed consent was obtained prior to the subject's participation in the study. True or False?

15-143 The correct answer is: True.

15-144 A investigator is required to prepare and maintain adequate and accurate records and case histories for all study subjects. True or False?

15-144 The correct answer is: True.

15-145 For how many years must a investigator retain records of investigational drug supplies and study subject case records?

15-145 The correct answer is: Two years after NDA approval or, if an NDA is not approved, two years after the investigation has been discontinued and the FDS has been informed.

15-147 What information must an investigator provide to the sponsor regarding his/her financial interests?

15-147 The correct answer is: Sufficient, accurate information to allow the sponsor to file required reports with the FDA, and any changes to their financial interests during or for one year after the close of the study.

15-148 Name at least two types of information which an investigator must promptly report to the reviewing IRB?

15-148 The correct answer is: 1. All changes in the research. 2. All unanticipated problems involving risk to human subjects or others.

15-166 In general, FDA accepts foreign studies not conducted under an IND, provided what conditions are present?

15-166 The correct answer is: Provided the studies are: 1. Well designed. 2. Well conducted. 3. Performed by qualified investigator. 4. Conducted in accordance with ethical principles acceptable to the world community.

Nuremberg Code

1947

When was the Nuremberg Code issued?

1947

Declaration of Helsinki

1964

When was the Declaration of Helsinki released?

1964

Belmont Report

1979

When was the Belmont Report released?

1979

Publication of FDA Regulations

1980

HHS and FDA Revise Regulations

1981

Publication of Common Rule

1991

GCP and HIPAA

1996

How long should sponsors keep study records for drug trials?

2 years after approval of marketing application or 2 years after shipment/delivery of IP discontinued and FDA notified

How long should sponsors keep study records for device trials?

2 years after investigation is terminated/completed or 2 years after date that records are no longer required for supporting a PMA or notice of completion of product development protocol

What FDA regulations are for electronic records and signatures for a closed system?

21 CFR 11

What FDA regulations govern SAE reporting?

21 CFR 312

What FDA regulation defines the contents of an Investigator's Brochure?

21 CFR 312.23(a)(5)

What FDA regulations govern continuing review reports?

21 CFR 312.33 21 CFR 812.150(b)(5)

What FDA regulation governs the documents a sponsor should get from an investigator before trial initiation?

21 CFR 312.53(c)

What FDA regulations govern the contents of a clinical trial protocol?

21 CFR 312.53(c)(3)

Who is responsible for generating a protocol per regulations, sponsor or investigator?

21 CFR 312.53(c): investigator provides to sponsor (not usually case) 5.6.1-2 ICH GCP: sponsor utilizes qualified individuals as appropriate throughout all stages of trial process from protocol design to analysis; sponsor should provide investigators with protocol, updated IB and time to review information before entering into agreement

What FDA regulation discusses FDA audits?

21 CFR 312.68

What FDA guideline lists the basic elements of informed consent?

21 CFR 50 (50.25)

What FDA regulation states that investigators can discontinue/withdraw a subject's participation in a trial at any time?

21 CFR 50.25(b)(2)

What FDA regulation governs financial disclosure?

21 CFR 54

What FDA regulations govern financial disclosure?

21 CFR 54

What FDA regulations govern IRB related topics?

21 CFR 56

What FDA regulations govern IRB documentation requirements?

21 CFR 56.115

What FDA regulations define in-vitro diagnostics?

21 CFR 809.3(a)

What FDA regulations govern UADE reporting?

21 CFR 812 (.15 and .3)

What FDA regulation requires investigators to keep records of deviations from protocol with dates and reasons?

21 CFR 812.140(a)(4)

What FDA regulation specifies sponsor roles and responsibilities?

21 CFR 812.40

How soon must a sponsor conduct investigations of Unanticipated Adverse Device Effects?

21 CFR 812.46(b) - immediately

Protection of Human Subjects

21CFR50 Title

According to ICH guidelines, IRB must retain records for...

3 years

How often must an IRB renew it's registration?

3 years

How long must an IRB retain records per 21 CFR 56?

3 years after completion of research

How many days must a sponsor wait after submitting an IND to conduct investigations?

30 calendar days

5-21: How much time does the FDA have to provide a sponsor with written approval o proceed with an IND that involves waiver from informed consent due to emergency conditions?

30 days

How many days does an IRB have to inform the FDA that it is reviewing different types of FDA products?

30 days

5-46 How soon does a sponsor have to submit a new investigator amendment to an IND?

30 days following the addition of the investigator.

How many days does a sponsor have to submit a report to the FDA/investigators/IRBs about withdrawal of IRB approval?

5 working days

What regulations govern research with pregnant women and fetuses?

45 CFR 46 Subpart B

What regulations provide research protections to children?

45 CFR 46 Subpart D

How many members must sit on an IRB?

5

How long does a sponsor have to report study closure and full report to FDA if drug presented an unreasonable and significant risk to subjects?

5 working days

How many days does a sponsor have to report an emergency use of an IP to the FDA?

5 working days

How many days does a sponsor have to submit a report to FDA about SR device if sponsor suggested NSR?

5 working days

How many days does a sponsor have to submit a report to investigators/IRB about withdrawal of FDA approval?

5 working days

5-132 How long must a sponsor retain records of clinical investigations?

5-132 Two years after a marketing application is approved for the drug, or if an application is not approved for the drug, until two years after shipment and delivery of the drug for investigational use is discontinued and the FDA has been notified.

5-133 Sponsors are required to reserve samples of any test article and reference standards used in bioequivalence or bioavailability studies, yet are not required to release these samples to the FDA. True or False?

5-133 False. The sponsor is requested to release these samples to the FDA, upon their request.

5-134 What authority does the FDA have regarding inspection of sponsor records?

5-134 The FDA may have access to, inspect, copy, and verify any records and reports relating to a clinical investigation at reasonable times.

5-143 Maintenance of adequate and accurate case histories for study subjects includes documentation that informed consent was obtained prior to a subject's participation in the study. True or False?

5-143 True.

5-144 An investigator is required to prepare and maintain adequate and accurate records and case histories for all study subjects. True or False?

5-144 True.

5-145For how many years must an investigator retain records of investigational drug supplies and study subject case records?

5-145 Two years after NDA approval or, if an NDA is not approved, two years after the investigation has been discontinued and the FDS has been informed.

5-146 What types of reports is an investigator obligated to provide to the sponsor of a study?

5-146 1. Progress reports. 2. Safety reports. 3. A final report. 4. Financial disclosure reports.

5-147 What information must an investigator provide to a sponsor regarding his/her financial interests?

5-147 Sufficient, accurate information to allow the sponsor to file required reports with the FDA, and any changes to their financial interests during or for one year after the close of the study.

5-148 Name two types of information which an investigator must promptly report to the reviewing IRB?

5-148 1. All changes in the research. 2. All unanticipated problems involving risk to human subjects or others.

5-166 In general, the FDA accepts foreign studies not conducted under an IND, provided what conditions are present?

5-166 Provided the studies are: 1. Well designed. 2. Well conducted. 3. Performed by qualified investigator. 4. Conducted in accordance with ethical principles acceptable to the world community.

1. Unforseeable risks-subject or fetus 2. Termination of participation 3. costs to subject 4. withdraw consequences 5. findings that are new 6. number of subjects

6 additional elements of informed consent

Within what time period must a sponsor submit a final report to the FDA, all IRBs and all investigators after completion/termination of SR device trial?

6 months

At what reading level should ICFs be written?

6th-8th grade

How many calendar days does a sponsor have to report a fatal or life-threatening unexpected adverse drug reaction?

7 calendar days

Implant

A device that is placed into a surgically or naturally formed cavity of the human body if it is intended to remain there for a period of 30 days or more.

Implant

A device that is placed into a surgically or naturally formed cavity of the human body if it is intended to remain there for a period of 30 days or more. (21 CFR, sec. 812.3)

Translational device

A device that the FDA considered to be a new drug or antibiotic before May 28 1976

Investigational Device

A device, including a transitional device that is the object of investigation. (21 CFR, sec. 812.3)

Termination

A discontinuance, b a sponsor or by withdrawal of IRB or FDA approval, of an investigation before completion. (21 CFR, sec. 812.3)

Serious disease or condition

A disease or condition associated with morbidity that has substantial impact on day-to-day functioning.

What is a FDA Form 1571?

Cover page for IND application; lists information provided in submission

Form 1571

Cover sheet for an IND application

Audit Certificate

A declaration of the confirmation by the auditor that an audit has taken place. (ICH GCP E6 1.7)

A revised copy of an Investigator Brochure in an IND annual report must be accompanied by what additional information?

A description of the revision(s).

Multicentre Trial

A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator. (ICH GCP E6 1.40)

Coordinating Committee

A committee that a sponsor may organize to coordinate the conduct of a multicentre trial. (ICH GCP E6 1.18)

Investigator's Brochure

A compilation of the clinical and nonclinical data on the investigational products which is relevant to the study of the investigational products in human subjects. (ICH GCP E6 1.36)

5-44 What are the FDA's requirements for translation and inclusion of documents in an IND application which are not in English?

A complete English translation must be included as well as a copy of the original publication in the foreign language.

Crossover

A longitudinal study in which subjects receive a sequence of different treatments (or exposures).

Contract Research Organization (CRO)

A person or an organization (commercial academic or otherwise) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions. (ICH GCP E6 1.20)

5-7: What is the definition of a "contract research organization," according to the FDA's IND regulations?

A person working with the sponsor as an independent contractor who assumes one or more of the obligations of the sponsor.

Impartial Witness

A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject's LAR cannot read, and who reads the informaed consent for, and any other written information supplied to the subject. (ICH GCP E6 1.26)

Investigational Product

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trail, including a product with a marketing authorization when used or assembled in a different way from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use. (ICH GCP E6 1.33)

Audit

A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsors SOPs, GCP and the applicable regulatory requirements. (ICH GCP E6 1.6)

Case Report Form (CRF)

A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject. (ICH GCP E6 1.11)

Blinding/Masking

A procedure in which one or more parties to the trial are kept unaware of the treatment assignment. (ICH GCP E6 1.10)

Interim Clinical Trial/Study Report

A report of intermediate results and their evaluation based on analyses performed during the course of the trial. (ICH GCP E6 1.32)

Immediately life-threatening disease or condition

A stage of disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.

Good Clinical Practice (GCP)

A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of the trial subjects are protected. (ICH GCP E6 1.24)

5-51 What is the FDA's definition of disability, as it relates to serious adverse drug experiences?

A substantial disruption of a person's ability to conduct normal life functions.

5-106: What clinical items must a sponsor provide to the FDA at least one month in advance of an End-of-Phase 2 meeting?

A summary of Phase 1 and 2 investigations, specific protocols for Phase 3, plans for any pediatric studies or requests for waiver or deferral of pediatric studies, and tentative labeling for the drug. 21 CFR 312.47

Clinical Trial/Study Report

A written description of a trial/study of any therapeutic, prophylactic or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analysis are fully integrated into a single report. (ICH GCP E6 1.13)

Protocol Amendment

A written description of changes to or formal clarification of a protocol. (ICH GCP E6 1.45)

Audit Report

A written evaluation by the sponsor's auditor of the results of the audit. (ICH GCP E6 1.8)

Monitoring Report

A written report from the monitor or sponsor after each site visit and/or other trial-related communication according to the sponsor's SOPs. (ICH GCP E6 1.39)

Contract

A written, dated and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and if appropriate on financial matters. (ICH GCP E6 1.17)

What is a closed system?

Access to system is controlled by people who oversee the content

What is an open system?

Access to system is not controlled by people who oversee the content (record can be read, modified or compromised by others)

Compliance

Adherence to all the trial related requirements, GCP requirements and the applicable regulatory requirements. (ICH GCP E6 1.15)

What essential documents need only be kept by the investigator before a trial? (1)

Advertisements

Kefauver-Harris Amendment

Amendment to Food Drug and Cosmetic Act that requires informed consent for experimental drugs

5-125: What information document must a sponsor provide to an investigator prior to beginning an investigation?

An Investigator Brochure.

5-96 The treatment use application is similar to the IDE application except for what two items?

An available list of treatment regimens that should be tried before using the device or an explanation of why the device is preferable to marketed treatments and, information from other IDE's incorporated by reference to support the treatment use in determining the device's safety and effectiveness.

Independent Ethics Committee (IEC)

An independent body (a review board or a committee, institutional, regional, national or supranational), constitutes fo medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among, other things, reviewing and approving/providing favourable opinion on, the trial protocol, the suitability of the investigators, facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects. (ICH GCP E6 1.27)

Legally Acceptable Representative

An individual or juridicial or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subjects participation in the clinical trial. (ICH GCP E6 1.37)

Comparator (Product)

An investigational or marketed product (i.e. active control). or placebo, used as a reference in a clinical trial. (ICH GCP E6 1.14)

Comparator

An investigational or marketed product, or placebo, used as a reference in a clinical trial.

Coordinating Investigator

An investigator assigned the responsibility for the coordination of investogators at different centres participating in a multicentre trial. (ICH GCP E6 1.19)

Unanticipated Adverse Device Effects

An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 business days after the investigator first learns of the effect.

IDE Final Report

An investigator shall, within 3 months after termination or completion of the investigation or the investigator's part of the investigation, submit a final report to the sponsor and the reviewing IRB. In the case of a significant risk device, the sponsor shall notify FDA within 30 working days of the completion or termination of the investigation and shall submit a final report to FDA and all reviewing the IRB's and participating investigators within 6 months after completion or termination. In the case of a device that is not a significant risk device, the sponsor shall submit a final report to all reviewing IRB's within 6 months after termination or completion.

According to ICH E6 GCP, an inspection is defined as:

An official review of documents, facilities, records, and any other resources related to a clinical trial.

What is a clinical hold?

An order issued by the FDA to a sponsor to delay a clinical study.

Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. (ICH GCP E6 1.2)

Test Article

Any food or drug (including a biological product for human use), medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the act or under sections 351, and 354-360F of the Public Health Services Act. (21 CFR, sec. 50.3)

5-53 Sponsors are required to maintain an ongoing review of safety information from which sources?

Any foreign or domestic source including clinical, epidemiological, and animal investigations, commercial marketing experience, scientific literature reports, and unpublished scientific papers, and reports from foreign regulatory authorities not previously reported to the FDA.

Person

Any individual, partnership, corporation, association, scientific or academic establishment, government agency or organizational unit of a Government agency, and any other legal entity

Applicable Regulatory Requirements

Any laws and regulations addressing the conduct of clinical trials of investigational products (ICH GCP E6 1.4)

Family Member

Any one of the following legally competent persons: spouse; parents; children (including adopted children); brothers, sisters and spouses of brothers and sisters; and any individual related by blood or affinity whose close association with the subject is equivalent of a family relationship. (21 CFR, sec. 50.3)

What is the definition of a sub-investigator per FDA regulations?

Any other individual member of the clinical investigator's team

What is the definition of a serious adverse event (SAE)? (5 possibilities)

Any untoward occurrence that results in: 1) Death 2) Life threatening 3) Requires hospitalization or prolongation of hospitalization 4) Results in significant disability 5) Results in congenital abnormality/birth defect

Form 483

Inspectional Observations

Form 483

Inspectional observations

Unanticipated Adverse Device Event

Any serious adverse effect on the health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect or problem, or death was not previously identified in nature, severity or degree of incidence in the investigational plan or application. (21 CFR, sec. 812.3)

21CFR56-B: Which IRBs must register?

Any IRB that reviews clinical research for IND, IDE or marketing permits

5-52 What is the FDA criterion which classifies an adverse drug experience as unexpected?

Any adverse experience, the specificity or severity of which is not consistent with the current Investigator Brochure, or other designated document when an Investigator Brochure is not required.

21CFR56-A When is IRB Review Required?

Any clinical investigation that requires research permits (see 21CFR213), broad scope but exceptions are allowed

314

Application for FDA approval to market a new drug.

What is an IND?

Application to FDA to seek permission to test a new drug or biologic in clinical trial involving people

What is an IDE?

Application to FDA to seek permission to test new medical device or in-vitro diagnostic in clinical trial involving people

5-102: If an IND is placed on inactive status by the FDA, what action must the sponsor take with drug supplies?

Arrange with all investigators for return or other proper method of disposal of the investigational drug. 21 CFR 312.45

Viable

As it pertains to the neonate, means being able after delivery to survive.

How does the FDA defined source data or documents, and in what regulations?

As medical records and case histories - 21 CFR 312.62(b) and 21 CFR 812.140(3)

5-55: What is the time requirement for filing IND safety reports with the FDA?

As soon as possible and never later than fifteen calendar days after the sponsor's initial receipt of the information.

5-61: If a sponsor evaluates an adverse experience and determines that is reportable as an IND safety report, but it was originally reported as such, how long does the sponsor have to report the event as an IND safety report?

As soon as possible, but in no event later than fifteen calendar days after the determination is made.

5-60: When are sponsors required to file follow-up information for IND safety reports?

As soon as the relevant information is available

5-48 What is the FDA's preferred filing frequency for information amendments by sponsors?

At intervals of 30 days.

How long must an IRB maintain their records?

At least 3 years after the completion of research

How many members are required for an IRB?

At least 5

How often must research be reviewed by the IRB?

At least annually

21 CFR Part 56 - Title

Institutional Review Boards

How often and to whom must sponsors submit progress reports in device trials?

At regular intervals (at least yearly) - to all reviewing IRBs If SR device, to FDA at least yearly

IDE Progress Reports

At regular intervals, and at least yearly, a sponsor shall submit progress reports to all reviewing IRB's. In the case of a significant risk device, a sponsor shall also submit progress reports to FDA. A sponsor of a treatment IDE shall submit semi annual progress reports to all reviewing IRB's and FDA

21CFR56-A: When are waivers to IRB review granted?

At the discretion of the FDA but never granted until a research application has been submitted and reviewed

5-103: At what point in the clinical development process of a drug does the FDA encourage meetings with an IND sponsor?

At the end of a Phase 2 and prior to NDA submission. 21 CFR 312.47

What does ALCOA stand for?

Attributable Legible Contemporaneous (when was information obtained and was it corrected) Original Accurate

21 CFR 56

Institutional Review Boards IRB

If trial suspended by PI, inform sponsor and IRB

Investigator

If trial suspended by Sponsor, inform IRB

Investigator

Regulatory Authorities

Bodies having the power to regulate. In the ICH GCP guideline that guidelines the expression Regulatory Authorities includes the authorities that review submitted clinical data.

Inform PCP with subject's consent

Investigator

Whose responsibility is it to ensure investigators and staff are trained?

CTM or CRA

Inform and supply follow up treatment to subjects if trial is suspended

Investigator

Inform subject of concurrent/intercurrent illness

Investigator

What kind of background is required to become an IRB member?

Backgrounds must be dynamic and nondiscriminatory, diverse in gender and profession One member whose primary concerns are in a scientific area and one whose are non-scientific One member outside the institution of record must be part of the IRB No conflicts of interest for initial or continuing review, other than to offer information IRBs may invite non-voting experts from outside the membership board to offer insight into complex situations.

What are some examples of Class I devices?

Bandages, gloves, depressors, arm slings, and other devices posing little harm

Nonclinical Study

Biomedical studies not performed on human subjects. (ICH GCP E6 1.41)

What is the FDA monitoring program?

Bioresearch Monitoring program (BIMO)

5-105: Who may bring consultants to an End-of-Phase 2 meeting?

Both the FDA and the sponsor. 21 CFR 312.47

Which of these is not a good security practice for web browsing?

Browsing to sites using links sent in emails without taking steps to assure the destination is safe.

Maintain list of qualified persons with significant duties

Investigator

5-56: How soon must the FDA be notified of a fatal or life-threatening adverse experience which is associated with use of a drug?

By telephone or facsimile transmission, no later than seven calendar days after sponsor receipt of the information, followed by a written report no later than fifteen calendar days after the initial receipt of the information by the sponsor.

Must be qualified to carry out research

Investigator

No coercion or unduly influence participation

Investigator

Obtain IRB approval before start of study

Investigator

PI/Sub-I who is a physician is responsible for all medical decisions

Investigator

Permit monitoring/audit

Investigator

Provide protocol, ICF, ads, IB and all updates to IRB

Investigator

What are facilities/clinics that conduct Phase I studies called?

CPUs (Central Pharmacological Units)

What is Source Data Verification? (SDV)

CRF or other data collection instruments are compared to original source of information to confirm data accuracy

Under the federal HIPAA regulations, state health privacy laws:

Can remain in force if "more stringent" than HIPAA, complementing HIPAA's foundation of protections, provided there is no direct conflict in requirements.

Investigational product dispensing or administration information for the sponsor is recorded on the:

Case report form

Form 3454

Certification - Financial Interests and Arrangements of Clinical Investigators

What is FDA Form 3454?

Certification of financial disclosure for investigators with no financial disclosures

Form 3454

Certification of financial interest and arrangements of clinical investigators

Deviations from the investigational plan.

Changes to the investigational plan shall be submitted via a supplemental application to the FDA within 5 business days.

5-14: Describe the FDA requirement for charging for investigational drugs under an IND.

Charging for investigational drugs under an IND is not permitted without prior written approval from the FDA. Written explanation of why charges are necessary and not a normal cost of doing business is required.

45 CFR Part D

Children

Randomization only broken per protocol

Investigator

How are medical devices categorized to determine whether a 510(k) or PMA is needed?

Class I, II, III

ICH E6 has broader requirements than FDA or HHS concerning confidentiality of medical records and access by third parties. If investigators are complying with ICH E6 guideline, they must:

Clearly disclose to subjects in the informed consent form that the monitor, auditor, IRB/IEC, and the regulatory authorities may have access to the subject's medical records

How is QA done during a trial?

Clinical site's internal reviews of current procedures, processes and their documentation (like SOPs)

Uncontrolled Study

Clinical study that lacks a comparison group

What is necessary for submission of a Premarket Approval Application?

Clinical trials in humans needed to show safety and effectiveness

What kind of records must an IRB keep?

Copies of all research reviewed Minutes of meetings Continuing review records Correspondence IRB members named and credentials, and contributions to IRB, and relationship to the institution Written procedures Statements of significant new findings sent to subjects

What is the intention of a Phase II trial?

Compare new dug against SOC or placebo; first introduce drug to disease population

5-102 The FDA's approval for treatment use of an investigational device is conditioned on the sponsor and investigator(s) complying with what regulatory requirements?

Compliance with the safeguards of the IDE process and the regulations governing informed consent in 21 CFR 50 and institutional review boards in 21 CFR 56.

In completing Form FDA 1572, Statement of Investigator, the Investigator agrees to:

Conduct or supervise the investigation personally.

What is a MEDWATCH Form 3500b?

Consumer-friendly version of Form 3500

Report all SAE's to sponsor and IRB immediately

Investigator

Report all serious adverse drug reactions (ADR) to regulatory authorities and IRB immedidately

Investigator

Part 11

E-Records, E-Signatures

21CFR56-B: Which federal agency do IRBs register with?

DHHS

Report premature unblinding to sponsor

Investigator

What ethical standards are the ICH document based on?

Declaration of Helsinki

Should minimize the possibility of coercion or undue influence Language should be understandable to the subject No exculpatory language may be included, nor the waiver of any legal rights May not appear to release the researchers from liability for negligence

Describe a successful Informed Consent according to 21CFR50 Subpart B

Form 3455

Disclosure - Financial Interests and Arrangements of Clinical Investigators

Form 3455

Disclosure of financial interest and arrangements of clinical investigators

What is FDA Form 3455?

Disclosure statement for financial disclosure of clinical investigators who have disclosable interests

What is the Declaration of Helsinki?

Document that laid out general principles physicians should follow to conduct research with humans, based on Nuremberg Code. First effort of medical community to regulate itself

Audit Trail

Documentation that allow reconstruction of the course of events. (ICH GCP E6 1.9)

What are essential documents?

Documents that permit evaluation of the conduct of the trial and quality of data produced

Essential Documents

Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced. (ICH GCP E6 1.23)

What is the definition of a Non-Significant Risk device?

Doesn't meet criteria of a significant risk device. Not necessarily a minimal risk study.

What is the difference in AE reporting between drug and device trials?

Drug: all AEs are recorded and evaluated for drug relationship Device: due to local effect, not all AEs may need to be collected or evaluated

How is treatment cost different between drug and device trials?

Drug: provided to investigators for clinical trial use Device: investigators charged for devices and reimbursed by insurance or government plan

For what time period must financial interests be disclosed?

During course of study + 1 yr after completion (Course of study: from date PI signs agreement with sponsor to date all subject follow up completed or study cancelled)

21 CFR 11

Electronic Records/Signatures

21 CFR 11

Electronic Records; Electronic Signatures

Retain record of changes to research documents

Investigator

Belmont Report

Ethical principle and guidelines for protection of human subjects of research. Cornerstone document of ethical principles. Federal regulation of subject protection based on respect for persons, beneficence and justice----1979

3 regulatory agency sponsors of ICH

European Union, Japan, United States

How often must IRBs renew their registration?

Every 3 years

5-62: If a sponsor submits an IND safety report, it is assumed by the FDA that the drug caused or contributed to the event, unless it is specifically denied by the sponsor. True or False?

FALSE Mere submission of a report under the IND safety report requirements does not reflect the conclusion, by either the sponsor or the FDA, that the drug caused or contributed to the reported event.

Form FDA 1572, Statement of Investigator, is legally binding between the Investigator and the:

FDA

What FDA notification requirement does a Class II device have?

FDA 510(k) clearance - notify FDA 90 days prior to marketing as a pre-market notification; FDA then determines if device is equivalent to previously approved devices and allows it to be sold

What is the appropriate FDA form for the investigator to use when filing a treatment IND.

FDA FORM 1571

5-32: What FDA form specifies the content and order of an IND submission?

FDA Form 1571

5-116: What FDA document must all investigators sign prior t participation in an investigation of a drug?

FDA Form 1572

What form is used to communicate FDA audit findings?

FDA Form 483

What is an orphan drug program?

FDA program that provides development of drugs for rare diseases

Who reviews a SR device study first, FDA or IRB?

FDA; IRB assists in making determination but requires approved IDE to issue approval

5-96: Resumption of clinical investigations which were subject to a clinical hold must always be issued in writing by the FDA to a sponsor. True or False?

False If permitted in the clinical hold order, investigations may be resumed as soon as the deficiencies are corrected. Resumption notification for clinical hold cases requiring a sponsor response, may be made by telephone or other rapid communication means. 21 CFR 312.42

5-91: Only a sponsor may interrupt a treatment IND investigation if inadequate supplies are available to support it as well as concurrent controlled trials. True or False?

False The FDA may also place the treatment-IND on clinical hold under these circumstances. 21 CFR 312.42

5-92: The FDA may not place any investigator on clinical hold that employs the exception from informed consent criteria for emergency research, or that has not been determined by the President to waive the prior consent requirement. True or False?

False The FDA may place investigators in either of these situations on clinical hold if it determines that deficiencies or non-compliance are present. 21 CFR 312.42

Clinical holds always apply to all clinical investigations under an IND

False A clinical hold order may apply to one or more investigations covered under an IND.

FDA clinical holds apply to all sponsored clinical investigations under an IND, bur do not apply to treatment INDs.

False Clinic holds may apply to all research with a drug including a treatment IND.

Summary information for clinical trials activity within the past year is required in the IND annual report, while results of pre clinical studies are not

False Pre clinical summary information for studies completed or concluded within the past year must be included in the IND annual report.

5- 129: Although a sponsor reserves the right to terminate and ongoing clinical investigation for reason of patient safety, the sponsor is required to confer with the investigator prior to terminating the investigation. True or False?

False. The sponsor may terminate an investigation without conferring with an investigator.

5-122 A sponsor may not resume a terminated investigation without the IRB's and the FDA's approval on a non-significant risk device. True or False?

False. A sponsor cannot resume the investigation without the IRB's and FDA's approval on a significant risk device.

5-12: Investigational drugs may be commercially distributed or test-marketed by sponsors or investigators. T or F?

False. No commercial distribution of investigational products is permitted.

5-11: A promotional claim is acceptable on investigational drug supply labeling, provided the claim was previously approved by the FDA. T or F?

False. Promotional claims may not appear on investigational drug supply labels.

5-100 If the treatment use of an investigational device is impeding enrollment in, or otherwise interfering with an ongoing clinical investigation of the same, or another device, the FDA may disapprove or withdraw its approval; however, approval may not be denied or withdrawn if the device, or a similar device, receives marketing approval. True or False?

False. The FDA may deny approval or withdraw approval of a treatment IDE for both of these reasons.

5-35: Obligations transferred by a sponsor to CROs are always submitted as an information amendment to an IND, rather than being included in the original IND application.

False. The transferred obligations may be included in the original IND submission.

5-94 In the case of an immediately life-threatening disease, a device may be made available for treatment use only after the completion of all clinical trials. True or False?

False. Treatment use of the device may begin prior to clinical trial completion.

1. Objective of trial cannot be met by enrolling non-vulnerable subjects 2. Minimal risk 3. Trial not prohibited by law 4. IRB approves 5. Have the disease that the IP is intended for

Five conditions that allow PI to enroll vulnerable subjects

Form 3500A

For use by User-Facilities, Distributors, And Manufacturers for Mandatory Reporting

What is a Warning Letter from the FDA?

Formal notification that allows prompt voluntary corrective action to be taken - must be responded to within a specified amount of time

Study docs NOT contain language that releases PI, institute or sponsor of liability from negligence

Investigator

non-therapeutic

GAIN knowledge which may contribute towards future development of new forms of treatment ( MAY or MAY NOT benefit, usually Phase I)

What type of controls are Class III devices subject to?

General controls + premarket approval via Premarket Approval Application

What type of controls are Class II devices subject to?

General controls + special controls: special labeling, mandatory performance standards, post market surveillance, FDA medical device specific guidance

What type of controls are Class I devices subject to?

General controls: basic rules regulating adulteration, misbranding, device registration and listing, PMN, banned devices, notification (repair, replacement or refund), records/reports, restrictions and GMP

Fines and jail time (occasionally) for information security failures are:

Generally, only applied for serious, deliberate misuse, where someone intentionally accesses data in order to do harm or for personal gain.

Submit ICF amendment if new info relevant to consent

Investigator

What is a DSMB?

Group of experts that review research data to ensure subject safety and data validity per a DSMPlan

Submit changes affecting study conduct or increase risk to IRB/sponsor/instituion

Investigator

Class III Device

Highest risk, examples include heart valves, breast implants, pacemakers

5 working days

How long does a sponsor have to notify the FDA of IDE changes?

5 working days

How long does an investigator have to notify the sponsor of the withdrawal of IRB approval?

5 working days

How long does an investigator have to report an emergency use event?

5 working days

How long does an investigator have to report an event where informed consent is not obtained

10 working days

How long does an investigator have to report an unanticipated adverse device effect?

Every 6 months, starting 6 months after FDA IDE approval

How often must a sponsor submit a list of investigators (with contact information) to the FDA?

no less than yearly

How often must an investigator submit progress reports?

HIPAA allows healthcare organizations to control many information decisions. However, where the patient retains control, which of the following is true?

If a person has a right to make a healthcare decision, then generally that person has a right to control information associated with the decision.

Submit study's status summary (CR) at least annually to IRB

Investigator

5-101: Name the two conditions under which the FDA may place an IND on inactive status.

If no subjects are entered into clinical trials for a period of 2 years or more under the IND, or if all investigations under the IND remain on clinical hold for a period of more than one year. 21 CFR 312.45

5-100: On what grounds may the FDA terminate an IND immediately, without opportunity for sponsor response?

If the FDA concludes that continuation of the investigation presents a substantial danger to health of individuals. 21 CFR 312.44

5-119 Under what conditions would a sponsor not be obligated to require the investigator to either dispose of or return the device when non-compliance is observed and the study will be terminated.

If the rights, safety or welfare of a study subject would be jeopardized, the sponsor may not mandate the investigator to destroy or return the device.

When does subject discontinuation require reporting to the IRB?

If trial is greater than minimal risk and IRB has stated that it must be notified when subjects discontinue

Investigators must report SAEs to a sponsor within how many days of discovering the event?

Immediately (21 CFR 312.64)

What is the definition of an investigator per FDA regulations?

Individual who actually conducts a clinical investigation. If investigation is conducted by a team, the investigator is the responsible leader of the team. (21 CFR 312.3)

What is the definition of a sponsor-investigator per 21 CFR 312.3?

Individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.

How is source data defined by ICH GCP guidelines?

Information in original records and certified copies of clinical findings, observations, or other trial activities necessary for reconstruction and evaluation of the trial

5-41 Name three of the five required content elements in the Chemistry, Manufacturing, and Controls section of an original IND application.

Information on: 1. The drug substance. 2. The drug product. 3. Placebo composition if applicable). 4. Labeling. 5. Environmental analysis requirements.

5-124: When a sponsor is conducting investigations under 21CFR 50.24, in emergency research conditions, what information must the sponsor promptly file with the FDA under the IND?

Information received from the IRB concerning the public disclosure required by the regulation.

With respect to permissions for uses and disclosures, HIPAA divides health information into three categories. Into which category does information related to "treatment, payment and health care operations" go?

Information related to treatment, payment, and healthcare operations may generally be used or disclosed without any specific permission, at least under HIPAA. State law may set a higher standard.

What must case histories document, per 21 CFR 312?

Informed consent obtained prior to participation in the study

Phase II Clinical Trial

Initial demonstration of efficacy in patients, short-term safety information

Part 312

Investigation New Drug Application

21 CFR 812

Investigational Device Exemptions

Part 812

Investigational Device Exemptions

21 CFR 312

Investigational New Drug applications (IND)

5-8: What types of products are generally subject to the IND regulations?

Investigational new drugs, biological drugs and biological products used in vitro for diagnostic purposes that are used in a clinical investigation.

Purpose Protocol Risk analysis Description of Device Monitoring Labeling Consent Materials IRB information Institutional information Additional Records and Reports

Investigational plan:

All CT's involving vulnerable subjects be explained the study to the extent of their understanding

Investigator

Allowed to delegate IP accountability to pharmacist under PI's supervision

Investigator

Amendments to be communicated with current enrolled subjects (may need to re-consent)

Investigator

Be familiar with use of IP (protocol and IB)

Investigator

Comply with GCP

Investigator

Conduct trial in compliance with protocol

Investigator

Copy of ICF given to subject

Investigator

Corrections in CRFs should be dated and initialed - not obscure original

Investigator

Demonstrated a potential for recruiting a number of subjects

Investigator

Ensure CRF data derived from source docs

Investigator

Ensure Essential Documents retained at least 2 years (or longer per sponsor) after formal discontinuation of study

Investigator

Ensure accurate and timely submission of CRF/data

Investigator

Ensure all persons assisting in trial are informed of protocol

Investigator

Ensure illiterate subjects are consented in presence of witness to ensure accurate info explained

Investigator

Ensure medical care for AE's and CS lab values

Investigator

Ensure no protocol deviations without sponsor and IRB approval *UNLESS (must be reported asap) 1. to eliminate immediate hazard to subjects 2. logistical changes

Investigator

Ensure protocol includes measures to protect subject's rights, well-being and compliance with regulatory requirements - if there was an emergency and ICF cannot be obtained

Investigator

Have available staff and facilities

Investigator

ICF is signed by subject and person obtaining consent

Investigator

IP accountability - maintain records of delivery, inventory, use, return, or alternate disposition of unused IP

Investigator

IP stored per protocol

Investigator

If trial suspended by IRB, inform Sponsor

Investigator

Independent Data Monitoring Committee (IDMC)

May be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints. (ICH GCP E6 1.25)

What are pharmacodynamic studies (PD)?

Learn the mechanisms of drug action and impact of drug concentration on living organism (what drug does to body)

What are pharmacokinetic studies (PK)?

Learn what happens to drug in a living organism, from entrance to body to elimination (what body does to drug)

Which of these is not a good practice for protecting computing devices?

Login and screen-saver passwords, or token or biometric mechanisms, are disabled to make it easier to use the device quickly.

Class I Device

Low risk, examples include bandages, exam gloves, Q-tips

What is a MEDWATCH Form 3500a?

Mandatory reporting form for sponsors, manufacturers, distributors, importers and user facilities to report AEs

Form 3500A

Mandatory safety reporting by user facilities, distributors, and manufacturers

Acts as main line of communication between the sponsor and PI

Monitor

Communicate deviations from protocol to PI and take appropriate actions to prevent reoccurence

Monitor

Determine whether all AE's are appropriately documented in time periods required by GCP, protocol, IRB, sponsor

Monitor

Who created the Belmont Report?

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (at direction of National Research Act 1974)

What type of final report is required for drug studies?

None per FDA regulation; ICH GCP requires clinical trial report by submitted to appropriate regulatory agency as required

When does subject discontinuation require reporting to the FDA?

Not stated in regulation, but when discontinuation is due to AE or SAE

What is issued if an investigator may be disqualified on the basis of noncompliance?

Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE)

Form 482

Notice of Inspection

Form 482

Notice of inspection

How many days does a sponsor have to submit a report to FDA/investigators/IRB about returns, repairs or disposal of units of a device?

Notice to be provided within 30 days after request was made - to include rationale

When and to whom should final reports be submitted for SR studies?

Notify FDA within 30 working days of study closure; submit final report to FDA, IRBs and investigators within 6 months

If a clinical hold order is issued by the FDA for an ongoing study, what actions must the sponsor take?

Notify all investigators to stop recruitment of new subjects and to remove subjects from the investigational drug, unless specifically permitted to continue the ongoing patients, in the interest of safety.

When a clinical hold order is issued by the FDA for an ongoing study, what actions must the sponsor take?

Notify all investigators to stop recruitment of new subjects and to remove subjects from the investigational drug, unless specifically permitted to continue the ongoing patients, in the interest of safety.

In what order were historical declarations for human subjects protection released?

Nuremberg Code > Declaration of Helsinki > Belmont Report

The situation is life threatening and NEEDS the test article IC can't be obtained due to inability to communicate or obtain consent from subject There's not enough time to get consent from the LAR There is no alternative available which would provide an equal or greater likelihood of saving the person's life

Obtaining informed consent is required unless the investigator and an unrelated physician can certify in writing all of the following:

When may an IRB use expedited review processes? (2)

One or both: 1) Some or all of research is no more than minimal risk 2) Minor changes in previously approved research during approval period

Noninvasive diagnostic device or procedure

One that does NOT 1) penetrate the skin or mucous membranes of the body, ocular cavity or the urethra 2) enter the ear beyond the external auditory canal, the nose beyond the nares, the mouth beyond the pharynx, the anal canal beyond the rectum or the vagina beyond the cervical os. (21 CFR, sec. 812.3)

5-97: For what length of time must all clinical investigations under and IND remain on hold prior to the FDA converting the IND to inactive status?

One year or more. 21 CFR 312.42

5-115: To whom may a sponsor provide investigational drugs?

Only investigators participating in the clinical investigations under the IND.

What is QC?

Operational techniques and activities undertaken within QA system to verify that requirements for quality of trial-related activities have been fulfilled

How are source documents defined by ICH GCP guidelines?

Original documents, data and records

What type of findings must be reported in narrative format in IND safety reports for drug studies?

Overall findings or pooled analyses from published and unpublished, in-vitro, animal, epidemiological or clinical studies

Which of the following best describes when the majority of case report form (CRF) data are verified against source record information?

Periodic site visits

Direct Access

Permission to examine, analyze, verify, and reproduce any records and reports that are important to the evaluation of a clinical trial. (ICH GCP E6 1.21)

What is the definition of a sponsor per 21 CFR 312.3?

Person who takes responsibility for and initiates a clinical investigation. Doesn't actually conduct the investigation personally unless the person is a sponsor-investigator. Companies that employ investigators to conduct a study are sponsors.

5-118: According to the FDA Form 1572, what are the investigator's obligations for conducting the study and supervising those who assist him or her in the conduct of the study?

Personally conduct or supervise the investigation and ensure that all associates, colleagues, or employees involved in the investigation, are informed of the investigator's obligations.

5-23: A study of normal volunteers designed to evaluate the metabolic and pharmacologic actions of a drug with increasing doses would be considered as what phase of investigation?

Phase 1

5-25: What phase of clinical investigation includes a study that evaluates structure-activity relationships or mechanism of action in humans?

Phase 1

5-27 What phase of a study typically evaluates the pharmacokinetics of a drug in normal volunteers?

Phase 1

5-22: Name the three phases of a clinical investigation for a previously untested drug.

Phase 1 Phase 2 Phase 3

5-39 Describe the relative level of detail required for Phase 1 protocols vs. Phase 2 and Phase 3 protocols.

Phase 1 may be less detailed and more flexible than Phases 2 and 3. Phase 1 should outline the plan, specify the number of patients, describe safety measures and include a dosing plan. Phases 2-3 should be very detailed, and will generally not permit unanticipated protocol changes.

5-29: What are the FDA's primary objectives when reviewing an IND regarding the various phases of investigation?

Phase 1: Focus is on safety assessment. Phases 2 & 3: Focus is on safety and effectiveness and to assure scientific evaluation All phases: Assure the rights and safety of others.

5-26: Controlled trials evaluation the effectiveness of multiple doses of a drug in patients would be considered as what phase of investigation?

Phase 2

5-24: When several hundred to several thousand subjects are in a study, what phase is the clinical investigation typically in?

Phase 3

5-28: Studies which provide an overall evaluation of a drug and an adequate basis for physician labeling would be considered as what phase of the investigation?

Phase 3

What are some examples of Class II devices?

Physiologic monitors, X-ray machines, infusion pumps, acupuncture needles and powered wheelchairs (greater potential risk)

Phase III

Pivotal Trial- overall evaluation of drug, adequate basis for physician labeling, provides majority of data for marketing, randomized control, 1000's subjects

What is QA?

Planned and systematic actions that ensure a trial is being performed and data are generated, documented and reported in compliance with GCP and applicable regulations

Phase IV

Post Market Studies, may involve additional age or ethicnic groups, 1000's subjects, don't have control designs

Phase 4

Post-marketing study to delineate additional information about the drug's risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time.

Phase IV Clinical Trial

Post-marketing, continue assessing therapeutic value and monitor less common adverse events

What are Chemistry, Manufacturing and Control studies? (CMC)

Pre-clinical testing about the solubility, stability and formulation of a new drug in different forms (capsules, tablets, aerosol, injectable and IV)

45 CFR Part B

Pregnant Women and Fetuses

814

Premarket approval for medical devices

What criterion must otherwise unapprovable research in kids meet to be IRB-approved?

Presents opportunity to further understand, prevent or alleviate a significant problem affecting health/welfare of children and conducted with sound ethical principles

Confidentiality

Prevention or disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity. (ICH GCP E6 1.16)

General: should include reports of all prior investigations Bibliographies Summary of unpublished information Statements of compliance with regulations

Prior Investigations:

21CFR56-B: When and where must an IRB register?

Prior to reviewing any research Renew every three years Registration is effective after review and acceptance by HHS. Registration on OHRP website or through mail Changes must be made within 30 or 90 days based on the type of change

45 CFR Part C

Prisoners

What is the definition of minimal risk?

Probability and magnitude of harm anticipated aren't greater than those ordinarily encountered in daily life during performance of routine physical or psychological exams/tests (21 CFR 56.102(i)

Blinding/Masking

Procedure in which one or more parties to the trial are kept unaware of treatment assignments. Used to minimize/avoid bias.

What is a Corrective and Preventative Action Plan (CAPA)?

Process of creating SOPs to find the cause of issues or problems and developing/implementing new procedures and processes to resolve them

What should happen when a child research subject turns 18?

Re-consent

Which of the following lists the three principles included in the Belmont Report?

Respect for Persons, Beneficence, Justice

How is a case history defined by 21 CFR 312.62(b) and 812.140(3)?

Records of all observations and other data pertinent to the investigation for each individual administered the IP or control - Include CRFs and supporting data - Include consent forms and medical records

5-130: What records must a sponsor maintain regarding investigational drug supplies?

Records of receipt, shipment or other disposition of the drug, which should include the name of the investigator, as well as the date, quantity, and batch or code mark of each shipment.

What are an investigator's responsibilities regarding safety reports for device studies? (1)

Report UADEs to sponsor and reviewing IRB as soon as possible, but no later than 10 working days after discovery (21 CFR 812)

What is an Establishment Inspection Report?

Report created by FDA after an inspection visit that, with attachments, is submitted to the FDA center that originated the inspection request

What are IND safety reports?

Reports from a sponsor to the FDA and all investigators about any potential serious risks associated with the IP - generated by sponsor and submitted within 15 calendar days of notification

What requirements must be met for an IRB to approve research?

Risks are minimized Risk benefit ratio maximized Subject selection is equitable Informed consent appropriate Documentation of informed consent Adequate provision for data and safety monitoring Adequate provision to protect privacy and confidentiality Safeguards for vulnerable populations Compliant with policies on research involving children * Approved research can be further approved or disapproved by other institution officials, but no research can be approved without IRB approval first

What is the key regulatory difference between SR and NSR device review?

SR requires FDA approval through IDE then IRB approval; NSR only requires IRB approval

How are medical devices categorized to determine whether an IDE is needed?

SR vs. NSR vs. exempt

5-122: What is a sponsor's responsibility with respect to selecting monitors for a study?

Select monitors who are qualified by training and experience to monitor the progress of the investigation.

How should sponsors choose qualified investigators, per 21 CFR 312.53(a)?

Select them as qualified by training and experience as appropriate experts to investigate a drug

How often and to whom do sponsors submit progress reports if device is under a treatment IDE?

Semi-annual progress reports to all reviewing IRBs and FDA + annual report

5-103 How often must a sponsor of a treatment IDE submit progress reports to all reviewing IRBs and the FDA?

Semi-annually until the filing of a marketing application, and annually thereafter.

Which of these is not a good security practice for email?

Sending sensitive information in email messages or in attachments to such messages, as long as a legally-binding confidentiality notice is included.

Which of these is not generally a good practice for fax machine use?

Sensitive faxes -- inbound or outbound -- are left sitting in or around the machine.

When and to whom should final reports be submitted for NSR studies?

Sent to all IRBs within 6 months of completion/termination

5-50 What types of experiences does the FDA classify as serious adverse drug experiences in clinical trials?

Serious adverse drug experiences include any event that results in death, a life-threatening drug experience, in-patient hospitalization or prolongation thereof, a significant or persistent disability or a congenital anomaly or birth defect. Important medical events may also be serious events.

What is the definition of an adverse event (AE)?

Sign, symptom, illness or untoward experience that develops or worsens during a study, regardless of relation to study treatment

What are an investigator's responsibilities regarding IP in a device trial? 21 CFR 812

Similar to drug trials, but investigator must administer IP or supervise appropriate staff to do so

Phase I Clinical Trial

Small trials with healthy subjects, purpose is to determine pharmacokinetics and maximum tolerated dose

Any trial-related responsibilities not specifically transferred are assumed by sponsor

Sponsor

Can be assured 'appropriate conduct' per GCP if instead of having CRO to monitor - have: 1) Central monitoring 2) PI training 3) PI meetings 4) Extensive writing guidance

Sponsor

Coding system for blinding trials include mechanism that permits rapid identification in case of emergencies - but not permit undetectable breaks of blinding

Sponsor

Define, establish and allocate responsibilities before entering into an agreement

Sponsor

Designate a medical advisor

Sponsor

Determine appropriate storage temps, conditions, times, reconstitution fluids and procedures, device for product infusion (notify all parties)

Sponsor

Determine the extent and nature of monitoring

Sponsor

Document Auditor's qualifications

Sponsor

Document the transfer of duties to CRO

Sponsor

Ensure Auditors document their observation and findings

Sponsor

Ensure CRFs are designed to capture required data at all multicenter trial sites

Sponsor

Ensure IP is characterized as appropriate to: 1. Stage of development 2. Manufactured in accordance with applicable GMP 3. Coded and labelled to protect blinding

Sponsor

Ensure IP is stable over period of use

Sponsor

Ensure clinical trial report to Regulatory Authorities in marketing applications meets standards of ICF for structure and content

Sponsor

Ensure documentation of responsibilities of coordinating investigators prior to start of trial

Sponsor

Ensure electronic trial data is: 1. Validated and secured 2. Has edit trail and data back up 3. Has safeguards to blinding

Sponsor

Ensure facilitation of communication between investigators in multicenter trials

Sponsor

Ensure financial aspects are documented in agreement

Sponsor

Ensure instructions are given to all site's PI's on complying with a uniform set of standards for assessment of clinical and lab findings and on completing CRFs

Sponsor

Ensure monitor's qualifications are documented

Sponsor

Ensure monitoring verifies that the study is conducted in compliance with the protocol and GCP

Sponsor

Ensure protocol or agreement states the PI allows audit

Sponsor

Ensure studies are adequately monitored

Sponsor

Ensure sufficient evidence via non-clinical and clinical data to justify IP dose, route, duration and population -> safe and effective

Sponsor

Ensure sufficient quantities of IP for reconfirming specification

Sponsor

Ensure supplemental CRFs be provided to PI's who are collecting additional data in multicenter study sites

Sponsor

Ensure written consent forms from subjects are obtained for allowing Sponsor access to medical records for audit

Sponsor

If discontinue development of IP, notify PI and regulatory authorities

Sponsor

Implement quality control through all stages of data handling

Sponsor

Inform PI and Regulatory Authorities if prematurely terminating study

Sponsor

Inform PI and regulatory authorities of findings that may adversely impact subject safety or conduct of the trial or IRB's approval

Sponsor

Inform PI's in the need for record retention and when records are no longer needed

Sponsor

Maintain a list of subjects authorized to make changes to electronic trial data

Sponsor

Maintain a system for IP retrieval and disposition

Sponsor

Maintain quality assurance and quality control systems

Sponsor

Maintain records of batch samples

Sponsor

Maintain records that documents: IP shipment, receipt, disposition, return and destruction

Sponsor

May establish an Independent Data Management Committee (IDMC) to assess data for safety and critical efficacy end points and advise whether to modify trial design or discontinue study

Sponsor

May transfer some or all of duties to a CRO

Sponsor

What risk level do Class III devices pose?

Support or sustain human life, therefore present significant risk to illness and injury

5-119 What information must an investigator provide study subjects regarding the drug they may receive?

That the drug is being used for investigational purposes.

The FDA will apply:

The Code of Federal Regulations.

45 CFR

The Common Rule

5-165 Name the international doctrine of ethical principles that is the standard requirement for acceptance of foreign studies in support of an IND or NDA.

The Declaration of Helsinki.

5-94: What at the FDA is responsible for issuing a clinical hold?

The Division Director with responsibility for review of the IND. 21 CFR 312.42

5-54: Who must be notified, via an IND safety report, of serious, unexpected adverse experiences that are associated with use of the drug?

The FDA and all investigators conducting studies under the IND.

The device is intended to treat or diagnose a serious or life threatening disease There's no comparable alternative The device is under investigation in a clinical trial The sponsor is actively pursuing marketing approval

The FDA considers an investigational device under a treatment IDE if:

5-90: If enrollment in a sponsored, adequate and well-controlled investigation is being impeded by a treatment-IND investigation, what action may the FDA take?

The FDA may place the treatment-IND on clinical hold. 21 CFR 312.42

If an effective IND is withdrawn by a sponsor for safety reasons, whom must the sponsor notify?

The FDA, all clinical investigations, and all reviewing IRBs; notification must include the reason for such withdrawal.

5-120: Who has responsibility for ensuring that an IRB that complies with the requirements of 21CFR 56 will provide review and approval of an investigation?

The investigator.

Inspection

The act by a regulatory authority of conducting and official review of documents, facilities, records and any other resources that are deemed by the authorities to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organizations (CROs) facilities, or at other establishments deemed appropriate by the regulatory authorities. (ICH GCP E6 1.29)

15-43 Results of the pre-clinical studies on abuse potential and drug dependence are required in the original IND application for which classes of drugs?

The correct answer is: Psychotropic substances or any other drug with abuse potential.

15-156 What types of early consultation meetings are usually available for the INDs to evaluate life-threatening or severely debilitating illnesses?

The correct answer is: 1. A Pre-IND meeting to review animal data or study design, to discuss Phase 1 trial designs or data presentations in the IND. 2. An End-of Phase 1 meeting to discuss the design of Phase 2 trials. 21 CFR 312.82

Generally, sponsors may request FDA comment and advice for which components of an IND submission?

The correct answer is: 1. Adequacy of technical data to support an investigational plan. 2. Design of a clinical trial. 3. A determination of whether proposed investigations are likely to produce the data and information needed for an NDA.

15-108: What is the proper sequence of actions the sponsor should take when attempting to resolve an administrative or procedural dispute with the FDA>

The correct answer is: 1. Attempt to resolve the dispute with the reviewing division of CDER or CBER, beginning with the assigned Consumer Safety Officer (CSO). 2. If the dispute is not resolved via the CSO, seek resolution via an ombudsman.

15-131: What records are the sponsors required to retain regarding financial interests of its investigators?

The correct answer is: 1. Complete and accurate records showing any financial interest paid to investigators by the sponsor for the study. 2. Complete and accurate records concerning all other financial interests of the investigator in compliance with 21CFR part 54.

15-109: What is the proper sequence of actions the sponsor should take when attempting to resolve a scientific or medical dispute with the FDA?

The correct answer is: 1. Discuss the matter directly with the responsible reviewing officials. 2. If unresolved, request a meeting with the reviewing officials and management representatives.

15-45 Name two of the three categories of protocol amendments which require the sponsor to update the original IND application.

The correct answer is: 1. New protocols. 2. Changes in a protocol. 3. New investigators.

15-47 Give an example of the type of information required to be filed as an information amendment to an original IND application.

The correct answer is: 1. New technical information such as toxicology or chemistry. 2. Reports regarding discontinuation of a clinical investigation.

15-30: Name at least two factors that determine the amount of information that must be submitted in an IND.

The correct answer is: 1. Novelty of the drug. 2. Extent to which the drug has been previously studied. 3.Known or suspected risks. 4.Particular developmental phase.

15-40 List at least three required sections in a clinical protocol for a study conducted under an IND.

The correct answer is: 1. Objectives and purpose. 2. Name, address, and qualifications of investigators and of the reviewing IRB. 3. Inclusion/exclusion criteria. 4. Study Design. 5. Dosing information. 6. Planned observations and measurements. 7. Clinical procedures to evaluate safety.

15-33: FDA Form 1571 requires the names and titles of two persons with specific functions. Who are they?

The correct answer is: 1. Person responsible for monitoring the conduct and progress of the evaluation. 2. The person responsible for review and evaluation of safety information for the drug.

15-156 What are types of the early consultation meetings are usually available for IND's to evaluate life-threatening or severely debilitating illnesses? 21 CFR 312.82

The correct answer is: 1. Pre-IND meeting to review animal data or study design, used to discuss Phase 1 trial designs or data presentations in the IND. 2. End-of-Phase 1 meeting used to discuss the design of Phase 2 trials.

15-37 Name at least three elements required in the general investigational plan of an original IND application.

The correct answer is: 1. Rationale for the drug or study. 2. Indication (s). 3. General evaluation approach. 4. Types of trials to be conducted in the first year. 5. Estimated number of patients to be studied in the first year. 6. Any anticipated risks of particular severity or seriousness.

15-110: List at least three general responsibilities of the sponsors?

The correct answer is: 1. Select qualified investigators, providing them with information to properly conduct the trial. 2. Ensure proper monitoring. 3. Ensure the study is conducted in compliance with the protocol. 4. Maintain an effective IND. 5. Ensure FDA and investigators are provided full safety information.

Name at least two elements required to be reported for each individual study reported in an IND annual report

The correct answer is: 1. Study title, indentifier and purpose description of patient population and completion status. 2. Total number of subjects a) initially planned for inclusion, b) entered to date, c) who completed as planned, d dropped for any reason 3. Brief description of any interim or final analysis results, if available.

15-163 Import of investigational new drugs into the US is permissible provided the consignee meets one of three criteria. Please name the 3 criteria. 21 CFR 312.110

The correct answer is: 1. The US sponsor of the IND 2. A qualified investigator named in the IND 3. the domestic agent go the foreign sponsor, who is responsible for the control and distribution of the drug and is so identified in the IND.

15-117: Who must be specifically named on FDA Form 1572?

The correct answer is: 1. The investigator 2. The institution where the investigation will be conducted. 3.The clinical laboratory to be used in the study. 4.The IRB responsible for review and approval . 5. Any sub- investigators who will assist the investigator.

15-164 Name at least one of the two individuals who may submit a request for authorization to the FDA to export investigational drug outside of the United States. 21 CFR312.110

The correct answer is: 1. The person in the US who seeks to export the drug OR 2. An authorized agent of the country to which the drug is proposed to be shipped.

15-107: Name at least two major purposes for a Pre-NDA or Pre-BLA meeting between a sponsor and the FDA.

The correct answer is: 1. To uncover any major unresolved problems. 2. To identify studies on which the sponsor will rely to establish effectiveness. 3. To identify the status of ongoing or needed studies, to assess pediatric safety and effectiveness. 4. to acquaint FDA reviewers with technical content. 5. To discuss statistical analysis methods. 6. To determine the optimal approach for presenting and formatting of NDA data. 21 CFR 312.47

Name at least three grounds for FDA imposition of a clinical hold for a Phase 1, 2, or 3 investigation.

The correct answer is: 1.Subjects would be exposed to unreasonable and significant risk or illness or injury. 2. Unqualified investigators. 3. Inadequate Investigator Brochure. 4. Gender bias on subject eligibility.

15-154 Name the criteria for life-threatening diseases or conditions to which special IND regulations apply? 21 CFR 312.81

The correct answer is: Diseases or conditions: -Where the likelihood of death is higher unless the disease is interrupted - With the outcome where the end point of the clinical trial analysis is survival

15-41 Name two of the five required content elements in the Chemistry, Manufacturing, and Controls section of an original IND application.

The correct answer is: Information on: 1. The drug substance. 2. The drug product. 3. Placebo composition if applicable). 4. Labeling. 5. Environmental analysis requirements.

15-22: Name the three phases of clinical investigations for a previously untested drug.

The correct answer is: Phase 1 Phase 2 Phase 3

15-29: What are the FDA's primary objectives when reviewing an IND regarding the various phases of investigation?

The correct answer is: Phase 1: Focus is on safety assessment. Phases 2 & 3: Focus is on safety and effectiveness and to assure scientific evaluation All phases: Assure the rights and safety of others.

15-9: What statement must the label of all investigational drugs have?

The correct answer is: "Caution: New Drug--Limited by Federal [or United States] law to investigational use".

15-121: What actions must the investigator take to make changes in a study protocol?

The correct answer is: 1. Inform the sponsor, request the change, and obtain a protocol amendment, if required. 2 Inform the IRB as needed, and request review and approval of the amendment. 3. Modify the consent form, if required, and obtain IRB approval. 4. Inform study patients of the pertinent changes, and obtain new informed consent, if applicable.

15-21: How much time does FDA have to provide a sponsor with written approval o proceed with an IND that involves waiver from informed consent due to emergency conditions?

The correct answer is: 30 days

15-46 How soon does the sponsor have to submit a new investigator amendment to a IND?

The correct answer is: 30 days following the addition of the investigator.

15-44 What are FDA's requirements for translation and inclusion of documents in an IND application which are not in English?

The correct answer is: A complete English translation must be included as well as a copy of the original publication in the foreign language.

A revised copy of an Investigator Brochure in an IND annual report must be accompanied by what other additional information?

The correct answer is: A description of the revision(s).

15-155 Describe the FDA'S definition of a "severely debilitating" disease? 21 CFR 312.81

The correct answer is: A disease or condition that may cause irreversible morbidity

15-155 What is FDA's definition of a "severely debilitating" disease?

The correct answer is: A disease or condition that may cause irreversible morbidity. 21 CFR 312.81

15-7: Define "contract research organization," according to the FDA's IND regulations?

The correct answer is: A person working with the sponsor as an independent contractor who assumes one or more of the obligations of the sponsor.

15-51 What is FDA's definition of disability, as it relates to serious adverse drug experiences?

The correct answer is: A substantial disruption of a person's ability to conduct normal life functions.

15-106: What clinical items must a sponsor provide to the FDA at least one month in advance of an End-of-Phase 2 meeting?

The correct answer is: A summary of Phase 1 and 2 investigations, specific protocols for Phase 3, plans for any pediatric studies or requests for waiver or deferral of pediatric studies, and tentative labeling for the drug. 21 CFR 312.47

15-125: What information document must the sponsor provide to an investigator prior to beginning an investigation?

The correct answer is: An Investigator Brochure.

Define clinical hold?

The correct answer is: An order issued by the FDA to a sponsor to delay a clinical study.

15-52 What is FDA criterion which classifies an adverse drug experience as unexpected?

The correct answer is: Any adverse experience, the specificity or severity of which is not consistent with the current Investigator Brochure, or other designated document when an Investigator Brochure is not required.

15-53 Sponsors are required to maintain an ongoing review of safety information from what sources?

The correct answer is: Any foreign or domestic source including clinical, epidemiological, and animal investigations, commercial marketing experience, scientific literature reports, and unpublished scientific papers, and reports from foreign regulatory authorities not previously reported to the FDA.

15-102: If an IND is placed on inactive status by the FDA, what action must the sponsor take with drug supplies?

The correct answer is: Arrange with all investigators for return or other proper method of disposal of the investigational drug. 21 CFR 312.45

15-55: What are the time requirement for filing IND safety reports with the FDA?

The correct answer is: As soon as possible and never later than fifteen calendar days after the sponsor's initial receipt of the information.

15-61: If a sponsor evaluates an adverse experience and determines that is reportable as an IND safety report, but it was originally reported as such, how long does the sponsor have to report this event as an IND safety report?

The correct answer is: As soon as possible, but in no event later than fifteen calendar days after the determination is made.

15-60: When are sponsors required to file follow-up information for the IND safety reports?

The correct answer is: As soon as the relevant information is available

15-48 What is FDA's preferred filing frequency for information amendments by the sponsors?

The correct answer is: At intervals of 30 days.

15-103: At what point in the clinical development process of a drug does the FDA encourage meetings with an IND sponsor?

The correct answer is: At the end of a Phase 2 and prior to NDA submission. 21 CFR 312.47

15-105: Who may bring consultants to a End-of-Phase 2 meeting?

The correct answer is: Both the FDA and the sponsor. 21 CFR 312.47

15-31: What should be the main focus of an initial IND submission?

The correct answer is: The general investigational plan and the process for specific human studies.

15-56: How soon must FDA be notified of a fatal or life-threatening adverse experience which is associated with use of a drug?

The correct answer is: By telephone or facsimile transmission, no later than seven calendar days after sponsor receipt of the information, followed by a written report no later than fifteen calendar days after the initial receipt of the information by the sponsor.

15-154 What is the criteria for life-threatening diseases or conditions to which special IND regulations apply for clinical trials?

The correct answer is: Conditions or diseases: -Where likelihood of death is high unless the disease is interrupted -with outcomes where the end point of the clinical trial analysis is survival. 21 CFR 312.81

15-151 If an investigator is disqualified by the FDA, what impact might that cause the sponsor? 21 CFR 312.70

The correct answer is: Data received from the disqualified investigators may be eliminated from the NDA consideration, and ultimately result in the FDA's failure to approve the NDA. Also, for approved drugs, data from the disqualified investigators could result in withdrawal of marketing approval by the FDA.

15-161 For what type of studies do the FDA officials intend to monitor study progress and evaluation to facilitate appropriate progress of the study trials! 21CFR 312.87

The correct answer is: Drugs intended to treat life-threatening or for severely debilitating illnesses.

15-161 For what type of studies does the FDA officials intend to monitor study progress and evaluation to facilitate appropriate progress of the trials?

The correct answer is: Drugs intended to treat life-threatening or severely debilitating illnesses. 21 CFR 312.87

15-62: If a sponsor submits an IND safety report, it is assumed by FDA that the drug caused or contributed to the event, unless it is specifically denied by the sponsor. True or False?

The correct answer is: FALSE Mere submission of a report under the IND safety report requirements does not reflect the conclusion, by either the sponsor or the FDA, that the drug caused or contributed to the reported event.

What is the FDA form for the investigator to use when filing a treatment IND.

The correct answer is: FDA FORM 1571

15-32: What FDA form specifies the content and order of an IND submission?

The correct answer is: FDA Form 1571

15-116: What FDA document must all investigators sign prior to participation in an investigation of a drug?

The correct answer is: FDA Form 1572

Clinical holds always apply to all clinical investigations under the IND.

The correct answer is: False A clinical hold order may apply to one or more investigations covered under an IND.

The FDA clinical holds apply to all sponsored clinical investigations under an IND, but do not apply to treatment INDs.

The correct answer is: False Clinic holds may apply to all research with a drug including a treatment IND.

15-96: Resumption of clinical investigations which were subject to a clinical hold must always be issued in writing by FDA to a sponsor. True or False?

The correct answer is: False If permitted in the clinical hold order, investigations may be resumed as soon as the deficiencies are corrected. Resumption notification for clinical hold cases requiring a sponsor response, may be made by telephone or other rapid communication means. 21 CFR 312.42

Summary information for clinical trials activity within the past year is required in an IND annual report, while results of pre clinical studies are not

The correct answer is: False Pre clinical summary information for studies completed or concluded within the past year must be included in the IND annual report.

15-91: Only a sponsor may interrupt a treatment IND investigation if inadequate supplies are available to support it as well as concurrent controlled trials. True or False?

The correct answer is: False The FDA may also place the treatment-IND on clinical hold under these circumstances. 21 CFR 312.42

15-92: The FDA may not place any investigator on clinical hold that employs the exception from informed consent criteria for emergency research, or that has not been determined by the President to waive the prior consent requirement. True or False?

The correct answer is: False The FDA may place investigators in either of these situations on clinical hold if it determines that deficiencies or non-compliance are present. 21 CFR 312.42

15-167 The FDA may disclose the existence of an IND, even though it was not previously been made public. True or False? 21 CFR 312.130

The correct answer is: False. FDA may not disclose that an IND exists if the fact has not been previously disclosed.

15-152 Once an investigator is disqualified by the FDA, he or she may never again receive investigational drug. True or False?

The correct answer is: False. The FDA may reinstate a disqualified investigator if the FDA Commissioner determines the investigator presents adequate assurances that they will work in full compliance with applicable regulations. 21 CFR 312.70 .

15- 129: Although the sponsor reserves the right to terminate and ongoing clinical investigation for reason of patient safety, the sponsor is required to confer with the investigator prior to terminating the investigation. True or False?

The correct answer is: False. The sponsor may terminate an investigation without conferring with an investigator.

15-12: Can investigational drugs be commercially distributed or test-marketed by sponsors or investigators. T or F?

The correct answer is: False. Commercial distribution of investigational products is permitted.

15-11: Promotional claim is acceptable on investigational drug supply labeling, provided the claim was previously approved by the FDA. T or F?

The correct answer is: False. Promotional claims may not appear on the investigational drug supply labels.

15-35: Obligations transferred by a sponsor to CROs are always submitted as an information amendment to an IND, rather than being included in the original IND application.

The correct answer is: False. The transferred obligations may be included in the original IND submission.

15-120: Who has responsibility for ensuring that the IRB that complies with the requirements of 21CFR 56 will provide review and approval of an investigation?

The correct answer is: The investigator.

15-126 Investigators are responsible for periodically requesting updates regarding new information received by a sponsor during the course of a clinical investigation. True or False? 21 CFR 312.55

The correct answer is: False: The sponsor is responsible to provide relevant new information about a drug, particularly with respect to adverse events and safe use via revisions to an Investigators Brochure, reprints of the published studies or reports or through other appropriate means

15-152 Once an investigator has been disqualified by the FDA, the investigator may never again receive investigational drug True or False? 21 CFR 312.70

The correct answer is: False: The FDA may reinstate a disqualified investigator if the FDA Commissioner determines that the investigator presents adequate assurances that they will work in full compliance with applicable regulations.

15-160 For what purposes might FDA undertake focused regulatory research? 21 CFR 312.86

The correct answer is: For evaluating critical rate-limiting aspects of the drug development process in facilitating the development of therapies to treat life-threatening or severely debilitating illnesses.

15-104: End-of-Phase 2 meetings between the FDA and a sponsor are generally reserved for what type of IND?

The correct answer is: INDs involving new molecular entities or major new uses of marketed drugs. 21 CFR 312.47

15-101: Name the two conditions under which the FDA may place an IND on inactive status.

The correct answer is: If no subjects are entered into clinical trials for a period of 2 years or more under the IND, or if all investigations under the IND remain on clinical hold for a period of more than one year. 21 CFR 312.45

15-100: On what grounds may the FDA terminate an IND immediately, without opportunity for sponsor response?

The correct answer is: If the FDA concludes that continuation of the investigation presents a substantial danger to health of individuals. 21 CFR 312.44

15-124: When the sponsor is conducting investigations under 21CFR 50.24, in emergency research conditions, what information must the sponsor promptly file with the FDA under the IND?

The correct answer is: Information received from the IRB concerning the public disclosure required by the regulation.

15-8: What types of products are generally subject to IND regulations?

The correct answer is: Investigational new drugs, biological drugs and biological products used in vitro for diagnostic purposes that are used in a clinical investigation.

15-10: What are labeling requirements for investigational drugs with respect to safety or effectiveness of the product?

The correct answer is: Label can bear no misleading statemetn and shall not represent that the drug is safe or effective for the purposes for which it is being investigated.

15-150 How must an investigator store the investigational drugs which are also controlled substances? 21 CFR 312.69

The correct answer is: Must be in a securely locked, substantially constructed cabinet or other enclosure with limited access to prevent theft or diversion of the substance into illegal channels of distribution.

15- 149 In addition to granting permission to authorized FDA representative to have access to, copy, and verify study records, what information is an investigator required to divulge regarding each study subject?

The correct answer is: None, no other information. The investigator may withhold subject names unless the records of particular subjects require a more detailed study, or if there is reason to believe the records do not represent the actual cases, or results. 21 CFR 312.68

15-97: For what length of time must all clinical investigations under an IND remain on hold prior to the FDA converting the IND to inactive status?

The correct answer is: One year or more. 21 CFR 312.42

15-115: To whom may the sponsor provide investigational drugs?

The correct answer is: Only investigators participating in the clinical investigations under the IND.

15-118: According to the FDA Form 1572, what are an investigator's obligations for conducting the study and supervising those who assist the investigator in the conduct of the study?

The correct answer is: Personally conduct or supervise the investigation and ensure that all associates, colleagues, or employees involved in the investigation, are informed of the investigator's obligations.

15-23: A study of normal volunteers designed to evaluate the metabolic and pharmacologic actions of a drug with increasing doses would be considered as what phase of an investigation?

The correct answer is: Phase 1

15-25: What phase of clinical investigation includes a study that evaluates structure-activity relationships or mechanism of action in humans?

The correct answer is: Phase 1

15-27 What is the phase of a study typically evaluates the pharmacokinetics of a drug in normal volunteers?

The correct answer is: Phase 1

15-39 Describe the relative level of detail required for a Phase 1 protocols vs. Phase 2 and Phase 3 protocols.

The correct answer is: Phase 1 may be less detailed and more flexible than Phases 2 and 3. Phase 1 should outline the plan, specify the number of patients, describe safety measures and include a dosing plan. Phases 2-3 should be very detailed, and will generally not permit unanticipated protocol changes.

15-26: Controlled trials evaluation the effectiveness of multiple doses of a drug in patients would be considered as what phase of investigation?

The correct answer is: Phase 2

15-24: When several hundred to several thousand subjects are in a study, what phase is the clinical investigation typically in?

The correct answer is: Phase 3

15-28: Studies which provide an overall evaluation of a drug and an adequate basis for physician labeling would be considered as what phase of the investigation?

The correct answer is: Phase 3

15-153 Name the basic premise, relative to risk, of the IND regulations regarding drugs intended to treat life-threatening and severely debilitating disease? 21 CFR 312.80

The correct answer is: Physicians and patients alike are generally more willing to accept greater risks or side effects from drugs intended to treat severely debilitating or life-threatening illnesses.

15-130: What records must the sponsor maintain regarding investigational drug supplies?

The correct answer is: Records of receipt, shipment or other disposition of the drug, which should include the name of the investigator, as well as the date, quantity, and batch or code mark of each shipment.

15-122: What is the sponsor's responsibility with respect to selecting monitors for a study?

The correct answer is: Select monitors who are qualified by training and experience to monitor the progress of the investigation.

15-50 What types of experiences does FDA classify as serious adverse drug experiences in clinical trials?

The correct answer is: Serious adverse drug experiences include any event that results in death, a life-threatening drug experience, in-patient hospitalization or prolongation thereof, a significant or persistent disability or a congenital anomaly or birth defect. Important medical events may also be serious events.

15-111: If the sponsor desires to transfer some obligations to a contract research organization, what documentations must the sponsor prepare?

The correct answer is: Sponsors must describe, in writing, the specific responsibilities being transferred unless all responsibilities are being transferred, in which case a general statement will suffice. Any obligation not described in writing is deemed no to have been transferred.

15-13: Sponsors are prohibited from unduly prolonging clinical investigations, once adequate data has been generated for support of a marketing application. True or False?

The correct answer is: TRUE

15-15: Charging a reasonable amount for the investigational drugs under a treatment IND is permissible provided certain criteria are met and there is no commercialization or promotion involved. True or False?

The correct answer is: TRUE

15-1: IND regulations typically do not apply to investigations with lawfully marketed drugs which are being studied for purposes other than supporting a change in labeling or a change in advertising, so long as the study complies with IRB and consent regulations and it does not significantly increase risks or decrease acceptability of risks. True or False?

The correct answer is: TRUE

15-2: Some clinical investigations that involve an in vitro diagnostic biologic product may be exempt from the IND regulations if it used only to confirm a diagnosis made by another medically established diagnostic product or procedure. True or False?

The correct answer is: TRUE

15-3: Clinical research on blood grouping serum, reagent red blood cells and anti human globulin are generally exempt from FDA's IND regulation. True or False

The correct answer is: TRUE

15-4: Clinical investigations involving placebos may be exempt from IND regulations if the investigation does not otherwise require a submission of an IND application. True or False?

The correct answer is: TRUE

15-59: For marketed drugs, a sponsor is not required to file the IND safety report for events which are from non-clinical trial sources. True or False?

The correct answer is: TRUE

15-5: Use of marketed drug or biologic product for an unlabeled indication in the practice of medicine is not subject to IND regulations. True or False?

The correct answer is: TRUE

15-6: Researchers planning an investigation may contact the FDA to obtain guidance regarding the applicability of the IND regulations to a particular study. True or False?

The correct answer is: TRUE

15-71: "Treatment use" protocols are generally used once a drug's initial safety in Phase 2 trials has been demonstrated. True or False?

The correct answer is: TRUE

15-98: If a sponsor fails to inform the FDA of all serious and unexpected adverse experiences, what is the most significant action the FDA may take relative to the IND?

The correct answer is: Termination of the IND. 21 CFR 312.44

15-119 What information must the investigator provide study subjects regarding the drug they may receive?

The correct answer is: That the drug is being used for investigational purposes.

15-165 Name the international doctrine of ethical principles that is the standard requirement for the acceptance of foreign studies in support of an IND or NDA.

The correct answer is: The Declaration of Helsinki.

15-94: What at the FDA has responsiblity for issuing a clinical hold?

The correct answer is: The Division Director with responsibility for review of the IND. 21 CFR 312.42

15-54: Who must be notified, via means of an IND safety report, of serious, unexpected adverse experiences that are associated with use of the drug?

The correct answer is: The FDA and all investigators conducting studies under the IND.

15-168 What additional information is available from FDA that applies to and supports interpretation of the FDA regulations? 21 CFR 312.145

The correct answer is: The FDA guidance documents which support interpretation of the regulations are available from both Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research.

15-90: If enrollment in a sponsored, adequate and well-controlled investigation is being impeded by a treatment-IND investigation, what action may FDA take?

The correct answer is: The FDA may place the treatment-IND on clinical hold. 21 CFR 312.42

Who must the sponsor notify if an effective IND is withdrawn by a sponsor for safety reasons?

The correct answer is: The FDA, all clinical investigations, and all reviewing IRBs; notification must include the reason for such withdrawal.

15-14: What is the FDA requirement for charging for investigational drugs under an IND.

The correct answer is: The charge for investigational drugs under an IND is not permitted without prior written approval from the FDA. Written explanation of why charges are necessary and not a normal cost of doing business is also required.

15-58: Who must approve modifications on the reporting format or frequency of the IND safety reports prior to a sponsor deviating from the regulations

The correct answer is: The director of the new drug review division of either the Center of Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER).

15-153 What is the basic premise, relative to risk, of the IND regulations regarding drugs which are intended to treat life-threatening and severely debilitating disease?

The correct answer is: The patients and physicians are generally more willing to accept greater risks or side effects from drugs intended to treat severely debilitating or life-threatening illnesses. 21 CFR 312.80

When FDA approves shipment of a drug for emergency use from a telephone request, what additional requirement typically is made of the sponsor

The correct answer is: The sponsor must make an appropriate IND submission as soon as practicable after receiving the approval.

15-128: What is the sponsor's obligation relative to review of patient data in ongoing investigation?

The correct answer is: The sponsor must review and evaluate safety and efficacy data as it obtained from the investigator.

15-49 What is FDA's definition of the term "associated with the use of the drug" with respect to the evaluation of adverse experiences?

The correct answer is: There is a reasonable possibility that the experience may have been caused by the drug.

15-150 How must investigators store investigational drugs which are also controlled substances?

The correct answer is: They must be securely locked, substantially constructed cabinet or other enclosure with limited access to prevent theft or diversion of the substance into illegal channels of distribution. 21 CFR 312.69

Unless the FDA notifies the sponsor that investigations in an IND are subject to a clinical hold, how soon may the sponsor begin a clinical investigation after filing the IND?

The correct answer is: Thirty days (30) after the FDA receives the IND submission.

15-42 The pharmacology and toxicology section of a original IND application requires the names and qualifications of the individuals who performed what tasks?

The correct answer is: Those who evaluated the results of pre-clinical studies and concluded it was reasonably safe to begin the proposed clinical investigations.

15-112: When the sponsor transfers some or all its obligations to a CRO, the CRO is required to comply with all regulations designated as sponsor requirements for the transferred obligations.

The correct answer is: True

15-123: During an investigator selection process, sponsors are required to obtain a commitment from an investigator to provide financial disclosure statements before, during, and for one year after the completion of a study?

The correct answer is: True

15-127: Even though the FDA Form 1572 is a contract between the investigator and the FDA, a sponsor may discontinue shipments of drug or terminate a study if the investigator fails to comply with the obligations on the signed for 1572 form. True or False?

The correct answer is: True

15-158 A NDA is required for drugs intended to treat life-threatening diseases, however, special recognition of the medical risk/benefit must be given by FDA. True or False 21 CFR312.84

The correct answer is: True

15-159 Along with the approval of a drug for a life-threatening or severely debilitating disease, the FDA may request that the sponsor conduct Phase 4 studies to further evaluate the drug, TRUE OR FALSE 21 CFR 312.85

The correct answer is: True

15-162 All safeguards incorporated in FDA regulations regarding informed consent (21CFR 50), IRB review (21 CFR 56), IND (21 CFR 312), NDA (21 CFR 314) and Biologics (21 CFR 600) also apply to drugs intended to treat life-threatening or severely debilitating illnesses. True or False? 21 CFR 312.88

The correct answer is: True

15-16: FDA may withdraw authorization to charge for a investigational drug.

The correct answer is: True

15-17: Sponsors can request waivers of IND requirements from the FDA

The correct answer is: True

15-18: Filing an IND application with FDA is required prior to commencing any clinical investigation with an investigational new drug

The correct answer is: True

15-19: Filing a separate IND with FDA is required if a sponsor elects to conduct investigations involving waiver of informed consent in emergency research.

The correct answer is: True

15-20: A sponsor must receive written approval from FDA, prior to beginning emergency research being conducted with waiver of consent.

The correct answer is: True

15-34: The FDA Form 1571 contains a statement that an IRB that complies with the requirements of 21 CFR 56 will be responsible for review of all studies conducted under the IND

The correct answer is: True

15-36: Foreign clinical experience with a drug must be submitted in an original IND application.

The correct answer is: True

15-38 The Investigator Brochure is a required component of a original IND submission. True or False?

The correct answer is: True

An IND annual report should include the update description of the general investigational plan for the coming year.

The correct answer is: True

FDA Commissioner may deny requests for treatment-use of a drug for serious or life-threatening diseases if there is insufficient evidence to support its use.

The correct answer is: True

For a treatment INDs, the investigator is responsible for reporting safety information directly to the FDA.

The correct answer is: True

For serious or life-threatening diseases in patients for whom no alternative drug or comparable therapies are available may be evaluated outside of sponsor-planned clinical trials in a treatment protocol

The correct answer is: True

IF a licensed medical practitioner files a treatment IND with the FDA, the investigator becomes a sponsor-investigator, even though the sponsor may be supplying the drug

The correct answer is: True

The sponsor may withdraw an effective IND at anytime, without prejudice.

The correct answer is: True

Do you keep informed consent records for patients who withdraw during study?

Yes

15-88: FDA may place a treatment IND or treatment protocol on clinical hold if a comparable or satisfactory alternative therapy or drug becomes available for patients with conditions intended to be treated in the investigation. True or False?

The correct answer is: True 21 CFR 312.42

15-89: FDA may place a treatment IND on clinical hold if a sponsor is not pursuing marketing approval with due diligence. True or False?

The correct answer is: True 21 CFR 312.42

15-93: Unless patients are exposed to immediate and serious risk the FDA will attempt to satisfactorily resolve deficiencies with the sponsors prior to issuing a clinical hold order. True or False?

The correct answer is: True 21 CFR 312.42

15-99: Sponsor failure to comply with any IND requirement of 21 CFR parts 312, 50 or 56 may result in FDA termination of the IND. True or False?

The correct answer is: True 21 CFR 312.44

15-158 Although a full NDA is required for drugs intended to treat life-threatening diseases, special recognition of the medical risk/benefit must also be given by the FDA. True or False?

The correct answer is: True. 21 CFR 312.84

15-159 Concurrent with approval of a drug for life-threatening or severely debilitating disease, the FDA may request the sponsor conduct Phase 4 studies to further evaluate the drug. True or False?

The correct answer is: True. 21 CFR 312.85

15-157: For INDs evaluating drugs for severely debilitating or life-threatening disease, the FDA may request that the sponsor initiate a treatment protocol, if Phase 2 data appears promising.

The correct answer is: True. 21 CFR 312.83

What does the phrase emergency use of an investigational drug imply, in FDA's IND regulations?

The correct answer is: Use of a drug in an emergency situation for which an IND application has not yet been filed.

15-95: In a clinical hold order is issued by telephone, how soon thereafter must FDA provide the sponsor with a written explanation of the basis for the clinical hold?

The correct answer is: Within 30 days of imposing the clinical hold. 21 CFR 312.42

15-63: What is the time frame in which the sponsor must file an IND annual report?

The correct answer is: Within 60 days of the anniversary date that the IND went into effect.

5-10: What are the labeling requirements for investigational drugs with respect to safety or effectiveness of the product?

The label can bear no misleading statemetn and shall not represent that the drug is safe or effective for the purposes for which it is being investigated.

5-58: Who must approve modifications on the reporting format or frequency of IND safety reports prior to a sponsor deviating from the regulations

The director of the new drug review division of either the Center of Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER).

5-31: What should be the main focus of an initial IND submission?

The general investigational plan and the process for specific human studies.

Which of the following is a correct statement about the balance among prevention, detection, and response (PDR)?

The greater the sensitivity and quantity of the data at issue, the more carefully the balance among these three must be evaluated.

Department of Agency Head

The head of any federal department or agency and any other officer or employee of any department or agency to whom authority has been delegated. (45 CFR, sec. 46.102)

Quality Control (QC)

The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled. (ICH GCP E6 1.47)

5-57: For purposes of filing IND safety reports with the FDA, what is the definition of a "life-threatening event?"

The patient was at immediate risk of death from the reaction as it occurred.

Randomization

The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias. (ICH GCP E6 1.48)

5-93 What is the purpose of a treatment use of an investigational device?

The purpose is to facilitate the availability of promising new devices to desperately ill patients as early in the device development process as possible, before the general marketing begins, along with obtaining additional data on the device's safety and effectiveness.

Privacy, in the health information context, refers to:

The rules about who can access health information, and under what circumstances.

When the FDA approves shipment of a drug for emergency use from a telephone request, what additional requirement typically is made of the sponsor

The sponsor must make an appropriate IND submission as soon as practicable after receiving the approval.

5-128: What is a sponsor's obligation relative to review of patient data in ongoing investigation?

The sponsor must review and evaluate safety and efficacy data as it obtained from the investigator.

Under which circumstance does the FDA allow verbal consent prior to participation in a research study?

The study is minimal risk.

5-49 What is the FDA's definition of the term "associated with the use of the drug" with respect to the evaluation of adverse experiences?

There is a reasonable possibility that the experience may have been caused by the drug.

Which types of clinical studies must submit an IDE?

Those that support an eventual premarket approval application and some 510(k) (notification) applications

5-42 The pharmacology and toxicology section of an original IND application requires the names and qualifications of the individuals who performed what tasks?

Those who evaluated the results of pre-clinical studies and concluded it was reasonably safe to begin the proposed clinical investigations.

5-98 How soon following submission of an IDE to the FDA may treatment use begin?

Treatment use may begin 30 days after the FDA receives the treatment IDE unless notified that treatment use may or may not begin.

5-157: For INDs evaluating drugs for severely debilitating or life-threatening disease, the FDA may request that the sponsor initiate a treatment protocol, if Phase 2 data appears promising.

True. 21 CFR 312.83

HIPAA's "incidental uses and disclosures" provision excuses deviations from the minimum necessary standard. What is excused?

Truly accidental "excess" uses and disclosures, where reasonable caution was otherwise used and there was no negligence.

Where would you look to find official government information regarding GCP?

US Code of Federal Regulations

What is the medical device equivalent of an SAE?

Unanticipated Adverse Device Effect (UADE)

What can happen if the FDA finds noncompliance with an IRB?

Until corrective action is taken, the FDA may: Withhold approval of new studies Direct no new subjects be added to ongoing studies Terminate ongoing studies when doing so would not endanger subjects OR when the noncompliance creates a significant threat to the welfare of subjects Notify relevant agencies about the deficiencies of the operation of the IRB *Normally action falls to the institution unless it is grievous

Within what timeline must a sponsor notify the FDA of a fatal or life-threatening SUSAR for drug studies?

Up to 7 calendar days

Phase III Clinical Trial

Use in large numbers of patients, long-term safety

What does the phrase emergency use of an investigational drug imply, in the FDA's IND regulations?

Use of a frug in an emergency situation for which an IND application has not yet been filed.

Which of these is generally not a good practice with respect to oral communications (that is, talking) in organizations like healthcare facilities?

Use of full names in public areas or on intercom/paging systems, because there is no security issue with identifying persons in public areas and using full names helps avoid misidentification.

How is power calculated?

Using effect size and variability - usually a higher # of subjects is needed for higher power

Which of these is not generally a good practice for telephone use?

Using voicemail systems and answering machines that do not require a password or PIN for access.

What is the legal age to provide consent in US?

Varies by state, but generally 18

Form 3500

Voluntary Reporting of Adverse Event and Product Problem

What is a MEDWATCH Form 3500?

Voluntary reporting for healthcare professionals and consumers to report AEs found in course of clinical care

Form 3500

Voluntary safety reporting of adverse events and product problems

What special population must the IRB pay special attention to?

Vulnerable subjects

What is an in-vtiro diagnostic?

Way to test for a certain property or result outside the human body

Research (Roy) Risks (ran) Benefits (by) Alternatives (a) Confidentiality (creepy) Contact (crazy) Compensation (crackling) Voluntary (volcano)

What are the required elements of an Informed Consent?

Terminate investigations no later than 5 working days after determination is made - no later than 15 working days after discovering the event

What must the sponsor do in the event an unanticipated adverse device risk presents an unresasonable risk to subjects?

When can a CRF be considered a source document?

When CRF is signed, dated and initialed by person recording the information

5 working days

When an exception to informed consent due to an emergency occurs, how long does the investigator have to report the use to the IRB?

Within 3 months after completion or termination of the investigation (or the investigators part in the investigation)

When is the investigator's final report due?

When does an SAE have to be reported to the FDA within 15 calendar days?

When it fits all SAE criteria but is not life-threatening and does not result in death.

Failure to comply with any requirement Application omits or falsifies information Sponsor does not provide additional information upon request There is reason to believe the device is too risky, ineffective, consent is inadequate, or the investigation is not scientifically sound It is unreasonable to begin or continue due to the way the device is used or inadequacy of The report of prior investigations/investigational plan The methods, facilities, and controls for the device Monitoring and review of the investigation

When might the FDA disapprove or withdraw an IDE application?

5-95: In a clinical hold order is issued by telephone, how soon thereafter must the FDA provide the sponsor with a written explanation of the basis for the clinical hold?

Within 30 days of imposing the clinical hold. 21 CFR 312.42

When are historical controls used in a clinical trial?

When other controls aren't practical or ethical; but similarity between patients in historical control group and current treatment group is important

When is SOC used as opposed to placebo in clinical trials?

When placebo would be unethical and harmful to patients

The armed forces (under certain circumstances)

Who can the president waive consent requirements for?

FDA will not disclose the existence of an IDE unless it's been previously publicly acknowledged The FDA may use discretion based on circumstances FDA may disclose adverse device effects at their discretion

Will the FDA talk publicly about a device under investigation?

Who developed the Declaration of Helsinki?

World Medical Association (WMA)

According to GCP guidelines, does the term vulnerable subject also include employees under direct supervision of clinical investigator?

Yes

Are devices intended solely for veterinary use exempt form IDE regulations?

Yes

human subject

a patient or healthy individual participating in a research study. A living individual about whom an investigator obtains private information or data through intervention or interaction

Placebo

a pharmaceutical preparation that contains no active agent

Assent

a child's affirmative agreement to participate in a clinical investigation

source data

all information contained in original records and certified copies of results, observations, or other facets required for reconstruction and evaluation of the study that is contained in source documents

common rule

also known as 45 CFR 46 Subpart A --ABC's of this are Assurance, Board review (IRB), Consent

placebo

an inert substance used as a comparison to an active ingredient in clinical trials

International Conference of Harmonization (ICH)

an organazation composed of expert working groups from industry and regulatory bodies in the European Union, Japan and the US. This publishes guidelines for worldwide GCP with the goal of standardization for clinical trials of drugs.

serious adverse event (SAE)

any event that results in death, a life threteaning situation, hospitalization or prolonged hospitalization, disability, incapacity or a congenital anomaly/birth defect

Adverse Event

any unfavorable or unintended event associated with a research study

According to ICH guidelines, how many members should an IRB have?

at least 5

The packaging of investigational drugs should ideally

be designed to help with subject compliance

1. Must have at least 5 members w/ varied backgrounds 2. must posse appropriate professional competence to review diverse types of protocol 3. 1 member not associated with the institution and no immediate family 4. 1 lay person (non-scientific member)

describe the IRB organization and membership as required by federal regulations

Noninvasive

diagnostic device or procedure that does not by design or intention: 1) Penetrate or pierce the skin or mucous membranes of the body, ocular cavity or the urethra or; 2) enter the ear beyond the external auditory canal, nose beyond the nares, the mouth beyond the pharynx, the anal canal beyond the rectum, or the vagina beyond the cervical os

What is respect for persons according to the belmont report?

informed consent, autonomy, protect the vulnerable, protect confidentiality

good clinical practice (GCP)

international ethical and scientific quality standard for designing, conducting, monitoring, recording, auditing, analyzing and reporting studies. Insures that the data reported is credible and accurate and that the subject's rights and confidentiality are protected

Phase I

investigates pharmacokinetics of drug- typically smaller # of subject less than 100. Tests safety, toxicity, pharmacokinetics, identify side effects, dose escalation, single dose, placebo

What was the purpose of the Nuremberg Code

protect human subjects following the Nuremberg trials in which WWII Nazis were tried for human experimentation

What was the purpose of the Belmont Report

provide basic ethical principles, boundaries between practice and research

What was the purpose of the Declaration of Helsinki

provide ethical principles for the World Medical Association

Clinical Equipoise

refers to the state in which there is an honest, professional disagreement among experts about whether the proposed study interventions should be the preferred treatment or practice. Genuine uncertainty about which intervention is better, experimental or control intervention.

Assurance

renewable permit granted by a federal department to an institution to conduce research

declaration of helsinki

statement of ethical principles first published by world medical association in 1964 to define rules for therapeutic and non-therapeutic research

food drug and cosmetic act

states only drugs, biologics and devices proven safe and effective can be marketed--1938

Clinical research

study of drug, biologic or device in human subjects with the intent to DISCOVER potential beneficial effects and/or determine its safety and efficacy.

what is justice according to the belmont report?

subject selection is fair, benefits and burdens should be justly distributed

Minimum risk

the probability and magnitude of anticipated harm or discomfort are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

minimal risk according to 21 CFR 56

the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests

National Research Act

this Act created the National Commission for Protection of Human Subjects of Biomedical and Behavioral research in 1974 and mandated review of studies by institutional review boards and subject protection by informed consent

therapeutic

treatment under investigation is BELIEVED to be likely to benefit subjects in some way

Contract Research Organization

A person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the FDA. (21 CFR, sec. 312.3)

Sponsor

A person who initiates a clinical investigation but who does not actually conduct the investigation, i.e., the test article is administered or dispensed to, or used involving, a subject under the immediate direction of another individual. A person other than the individual (e.g., corporation or agency) that uses one or more of its own employees to conduct a clinical investigation it has initiated it has initiated is considered to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators. (21 CFR, sec. 50.3)

Open system

An environment in which system access is not controlled by persons who are responsible for the content of the electronic records that are on the system. (21 CFR, Sec. 11.3)

Legally Authorized Representative (LAR)

An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedures involved in the research. (45 CFR, sec. 46.102)

Legally Authorized Representative

An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedures involved. (21 CFR, sec. 50.3)

Investigator

An individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team. (21 CFR, sec. 50.3)

Which of the following statements in a consent form is an example of language that appears to waive a subject's rights?

I waive any possibility of compensation for injuries that I may receive as a result of participation in this research.

Which of the following best describes the principle of informed consent as described in the Belmont Report?

Information, comprehension, voluntariness.

Which of the following is required at a prestudy site visit?

Evaluation of the site's capacity to conduct the study

Development of most new drugs from discovery to marketing approval usually takes:

9 years or more

Ward

A child who is placed in legal custody of the State or other agency, institution, or entity, consistent with applicable Federal, State or Local law. (21 CFR, sec. 50.3)

Assent

A child's affirmative agreement to participate in a clinical investigation. Mere failure to object may not, absent affirmative agreement, be construed as assent. (21 CFR, sec. 50.3)

Parent

A child's biological or adoptive parent. (21 CFR, sec. 50.3)

Electronic Signature

A computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be legally binding equivalent of the handwritten signature. (21 CFR, Sec. 11.3)

Custom Device

A device that 1) necessarily deviates from devices generally available 2) is not generally available to Physicians/dentists 3) not generally available in finished form for purchase or dispensing 4) is not offered for commercial distribution through labeling/advertising 5) is intended for use by an individual patient named in the order of the physician or dentist and is made to be in a specific form for that patient. (21 CFR, sec. 812.3)

Translational Device

A device that FDA considered to be a new drug or and antibiotic drug before May 28, 1976. (21 CFR, sec. 812.3)

Human Subject

A living individual about whom an investigator conducting research obtains 1)Data through intervention or interaction with the individual 2) Identifiable private information. (45 CFR, sec. 46.102)

Biometrics

A method of verifying an individual's identity based on measurement of the individual's physical features or repeatable actions where those features and or actions are both unique to that individual and measurable. (21 CFR, Sec. 11.3)

Independent Ethics Committee (IEC)

A review panel the is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection. An IRB is one type of IEC. (21 CFR, sec. 312.3)

According to ICH E6 GCP, an "Audit" is defined as:

A systematic and independent examination of trial-related activities and documents.

Which of the following reports must be filed using an Form FDA 1572?

Addition of a new investigator

Digital Signature

An electronic signature based upon cryptographic methods of originator authentication, computed by using a set of rules and a set of parameters such that the identity of the signer and the integrity of the data can be verified. (21 CFR, Sec. 11.3)

Sponsor-Investigator

An individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject. The term does not include any other person other than an individual, e.g. corporation or agency. (21 CFR, sec. 50.3)

Guardian

An individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care when general medical care includes research. (21 CFR, sec. 50.3)

Human Subject

An individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient. (21 CFR, sec. 50.3)

Significant Risk Device

An investigational device that 1) is intended as an implant and presents a potential for serious risk to the health, safety or welfare of the subject 2) is purposed or represented to be for a use in supporting or sustaining human life and presents a potential serious risk 3) is for a use of substantial importance in diagnosing, curing , mitigating or treating disease or otherwise preventing impairment of human health. (21 CFR, sec. 812.3)

IND

An investigational new drug application. Is synonymous with "Notice of Claimed Investigational Exemption for a New Drug". (21 CFR, sec. 312.3)

Institutional Review Board (IRB)

Any board, committee, or other group formally designated by an institution to review biomedical research involving humans as subjects, to approve the initiation of and conduct periodic review of such research. The term has the same meaning as the phrase institutional review committee as used in section 520(g) of the act. (21 CFR, sec. 50.3)

Electronic Record

Any combination of text, graphics, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved or distributed by a computer system. (21 CFR, Sec. 11.3)

Clinical Investigation

Any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the Food and Drug Administration under section 505(i) or 520(g) of the act, or is not subject to requirements for prior submission to the Food and Drug Administration under these sections of the Act, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. (21 CFR, sec. 50.3)

Institution

Any public or private entity or agency (including Federal, State or other agencies). The word facility as used in section 520(g) of the Act is deemed to by synonymous with the term institution for purposes of this part.(21 CFR, sec. 50.3)

The FDA requires retention of investigational drug study records for:

At least two years after the investigational drug's approval by the FDA.

A double-blinded trial for a new indication is conducted under an IND comparing 2 marketed drugs, at twice the approved prescribed doses. On Day 2, subject 603 had difficulty breathing. Although it was life-threatening initially, subject 603 was treated and discharged directly from the emergency department after complete recovery. On Day 5, subject 20 had a headache, which led to hospitalization and required blood pressure lowering medications. These episodes cannot be explained on the basis of the pharmacological property of either drug or the subjects' medical histories. The investigator would submit an SAE report for:

Both of the subjects.

Which of the following is an example of how the Principle of Beneficence can be applied to a study employing human subjects?

Determining that the study has maximized benefits and minimized risks.

A 46-year-old man is currently enrolled in a phase III study of a drug for severe diabetic neuropathy. While the study is ongoing, a new drug becomes commercially available that may have equal or greater benefit to the subject. The investigator should do which of the following?

Discuss the pros and cons of both the investigational drug and the commercially available drug and then allow the subject to decide whether to withdraw from the research to take the new drug

Which of the following is an important component of drug accountability?

Drug shipping and disposition records

When must the investigator update the IRB about the progress of a trial?

During the conduct of the study and at termination

The overall goal of monitoring, audits, and inspection activities is to:

Ensure the protection of human research subjects and data integrity.

Accurate reporting of adverse events is most important for:

Ensuring subject safety.

In terms of explaining the probability of assignment to trial arms in consent forms, which is true?

ICH notes that it should be included, but does not specify how the information should be presented.

When the sponsor-investigator holds the IND for an investigational drug he or she is responsible for annual reporting of which one of the following to FDA?

IND report

Which of the following should take place during periodic site visits?

Identification of protocol violations

The new ICH E6 integrated addendum (R2) requires sponsors to implement systems to manage quality throughout all stages of the trial process. The system should use a risk-based approach including which of the following?

Identification of study risks to determine which may safely be omitted from continual monitoring.

Where is information on storage requirements for the investigational product usually found?

In the study protocol

What is the legal status of ICH in U.S.?

It is a FDA guidance

Minimal Risk

Means that the probability and magnitude of harm or discomfort anticipated in the research are no greater in an of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. (21 CFR, sec. 50.3)

Children

Persons who have not attained the legal age for consent to treatment or procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the clinical investigation will be conducted. (21 CFR, sec. 50.3)

Pharmacokinetics and pharmacodynamics of a new formulation of an investigational drug most likely refers to which clinical phase of a study in humans?

Phase I

The first randomized, controlled study of an experimental drug versus aspirin for postoperative pain control will enroll 55 subjects in each arm. Which of the following best describes the clinical phase of this study?

Phase II

Adults with more than a 12-month history of migraines were assigned randomly in a double-blinded study to receive treatment with experimental drug X (10 or 20 mg/day) or placebo. The primary efficacy measure was the reduction in severity of the migraine attacks. Enrollment was 1200 subjects. Which of the following best describes the clinical phase of this study?

Phase III

Long-term toxicology of an experimental drug in animals most likely refers to which part of drug development?

Preclinical

For a phase I new drug study in humans, what is the primary source of the data included in the initial Investigator's Brochure?

Preclinical data

Which monitoring visit would NOT include an inventory of investigational agents?

Prestudy site visit

A subject presents to the emergency department (ED) with complaints of chest pain and shortness of breath. Blood studies are positive for a heart attack and the subject is hospitalized. The subject has a history of coronary artery disease. The subject reports to the ED nurse that he is currently enrolled in a phase I study of a new lipid lowering agent. Which individual should determine causality of the serious adverse event?

Principal Investigator

A subject is a passenger in a car involved in a motor vehicle crash. The subject sustained a broken wrist and mild concussion. The subject was treated and released from the emergency department. What should the investigator do when learning of the crash?

Report adverse events of both a broken wrist and a mild concussion.

Subject 311 has had elevated white blood cell (WBC) counts for the past 2 study visits, with no clinical signs or symptoms. "Increased WBC count" is not listed in the Investigator's Brochure (IB) as an adverse event. The investigator should:

Report the elevated WBC to the sponsor as an unexpected adverse effect.

If the FDA Investigator issues a FDA Form 483 after an inspection, the clinical investigator should:

Respond in writing to the FDA within 15 business days

When the FDA conducts an inspection, the inspectors will:

Review regulatory records.

The ICH GCP Guidelines:

Set standards for the design, conduct, monitoring and reporting of clinical research.

Permission

The agreement of the parent(s) or guardian to the participation of their child or ward in a clinical investigation. Permission must be obtained in compliance with part 50 subpart B and must include all the elements of the informed consent. (21 CFR, sec. 50.3)

When should the sponsor-monitor conduct the most detailed review of the study protocol with the site's study staff?

Site initiation visit

The investigator must report adverse events to the:

Sponsor.

During the course of administration of an investigational drug, the following events occur: On Day 7, subject 603 has an unexpected stroke that requires hospitalization. On Day 15, subject 415 complains of nausea, vomiting, and headache relieved by aspirin. On Day 21, subject 20 has brief dizzy spells upon trying to stand. An IND Safety Report is most likely filed by the sponsor with the FDA for the observations associated with:

Subject 603 only

Which of the following is an investigator's commitment to the sponsor?

Submit a new Form FDA 1572 to sponsor as needed

Act

The Food, Drug and Cosmetic Act, as amended.

IRB Approval

The determination of the IRB that the clinical investigation has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and federal Requirements. (21 CFR, sec. 56.102)

An investigator is confronted with a life-threatening situation that necessitates using a test article in a human subject who is unable to provide informed consent and there is no time to obtain consent from the individual's legal representative. Under the FDA regulations, which of the following describes the best course of action for the investigator:

The investigator and another physician who is not part of the study team agree that the situation necessitates the use of the test article and the IRB will be notified later.

Certification

The official notification by the institution to the supporting department or agency, in accordance with the requirements of this policy, that a research project or activity involving human subjects has been reviewed and approved by an IRB in accordance with an approved assurance. (45 CFR, sec. 46.102)

Handwritten Signature

The scripted name or legal mark of an individual handwritten by that individual. (21 CFR, Sec. 11.3)

Identify which party is responsible for reporting directly to the FDA the investigator's financial interests with the sponsor:

The sponsor

Which of the following is a criterion for determining if a study of an approved drug is exempt from the require of an IND?

The study is not intended to be reported to FDA to support a new indication or support a labeling change.

When evaluating the causality of an adverse event, which of the following should be a consideration?

The timing of the event in relation to administration of the investigational agent

Emergency Use

The use of a test article on a human subject in a life-threatening situation in which no standard acceptable treatment is available, and in which there is no sufficient time to obtain IRB approval. (21 CFR, sec. 56.102)

In the United States, following the ICH E6 GCP is:

Voluntary for FDA-regulated drug studies.

Monitor

When used as a noun, means an individual designated by a sponsor or contract research organization to oversee the progress of and investigation. When used as a verb, means to oversee and investigation. (21 CFR, sec. 812.3)