SOCRA Practice 2

Beneficience

-Do not harm -Maximize possible benefits while minimizing possible harms

Oral Consent

-Done with subject or LAR cannot read and understand the written approved consent form. A short form version which is approved by the IRB may be used. It states that all required elements of informed consent (21 CRF Part 50.25) have been presented verbally. -A witness must be present for oral consent. Only short form signed by subjects/lar. Witness will sign both. Person performing consent will sign copy of the summary.

5 classes of products that informed consent regulations apply to

-Drugs -Medical devices -Biological Products -Electronic products -Food -Color additives

Standard Operating Procedures (SOPs)

-Ensure that the site has consistent processes that meet or exceed regulatory and GCP standards and that all employees are familiar with the process -A clearly written description of how a particular task is to be performed

Class III Device

-Highest Risk -PMA usually required -Heart valves, breast implants, pacemakers

ICH GCP guidelines

-ICH developed GCP guidelines on 4/30/1966 -Guidelines developed in consideration of current GCPs of the EU, Japan, and US as well as Australia, Canada, Nordic countries, and WHO. -Compliance to guidelines provides public assurance that the rights, safety, and well-being of trial subjects are protected and that the clinical trial data are credible.

Official Action Indicated (OAI)

-Identifies serious deviations, requires prompt action. -FDA may also inform sponsor and IRB and issue a warning letter.

Primary reason to close a study

-It is completed and finished. -Enrollment has stopped, all subjects have completed their activities, and the data is complete and correct

3 Regulatory agency sponsors of ICH

-Japan -US -European Union

Which of the following are necessary to satisfy 21CFR50.24 Subpart B?

- The Clinical investigation could not practicably be carried out without the waiver. - The human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include evidence obtained through randomized placebo-controlled investigations, is necessary to determine the safety and effectiveness particular interventions. - Participation in the research holds out the prospect of direct benefit to the subjects - as described in 21CFR50.24 - Obtaining informed consents not feasible - as described in 21CFR50.24. - The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence and the investigator has committed to attempting to contact a legally authorized representative for each subject within that window of time and if feasible, to asking the legally authorized representative contacted for consent within that window rather than proceeding without consent.

Oral consent requirements

- 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

Justice

-"Fairness of distribution" or "What is Deserved" -To each person an equal share (Fair procedures/outcomes in the selection of subjects)

Nonclinical Study

-A biomedical study not performed on human subjects. -Purpose is to provide information on safety and efficacy -Focuses on collecting data and information to establish that humans will not be exposed to unreasonable risks in early phase clinical trials.

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. -Standardizes the collection of study data and helps to ensure that the medical, statistical, regulatory, and data management needs of the study are met.

Informed Consent

-A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form. -MUST be written at a 6th or 8th grade level

Independent Ethics Committee (IEC)

-A review panel that 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 independent body (or review board, committee, institution, regional or national or supranational) of constitutes (medical professionals and non-medical professionals), whose responsibility it is to ensure that 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 favorable opinion on the trial protocol, the suitability of the investigator's facilities and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

IND withdrawal

-A sponsor may withdraw at any time by notifying the FDA and stopping all studies and notifying investigators.

Permission

-Agreement of the parent(s) or gaurdian to the participation of their child or ward in a clinical trial. -Must be obtained in compliance with 45 CFR 46 Part D and must include all the elements of an ICF.

IND Safety Reports (21 CFR Part 312.32)

-An SAE leads to an IND -Used for report of adverse experience associated with the use of the drug that is both serious and unexpected (Not in IB), or, for any findings from tests in laboratory animals that suggests and significant risk for human subjects. -Required that the Sponsor must notify the FDA and all participating Investigators no later than 15 calendar days after the sponsors initial receipt of the information.

Digital Signature

-An electronic signature based upon cryptographic methods of originator authentication. -Computed by using a set of rules and parameters such that the identity of the signer and the integrity of that data can be verified.

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.

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. -The responsible leader of a team in the event of an investigation.

Human Subjects

-An individual whom an investigator conducting research obtains data through interpretation or interaction and identifiable private information. -An individual who is or becomes a participant in research, either as a recipient of the test article or as a control.

Significant Risk Device

-An investigational device that is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of the subject -Is proposed or represented to used in supporting or sustaining human life and presents a potential serious risk. -Is used for substantial importance, diagnosing, curing, mitigating, or treating disease or otherwise impairment of human health.

IND contain:

-Animal pharmacology and toxicology studies -Any previous experience with the drug in humans -Manufacturing information -Clinical protocols and investigator information

Amendments

-Any changes in a phase I trial that significantly affects safety of subjects -Any changes in a phase II or III trial that affects safety of subjects scope of investigation or scientific quality of study -When a new investigator is added -When there is a change to the chemistry, microbiology, pharmacology, or toxicology

Investigator Reporting Responsibilities

-Any changes or amendments -Any increased risk -Immediately reportable AEs -Unanticipated problems that involve risk to subjects -Annual progress reports (continuing reviews)

Clinical Investigation

-Any experiment that involves a test article and one or more human subjects. -Subject to requirements for prior submission to the FDA under section 505 (i) or 520(g) of the act, or is not subject to requirements for prior submission to the FDA under these sections of the act, but the results of which are intended to be submitted later on, or will be held for inspection by the FDA as part of an application for research or marketing permit.

Site Closure Visit

-Conducted when the study is over, but may occur if the site is withdrawing from the study. -Conducted after query resolution is complete. -Perform drug accountability -Regs - 2 years after NDA approval or Non-approval or discontinuation of IND -Industry standard 15 years -MUST notify sponsor prior to moving documents to different storage area and prior to disposal. -Final report to IRB

Phase 3 Clinical Trials are conducted to:

-Confirmation of short-term efficacy and establish long term efficacy -Establish benefit-risk relationship -Provide adequate basis for labeling -Several hundred to several thousand subjects

Phase II Clinical Trials

-Controlled studies conducted to evaluate the effectiveness of the drug for a particular.indication(s) in patients with the disease/condition under study. -Well-controlled, closely monitored -Determines common short-term side effects and risks associated with the drug. -Relatively small total number of subjects usually no more than several hundred.

HIPAA

-Created in 2003 -Health Insurance Portability and Accountability Act -Protect individual rights to control access to and disclosure of private and confidential information and to ensure continuity of coverage between health insurance plans -See CFR 160 and 164

Investigator must submit their _________ to the IRB

-Current CV with their qualifications for conducting research -Study protocol -Investigator brochure -Proposed informed consent -Subject advertisement and recruitment procedures -1572 -Grant application if federally funded -Any other materials required by the IRB

Noninvasive diagnostic device or procedure

-DOES NOT penetrate the skin -enters the body through the external auditory canals, nose beyond nares, mouth beyond pharynx, and the anal canal beyond the rectum

Ten Directives for Human Experimentation

1 All unnecessary physical and mental suffering and injury should be avoided. 2 Voluntary consent of the human subject is absolutely essential. 3 The experiment must yield generalizable knowledge that could not be obtained in any other way and is not random and unnecessary in nature. 4 Animal experimentation should precede human experimentation 5 No experiment should be conducted if there is reason to believe that death or disabling injury will occur. 6 The degree of risk to subjects should never exceed the humanitarian importance of the problem. 7 Risks to the subjects should be minimized through proper preparations. 8 Experiments should only be conducted by scientifically qualified investigators. 9 Subjects should always be at liberty to withdraw from experiments. 10 Investigators must be ready to end the experiment at any stage if there is cause to believe that continuing the experiment is likely to result in injury, disability or death to the subject.

Test Calculations

1 kilogram = 2.2 lbs 1 inch = 2.53 cm % of something = decrease dose

How long does the investigator need to disclose relevant financial information to the sponsor after the completion of a study?

1 year (sponsor then needs to update info with FDA.

What must a Sponsor do if they determine that investigational product presents significant and unreasonable risk to Subjects?

1) Immediately discontinue all studies that present risk 2) Report to FDA and IRB 3) Assure return and accounting for all investigational products/devices

Elements of consent

1) PURPOSES 2) FORESEEABLE RISKS OR DISCOMFORTS 3) BENEFITS 4) ALTERNATIVE PROCEDURES or courses of treatment 5) CONFIDENTIALITY 6) COMPENSATION & ans explanation as to weather any medical treatment are available if injury occurs 7) Whom to CONTACT FOR ANSWERS 8) VOLUNTARY

What are the clinical development stages for devices?

1) Pilot Study 2) Pivotal Study 3) Post-market studies Compared to drugs and biologics, which typically have 1000's of subjects, device studies usually have 100's of subjects

Waiver of Consent

1) The research involves no more than minimal risk to the subjects; (2) The waiver or alteration will not adversely affect the rights and welfare of the subjects; (3) The research could not practicably be carried out without the waiver or alteration; and (4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

Additional Elements of Consent

1) UNFORESEEABLE RISK 2) Subjects participating may be TERMINATED by the investigator with out regard to the subject consent 3) ANY ADDITIONAL COSTS to the subject 4) CONSEQUENCES IF subject withdraw 5) Statement that Significant New Findings developed during the course of the research 6) NUMBER OF SUBJECTS involved in the study 7) As required by US law register clinical investigation to WWW.CLINICALTRIALS.GOV 8) Follow Federal, State and Local Laws 9)Nothing in these regulations is intended to limit the authority for a Dr to provide emergency medical care

What are the Monitor's responsibilities?

1) Verify that the rights and well being of Subjects are protected 2) Verify that the reported trial data are accurate, complete and verifiable 3) Verify that study is being conducted in accordance with GCP and protocol

16.36. For federally funded research, minutes of IRB meetings are required to include sufficient information to define which items?

1). Attendance at the meetings. 2). Actions taken by the IRB, including the vote with the number of members voting for, against, and abstaining. 3). The basis for requiring changes in or disapproving research. 4). A written summary of the discussion of controverted issues and their resolution.

16.30. The IRB must pay particular attention to ensure additional safeguards have been taken for vulnerable subjects in federally supported research. List at least three groups of vulnerable subjects of concern.

1). Children. 2). Prisoners. 3). Pregnant women. 4). Mentally disabled persons. 5). Economically or educationally disadvantaged persons.

16.51. An IRB can waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds one of two conditions are present. Name these conditions.

1). The only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. 2). The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

16.61. No pregnant woman is allowed to participate as a subject in a research study unless what conditions are present?

1). The purpose of the research is to meet the health needs of the mother while minimizing the health risks to the fetus. 2). The risk to the fetus is minimal.

16.43. When obtaining informed consent from prospective research subjects, investigators are required to ensure certain circumstances or conditions are present. Name these circumstances or conditions.

1). The subject has sufficient opportunity to consider whether to participate. 2). The possibility that coercion or undue influence is minimized.

5-156 What types of early consultation meetings are usually available for IND's to evaluate life-threatening or severely debilitating illnesses? 21 CFR 312.82

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.

5-140 What action may the FDA take with a investigator, following receipt of his/her explanation of a compliance complaint?

1. Accept the explanation and terminate the disqualification process. 2. Not accept the explanation and offer the investigator an opportunity for a regulatory hearing on the question of whether he/she is entitled to receive investigational drugs. 21 CFR 812.119

Monitoring Responsibilities

1. Collecting 1572 forms 2. Investigator selection 3. Facilities assessment 4. Delegation of responsibilities at the site 5. Confirmation of IB review of protocol 6. Ensuring record access at the site 7. Management of study suspension by IRB or DSMB

7 types of records the IRB must keep:

1. Copies of all research proposals reviewed, scientific evaluations, approved sample consent documents, progress reports submitted by investigators, and reports of injuries to subjects. 2. Minutes of IRB meetings to show attendance at the meetings; actions taken; the vote on these actions; the basis for requiring changes in or disapproving research; A written summary of the discussion of controverted issues and their resolution. 3. Records of continuing review activities. 4. Copies of all correspondence between the IRB and the investigators 5. A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc. 6. Written procedures for the IRB 7. Statements of significant new findings provided to subjects

What qualifies for a Serious Adverse Event (SAE - 21 CFR 312)

1. Death 2. life-threatening 3. Inpatient hospitalization (or prolonged) 4. Persistent incapacity 5. Congenital abnormality Examples: allergic bronchospasm to ER, convulsions, blood dyscrasias, drug dependency NOTE: if not listed in the IB, it is also an "unexpected event" = UE. See page 85 for UE discussion.

What 3 things must an IND waiver include?

1. Explanation why the sponsor's compliance is unnecessary or can't be achieved. 2. Description of alternative submission. 3. Any other information the FDA requests to justify the waiver.

Sponsor Responsibilities

1. MEDICAL EXPERTISE- falls on Sponsor 2. Protocol prep, protocol updates, clin trial design 3. Preparation of IB and updates 4. CRF development may be done by sponsor or CRO 5. Manufacture of product and supply of product 6. Determining storage, admin, packaging, formulation changes 7. Prep of pharmacy manual 8. Product labeling as "For investigational use only- not for routine clinical use" 9. Drug destruction may be done by sponsor, or delegated to CRO , or delegated to a third party drug management entity. 10. May dictate that unused drug be returned to the sponsor, or destroyed by mechanisms by above 11. DSMB collection and management-- collected by sponsor, then sent to CRO, then to sites, to IRB

Sponsor Responsibilities

1. Maintain an effective IND or IDE 2. Ensure studies are conducted according to the general investigative plan and protocols in IND/IDE 3. Promptly report adverse events 4. Select qualified Investigators 5. Provide information such as: investigative brochure 6. Ensure proper monitoring (medical monitor, DSMB, on-site monitoring) 7. Manufacture and label drug/device

Sponsor may charge for an IND if:

1. Sponsor has authorization from FDA 2. must provide evidence that the drug would provide a significant clinical advantage over other available options 3. able to demonstrate that data to be obtained from the trial is essential 4. able to demonstrate that the trial could not be done without charging because the cost is extraordinary to sponsor

Roles of CRO

1. Sponsors may transfer all of sponsor's duties/ functions to CRO (must be in writing) 2. RESPONSIBLE FOR DATA QUALITY, DATA INTEGRITY 3. FORM 1571: Identity and role of CRO must be specified by sponsor 4. DISTRIBUTE IB and IB updates/ protocol updates and changes 5. CRF development may be done by sponsor or CRO 6. Distributing product to sites 7. Drug destruction may be done by sponsor, or delegated to CRO , or delegated to a third party drug management entity. 8. Monitoring responsibilities 9. Monitoring accuracy of data collection, timeliness and completeness of procedures 10. Presenting collected data to sponsor for eventual submission to FDA 11. Monitoring reg binder and lab component 12. Managing payment to sites 13. Managing randomization process- incl. IVRS 14. SAE reported by CRO to sponsor 15. CRO NOT RESPONSIBLE FOR ANY DSMB MANAGEMENT

5-53 Under what 3 conditions must a sponsor submit an IDE application to the FDA?

1. The investigation involves a significant risk device. 2. The investigation involves an exemption from informed consent criteria under 21 CFR 50.24 3. The FDA notifies the sponsor that an IDE application is required for an investigation. 21 CFR 812.20.

5-164 Name 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

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.

5-148 State the specific documentation records an investigator must retain related to the use or disposition of a device.

1. Type and quantity of the device, the date(s) of its receipt, and batch number or code mark. 2. Names of all persons who received, used, or disposed of the device. 3. Why and how many of the units of the device have been returned to the sponsor, repaired, or otherwise disposed of. 21 CFR 812.140

Non-fatal or not life-threatening SAEs must be reported within

15 Calendar days

How many days does Physician or Sponsor have to submit written summary of expanded access to the FDA after use?

15 days

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.

15-146 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.

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.

17-1 To what types of products does the FDA Guideline for the Monitoring of Clinical Investigations apply?

17-1 Drugs, biological products, and devices.

17-4 What are the FDA's recommendation regarding the sponsor's preparation and maintenance of written monitoring procedures?

17-1 Sponsors should have general written monitoring procedures that cover all studies; these should be supplemented by more specific procedures tailored to individual studies.

17-10 Which method should monitors use to ensure that information submitted to sponsors by investigators is accurate?

17-10 Comparison of individual subject records and other supporting documentations with the reports being submitted to a sponsor.

17-11 List two of the five data verifications that monitors should perform during monitoring visits.

17-11 1. No data is missing. 2. Data is accurate, complete, and legible. 3. Missing visits or examinations are documented. 4. Reasons are reported for any subject who failed to complete the study. 5. Informed consent was properly documented.

17-12 List two of the four recommended components that should be included in a sponsor's monitoring report following a visit with an investigator.

17-12 1. Name of the visiting monitor. 2. Visit date. 3. Name and address of the investigator visited. 4. Findings, conclusions, and actions taken to correct any noted deficiencies.

17-2 What is FDA's guideline regarding involvement of a monitor who is qualified to diagnose and treat the disease or condition which is being investigated?

17-2 Person so qualified need not be the actual monitor, but should be directly involved in the review of the study data.

17-3 List two recommended factors that should be used by sponsors to determine the number and qualifications of monitors.

17-3 1. Complexity of the study. 2. Number of Investigators. 3. Number and location of facilities. 4. Type of product in the study. 5. The nature of the disease or condition being studied.

17-5 What is the general purpose of a pre-investigation visit as defined in the FDA guidelines.

17-5 Assure that an investigator has adequate facilities and staff, understands the study plan, and is aware of all of his or her obligations with respect to conducting the study.

17-6 What is a recommended frequency/occurrence for monitoring visits by sponsors of a clinical investigation?

17-6 Sponsors should make periodic visits at frequent enough intervals to determine that the investigator is meeting their obligations in the study.

17-7 Name who is responsible for ensuring that accurate and complete records are kept of subject participation in a clinical study?

17-7 Investigator and monitor on behalf of a sponsor.

17-8 What should a monitor evaluate with respect to an investigator's facilities prior to and during an investigation?

17-8 Adequacy of the facilities as required by a particular study.

17-9 Who is responsible to ensure data submitted in an NDA is accurate and complete?

17-9 Sponsor.

Describe the food and drugs act Including year.

1906. prohibited interstate transfer of mis branded food drinks and drugs. Wiley's act Made the bureau of chemistry, the FDA's predecessor, responsible for this. Not known as the FDA until 1930

When did the Tuskegee Experiments take place?

1932-1972

What year was the Sulfanilamide disaster?

1937

What federal act required new drugs to demonstrate safety before marketing?

1938 Food Drug and Cosmetics Act

What led to 21CFR Chapter 1?

1938 Food Drug and Cosmetics Act In reaction to the 1937 Sulfanilamide Disaster

Exceptions from consent

-Research involving the individual's emergency use of a test article in a single individual -Emergency research exception - involves entire studies -Individual exceptions (life-threatening situation) -Only allowed by IRB with an agreement from a licensed physician not associated with the research

21 CFR Part 20.25 (8 requirements of consent)

-Research is involved -Contact info (IRB, Investigator, Sponsor) -Treatment alternatives -Risks and discomforts -Benefits -Voluntary Participation -Confidentiality of records -Compensation being offered/not offered

What are the 3 Principles of Belmont Report?

-Respect for Persons -Beneficence -Justice

Three Ethical Principles of The Belmont Report

-Respect for persons [consent] -Beneficence [do not harm, studies of max benefits to society/systematic assessment of risks and benefits] -Justice [fairness of distribution of research, equitable selection of Subjects]

Describe: Food drug and cosmetic act

1938. Precipitated by elixir of sulfanilamide . Diethylene glycol was used in a children's medication . Pre market approval of drugs was required for the 1st time.

When was the Federal Food, Drug, and Cosmetic Act established & why?

1938; to establish the FDA's jurisdiction over cosmetic and medical devices in the US.

What year was The Nuremburg Code established?

1949

What year was the Declaration of Helsinki established?

1964

Describe the year-and character of the declaration of Helsinki

1964. World Medical Association

What year was the National Research Act passed by Congress?

1974

What year did they amend the Federal Food Drug and Cosmetic act specifically for medical devices?

1976

What year was the Belmont Report established?

1979

What year was the Belmont report published AND what are the basic principles

1979 - Respect for Persons, Beneficence and Justice. Followed National Research Act of 1774, which established IRB requirement. Both followed outrage over Tuskegee;

How long should study Sponsor/Investigator keep documents upon completion of a trial?

2 years

Retain the records and reports required by this part for

2 years after a marketing application is approved for the drug

If an application is not approved, until

2 years after shipment the drug is discontinued and FDA has been notified

Record retention: if no application is to be filed or if the application is not approved for such indication, until

2 years after the investigation is discontinued and FDA is notified

Essential documents should be retained at least

2 years after the last approval of a marketing application or formal discontinuation of clinical development of the investigational product

Record retention: retain records for a period of

2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated

1 kilogram (kg) = ___ lbs

2.2

1 inch = ___cm

2.53

Which CFR # deals with marketing a new drug

21 CFR PART 314 APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

21 CFR Part 312 vs 21 CFR Part 812

21 CFR Part 312 = FDA Form 1572 21 CFR Part 812 = Investigational Agreement 21 CFR Part 312 = Serious Adverse Event 21 CFR Part 812 = Unanticipated Adverse Device Effects

In what section of the federal regulations are IND Safety Reports?

21 CFR Part 312.32

IRB may waive consent under which rule

21 CRF 50.24 Emergency Research

The Code of Federal Regulations that applies to Electronic Records; Electronic Signatures is...

21CFR11

The Code of Federal Regulation that applies to Investigational New Drug Applications is....

21CFR312

Which of the following is IRB Functions and Regulations?

21CFR56.108 Subpart C

Henry K. Beecher Paper - 1966

22 published medical studies where patients had been experimented on with no expected benefit to the patient Evidence presented that unethical studies were widespread and represented a systemic problem in medical research rather than exceptions

How many copies of a research application must be submitted to the FDA?

3

The IRB records shall be retained for _____ years after the completion of research.

3

How long must IRB records be retained?

3 years

How long should IRB retain all relevant records upon completion of a trial?

3 years

IRB Retains records for how long after completion

3 years

An IND goes into effect

30 after FDA receives the IND, unless the FDA notifies the sponsor that investigations are subject to a clinical hold

How long is the waiting period before a treatment IND study can be initiated?

30 days

FDA will notify A sponsor in writing once an IDE has been RECEIVED. FDA may or may not send notice of approval (FDA will always notify in writing of disapproval or if they need more info or modifications)so an investigation may begin when:

30 days have passed from the application submission or when/if the FDA approves the IDE in writing.

General content of 300 & 800 Series regulations

300 series :Drug regulations 800 Series: Device Regulations

Certification of Financial Interests

3454

Financial Disclosure Form

3455

Which form discloses financial interests of investigators?

3455

Exempted Investigations

4) A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk (5) A device intended solely for veterinary use (6) A device shipped solely for research on or with laboratory animals and labeled accordingly (7) A custom device, unless the device is being used to determine safety or effectiveness for commercial distribution

What does Subpart D deal with? (21 CFR 50.50 or 45 CFR Part 46)

45 CFR Part 46, Subpart D - Additional Protections for Children (Also 21 CFR 50.50, Subpart D)

What CRF code is known as the "common rule"

45 CRF 46 Part A

The Code of Federal Regulations that applies to the Protection of Human Subjects is:

45CFR46

Per ICH guidelines, IRB must

-Retain records for 3 years. -Follow written procedures. -be audited by regulatory authorities -be held responsible for having appropriate written procedures and for following them.

Additional Informed Consent Sections

-Risks to EMBRYO/FETUS -TERMINATION procedures -COST to study subjects -NUMBER of study subjects -STATEMENT OF NEW FINDINGS if they may impact a patient's willingness to participate.

1. What is the minimum number of Institutional Review board (IRB) members?

5

How many Board Members must an IRB have?

5

What is the minimum number of institutional Review Board (IRB) members?

5

What is the minimum number of members required to form an IRB committee?

5

How many members for IRB

5 Memebers

How many days do you have to report a deviation from an investigational device plan to Sponsor and IRB, and why?

5 days. Deviations are to protect human life or physical well-being.

If ICF is not signed, it must be reported to the IRB within:

5 working days

Significant risk device determinations. If an IRB determines that a device is a significant risk device, and the sponsor had proposed that the IRB consider the device not to be a significant risk device, the sponsor shall submit to FDA a report of the IRB's determination within

5 working days after the sponsor first learns of the IRB's determination.

If an unanticipated adverse device effect presents an unreasonable risk to subjects the sponsor shall terminate all investigations or parts of investigations presenting that risk as soon as possible. Termination shall occur not later than

5 working days after the sponsor makes this determination and not later than 15 working days after the sponsor first received notice of the effect

Retain reserve samples of any test article and reference standard identified in, and used in any of the bioequivalence or bioavailability studies, and release the reserve samples to FDA upon request, in accordance with, and for the period

5 years

Fatal or life-threatening SAEs must be reported within

7 Calendar days

Life threatening event report

7 calendar days to FDA

7. Responsibility for the participant's safety lies with:

7. Responsibility for the participant's safety lies with: a. The sponsor b. The investigator c. The IRB d. All of the above

2. The initial drug dose is 110mg/m2. Due to toxicity, the drug needs to be decreased by 30%. The new dosage would be?

77

The initial Drug Does is 110 mg/m2. Due to toxicity, the drug needs to be decreased by 30%. The new dosage would be?

77

Record Retention

A SPONSOR shall retain the records and reports for 2 years after a marketing application is approved for the drug; or, if an application is not approved for the drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued and FDA has been so notified.

Biologics

A biological produce mean any virus, therapeutic serum, toxin, or antitoxin, or analogous product applicable to the prevention, treatment, cure of disease or injuries. Requires informed consent.

Ward

A child who is placed in legal custody of the state or other agency, institution, or entity consistent with applicable state or federal laws.

Assent

A child's affirmative agreement to participate in a clinical investigation.

16.68. What is the DHHS definition of "assent" by a child?

A child's affirmative agreement to participate in research. Mere failure to object, absent of affirmative agreement, should not be construed as assent.

What is a clinical hold?

A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. §312.42

Multicenter Trial

A clinical trial conducted according to a single protocol but at more than one site, therefore by more than one investigator

Data Safety Monitoring Board (DSMB)

A committee of scientists who are not associated with the conduct of a study who evaluate AES at regularly scheduled intervals during the course of a study and provide feedback to the investigator and the IRB regarding continuation of a study as planned

Monitoring

-The overall purpose is to verify the rights and well-being of human subjects are protected. -Ensure that the study is conducted in compliance with study protocol, GCP guidelines, applicable regulations

Investigator's Brochure

A compilation of the clinical and nonclinical data on the IP which is relevant to the study of the IP in human subjects.

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.

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.

Electronic Signature

A computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual's handwritten signature.

Electronic Signature:

A computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual's handwritten signature.

Audit Certificate

A declaration of the confirmation by the auditor that the audit has taken place.

Required Element: (All Studies):

A description of any benefits to the subject or to others, which may reasonably be expected from the research

Required Element: (All Studies):

A description of any reasonably foreseeable risks or discomforts to the subject

Required Element: (All Studies):

A description of the procedures to be followed.

Custom device

A device intended for use by an individual patient named in the order of a physician or dentist, and is to be made in a specific form for that patient

Transitional device

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

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 30 days or more.

Transitional Device

A device that the FDA considers to be a new drug or an antibiotic drug before May 28th, 1976

15-23 According to the FDA's IDE regulations, please define 'investigational device'.

A device, including a transitional device, that is the object of an investigation.

Investigational Device

A device, including a transitional device, that is the object of the investigation

Required Element: (All Studies):

A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.

5-155 What is the FDA'S definition of a "severely debilitating" disease? 21 CFR 312.81

A disease or condition that may cause irreversible morbidity

Monitoring Plan

A document that describes the strategy, methods, responsibilities, and requirements for monitoring the trial.

What is a "double-dummy" study?

A form of double-blind study called a "double-dummy" design allows additional insurance against bias. In this kind of study, all patients are given both placebo and active doses in alternating periods.

Biometrics

A method of verifying an individual's identity based on measurement of the individual's physical feature(s) or repeatable action(s) where those features and/or actions are both unique to that individual and measurable.

Source documents

-any document where the data are first recorded -Verifies subject exists and verifies data in the CRF is consistent with the information found in source documents

Custom Device

-necessarily deviates from devices generally available to physicians -not fully available to physicians -not available in finished form for purchasing or dispensing -not offered through labeling/advertising commercially -intended for use by an individual patient and is made in a specific form for the patient

IRBs needs

-ongoing plan for sponsor safety, and monitoring of data with goal of ensuring the safety of the subject during the research. -adequate provisions in the research to protect the privacy of the research subjects and maintenance of confidentiality of the data. -outline of planned compensation to ensure that it does not constitute an undue influence, or coercion, that could influence the subject's decision to participate. -outline of proposed advertising to ensure it does not make misleading or untruthful claims and it does not constitute undue influence.

Favorable reasons to close a study

-the treatment was beneficial, overall enrollment was met

HOW MANY DAYS TO REPORT after emergency use of an unapproved article

.• Within 5 days use must be reviewed by outside physician and submitted to IRB • President may waive military use

2.2 lbs = ___ kg

1

2.53 cm = ___ inch

1

Impartial Witness

A person 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 informed consent form and any other written information supplied to the subject.

Sponsor

A person or other entity that initiates a clinical investigation, but that does not actually conduct the investigation

Sponsor

A person who initiates a clinical investigation but who does not actually conduct the investigation.

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.

Investigational Product

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, 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.

Blinding/Masking

A procedure in which one or more parties to the trial are kept unaware of the treatment assignment.

Randomization

A process of randomly assigning subjects to different treatment groups

Interim Clinical Trial

A report of intermediate results and their evaluation based on analyses performed during the course of the trials.

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.

Protocols involving an exception to Informed consent must:

A separate IND or IDE that clearly identifies such protocols that may include subjects that are unable to consent

The Nuremberg Code

A set of 10 ethical principles for human experimentation developed in 1947. Physicians were conducting trials on prisoners in concentration camps.

A sponsor must obtain prior written authorization from FDA to charge for an investigational drug

A sponsor may recover only the direct costs of making its investigational drug available.

What are the steps for withdrawing and IND? 21 CFR Part 312.38

A sponsor may withdraw an IND at any time without prejudice by: -Notifying the FDA. -Stopping all studies and notifying the Investigators -Returning all drug to the Sponsor, or destroying all drug as directed by Sponsor. -If the study is withdrawn for safety reasons, the Sponsor must notify Investigators and the IRBs.

Good Clinical Practice:

A standard for designing, conducting, performing, monitoring, auditing, recording, analyzing, and reporting clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected

Good Clinical Practice (GCP)

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credibly and accurate, and that the rights, integrity, and confidentiality of the trial subjects are protected.

Good Clinical Practice

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and results are credible and accurate and that the rights, integrity, and confidentiality of subjects are protected.

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.

Required Element: (All Studies):

A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained.

Required Element if FDA Regulated Research:

A statement that notes the possibility that the Food and Drug Administration may inspect the records.

Required Element: (All Studies):

A statement that participation is voluntary.

Required Element: (All Studies):

A statement that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled.

Required Element: (All Studies):

A statement that the study involves research.

Required Element: (All Studies):

A statement that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

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 recorded, analyzed and accurately reported according to the protocol, sponsor SOPs, GCP, and the applicable regulatory requirements.

Expedited Review

A type of review by an institutional review board that can occur quickly; an IRB may conduct an expedited review if there is minimal risk to human subjects

Protocol Amendment

A written description of changes to, or formal clarification, of a protocol.

Audit Report

A written evaluation by the sponsor's auditor of the results of the audit.

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.

What is the acronym to remember for good source documentation

ALCOA- data should be attributable, legible, contemporaneous, original and accurate

How soon should a fatal or life-threatening experience associated with investigational drug be reported?

ASAP but within 7 days. Full report should be supplied no later than 15 days.

What are the abbreviated requirements for device studies? 21 CFR Part 812.2(b)

Abbreviated Requirements: -Label device -Ensure Investigators maintain records and make reports -Obtain IRB approval: significant risk (SR) vs non-significant risk (NSR) -Informed consent -Monitoring of studies -Refrain from promotion

Viable

Ability of a newborn to survive after delivery.

FDA Form 3454

Absence of Financial Interest

Monitor Responsibilities

Act as the main line of communication between sponsor and investigator Verify investigators qualifications and resources throughout the trial Verify that investigational product is stored, administered and disposed of properly

21 CFR 56.124

Actions alternative or additional to disqualification (IRB)

Subpart C

Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects

What is 45CFR46 Subpart C?

Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects.

Subpart D

Additional Protections for Children Involved as Subjects of Research

21 CFR 50 Subpart D addresses:

Additional Safeguards for Children

What is 21 CFR Part 50 Subpart D?

Additional Safeguards for Children in Clinical Investigations

21 CFR Part 50 subpart D

Additional safeguard for children in clinical investigations (compare to 45 CFR 46 Subpart D: provides for assent of minors)

21 CFR Part 50 Subpart D

Additional safeguards for children in clinical investigations

21 CFR Part 312 Subpart C

Administrative Actions

21 CFR Part 56 Subpart

Administrative Actions for Noncompliance

ADR

Adverse Drug Reaction

AE

Adverse Event, caused or not caused by the drug

Local IRB

Affiliated with an institution

When can research begin after an application is submitted to the FDA?

After the FDA approves the research, or after 30 days if the FDA hasn't denied the research application.

What is taken into account to determine if a child is capable of providing assent?

Age Maturity Psychological state of child

Study Purpose

Aim or goal the researcher hopes to achieve Suggests the type of design to be used Implies the level of evidence to be obtained

Short form consent

All elements of ICF have been orally presented to subject or LAR. The short form must be signed by the subject or LAR. An IRB approved summary must be signed by a non-partial witness.

Adverse Drug Reaction

All noxious and unintended responses to a medicinal product related to any dose.

Significant Risk device is defined as an investigational device that is:

All of the following: - Intended as an implant and presents a potential for serious risk to the health, safety or welfare of a subject. - Purported or represented to be for a use in supporting or sustaining human life and presents a potential risk to the health, safety or welfare of a subject. - For a use of a substantial importance in diagnosing, curing, mitigating or treating a disease or otherwise preventing impairment of human health and presents a potential for serious risks to the health, safety or welfare of a subject.

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.

5-151 Describe the records an investigator is required to maintain related to adverse device effects.

All relevant observations including all adverse effects whether anticipated or unanticipated. 21 CFR 812. 140

21 CFR Part 314 New Drug Application

All research must be complete if they want to market the new drug.

Emergency Use IND

Allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND

45 CFR 46 addresses:

Also known as the Common Rule, this legislation established the role of IRBs for research on human rights.

Suspected Adverse Reaction

An AE for which there is a reasonable possibility that the drug caused the AE.

Unexpected Adverse Event

An AE that is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed or not consistent with risk info described in general investigational plan

Institutional Review Board (IRB)

Any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects.

Protocol amendments include:

Any change in a phase 1 protocol that significantly affects the safety of subjects or any change in a phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study.

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.

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.

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.

Test Article

Any drug for human use, biological product for human use, medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation

Information Amendments (and examples):

Any essential information that is not within the scope of a protocol amendment. This may include new toxicology, chemistry or other technical information or a report regarding the discontinuance of a clinical investigation.

Serious Adverse Event

Any event that: (1) results in death; (2) is life-threatening; (3) results in inpatient hospitalization or prolongation of existing hospitalization; (4) results in a persistent or significant disability/incapacity (5) results in a congenital anomaly/birth defect; or (6) based upon appropriate medical judgment, may jeopardize the subject's health and may require medical or surgical intervention to prevent one of the other outcomes listed above.

Test article

Any food or drug, including a biological product for human use, human food additive, medical device, color additive, electronic product, or any other article subject to regulation under the act or under section 351,354-360F or the Public Health Service Act.

Examples of changes requiring protocol amendments:

Any increase in drug dosage or duration beyond what is described in the current protocol, a significant increase in the number of subjects in a study, any significant change in the design of the protocol, or the addition of a new test or procedure.

Applicable Regulatory Requirements

Any laws and regulations addressing the conduct of clinical trials of investigational products.

Institution

Any public or private entity or agency

Institution (facility)

Any public or private entity or agency.

The ICH GCP guideline states that an IRB or IEC is required to have written procedures specifying that investigators should promptly report to the IRB or IEC the following?

Any unanticipated problems involving risks to human subjects or others Any instance of serious or continuing noncompliance with these regulations or the requirements or determinations of the IRB Any suspension or termination of IRB approval.

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.

Biologics Licensing Application

Application for approval from FDA is a PLA for biologics. Application submitted to Biologics evaluation and research. Application includes data derived from non-clinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency. Approval of a BLA or issuance of a biological license shall constitute a determination that the establishment and the product meet applicable requirements to ensure the continued safety, purity and potency of such products.

Sponsor Responsibility: Monitoring

Appointed by the sponsor

Phase III Clinical Trial

Are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects.

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.

What is the reporting period for Serious and Unexpected AE's?

As soon as possible but no longer than 15 days after the Sponsor's initial receipt of informaiton.

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.

How many days do you have to report an unanticipated adverse device effect?

As soon as possible, but no later than 10 days after Investigator first learns of the event.

Time frame for sponsor to report unexpected serious suspected adverse reaction to FDA:

As soon as possible, but no longer than 15 days.

Time frame for sponsor to report an unexpected fatal or life-threatening suspected adverse reaction to the FDA:

As soon as possible, but no longer that 7 days.

When is follow up reporting for an IND safety report due? (Any relevant additional information obtained by the sponsor that pertains to previously submitted IND safety report)

As soon as the information is available but no later than 15 calendar days

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

As soon as the relevant information is available

What if the FDA shows up?

Ask for ID and FDA Form 482. Give only what asked for, try not to leave alone, be honest and helpful, notify the HRPO, notify Sponsor, put in room without other materials.

Objectives of a human pharmacology study.

Assess tolerance - Estimate activity - Explore drug metabolism

Beneficence

Assessment of Risks and Benefits Protect from harm Secure well-being Do no harm Maximize benefits while minimizing possible risks

Assessment of an adverse event covers which 3 main areas?

Assessment of an adverse event covers three main areas: Assessment of Seriousness Assessment of Causality Assessment of Expectedness

How long is the reporting period for proprietary interest, equity interest or based on study outcome?

At any time.

Electronic signature components and controls

At least two distinct identification components (code and password) Used only by genuine owner Attempted use by another requires collaboration of 2 or more individuals Biometrics cannot be used by another

Compassionate Use IND

Available only to patients who have no therapeutic alternative and who are not eligible for clinical trials conducted under an IND. Must have ICF and IRB review/approval is required.

Site Management Organizations (SMOs)

-Organizations that bring together a group of sites and organizes them centrally to do studies. -Standardizes procedures, materials, and SOPs. -Assist sites in compiling and submitting regulatory documents.

Informed consent MUST contain:

-PURPOSE of research -DURATION of procedures -Description of PROCEDURES -Identification of any EXPERIMENTAL procedures -Any foreseeable RISKS -Statement about POTENTIAL BENEFITS to the subject -Statement if NO REASONABLE ALTERNATIVE PROCEDURES or treatments available -COMPENSATION and MEDICAL TREATMENT for injuries. -CONTACT INFORMATION

Ways to recruit study subjects

-Patient self-identification -Investigator identification of patients

Four types of controls

-Placebo -Active treatment -Dose comparison -No treatment

What are the requirements for expanded access? 21 CFR Part 312.300 (Subpart 1)

-Population must have serious or life-threatening disease or condition -No comparable/significant alternate therapy/treatment -Patient cannot obtain drug under another IND or protocol -Potential benefit outweighs risks of treatment -Expanded access won't interfere with completion of studies that could support marketing approval -Must apply to treatment protocols and should be for individual use (1 person)

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 and well-being of prisoners.

Phase IV clinical trial

-Post-marketing, done after NDA approval -Continues assessing therapeutic value and monitoring less common adverse events

IND Application Requirements

-Preclinical data (Animal pharmacology or toxicology) -Manufacturing information -Clinical protocol and Investigator information

What steps must be taken if IND is put on clinical hold? 21 CFR Part 312.42

-Proposed study: Subjects may not be given the investigational drug. -Ongoing study: No recruiting of new subjects & subjects receiving investigational drug must discontinue therapy unless specifically permitted by FDA in the interest of patient safety.

21 CFR 50

-Protection of human subjects -Informed consent

The Nuremberg Code of 1947

-Protects human subjects following the Nuremberg trials in which WWII Nazis were tried for human experimentation -States that voluntary consent is absolutely essential -Avoid unnecessary physical and mental suffering -Degree of risk should not exceed humanitarian importance -Gives patients the freedom to withdraw

The Belmont Report of 1979

-Provides basic ethical principles and boundaries between practice and research -Respect for privacy and confidentiality -Beneficence (do no harm and maximize benefit while minimizing risk) -Justice in ensuring equitable selection of subjects -Practice interventions designed solely to enhance well-being of subjects -Research meant to contribute to generalized knowledge

Children who are wards of the state can be included in clinical investigations only if

-Related to their status as wards -Conducted in schools,camps,hospitals, or institute similar settings in which the majority of children involved as subjects are not wards

Voluntary Action Indicated (VAI)

-Report contains findings and deviations, letter may or may not require a response

Pre-Market Approval (PMA)

-Required process of scientific review to ensure the reasonable safety and effectiveness of medical devices. -FDA approval required before device can be legally marketed. -Detailed, lengthy application, longer review time

45 CFR Part 46 (aka The Common Rule)

-Requires IRB oversight for all clinical trials. -Additional protection for vulnerable subjects: prisoners and children.

Oral Consent

-Requires a witness -Subject signs short form only -Witness must sign both short form and summary of what was said

5-126 Investigators are responsible for periodically requesting updates regarding new information gleaned by a sponsor during the course of a clinical investigation. True or False? 21 CFR 312.55

False: The sponsor must 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

5-152 Once an investigator has been disqualified by the FDA, he or she may never again receive investigational drug True or False? 21 CFR 312.70

False: The FDA may reinstate a disqualified investigator if the FDA Commissioner determines that the investigator presents adequate assurances that he or she will work in full compliance with applicable regulations.

Humanitarian Device Exemption (HDE)

Faster. A Device Manufacturer must submit an HDE application to the FDA that includes a Device description along with all data and experience with the product. FDA will only approve if Manufacturer proves the device is safe and will probably benefit in the intended Patient population. This is marking approval and therefore the devices is not considered investigational. IRB approval is still required, but doesn't require informed consent unless required by IRB. No data collected as it not research, but Device Manufacturer can collect data if they want.

An SAE meets one of the following conditions:

Fatal Disability Hospitalization Anomaly/Birth Defect Medically Significant Life Threatening

Differences between Federal Regulations and ICH-GCP Guidelines

Federal Regulations are the legal requirements for the conduct of clinical research established and monitored by federal authorities. ICH-GCP is the international ethical/moral responsibilities that should set the scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human Subjects.

What does 21CFR54 Deal with?

Financial Disclosure of Clinical Investigators.

21 CFR Part 54

Financial Disclosures

21 CFR 54

Financial disclosure

21 CFR Part 54

Financial disclosure for clinical investigator (form 3454 certification of financial interests and arrangements of clinical investigators form 3455 disclosure)

What does 21CFR54 deal with?

Financial disclosure of clinical investigators

Source Documentation

First place information is recorded (should be medical record), can be on multiple forms, specific for informed consent/HIPPA. If not charted, not done!

Required Element if Greater than Minimal Risk:

For research involving more than minimal risk an explanation as to whether any compensation is available if injury occurs and, if so, what it consists of, or where further information may be obtained.

Required Element if Greater than Minimal Risk:

For research involving more than minimal risk an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.

The form which is submitted to the FDA to report an drug adverse event is:

Form 3500

Which form is used for VOLUNTARY reporting of adverse events, product problems and product use errors? What about devices?

Form 3500 (Medwatch). For devices it's: 3500a

The form which is submitted to the FDA to report a MEDICAL DEVICE adverse event is:

Form 3500a

Describe form 3500a

Form 3500a is for Mandatory Device Reporting. User-facilities such as hospitals and nursing homes are legally required to report suspected medical device-related deaths to both FDA and the manufacturer, if known, and serious injuries to the manufacturer or to FDA, if the manufacturer is unknown.

Form FDA 483 is used for what purpose?

Form FDA 483,[2] "Inspectional Observations," is a form used by the FDA to document and communicate concerns discovered during inspections.

Grants

Formulated on a per-subject amount and prorated for number of visits a subject actually complete.

The international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects is known as...

GCP - Good Clinical Practice.

1996

GCP and HIPAA

21 CFR Part 50.20 Subpart D

General requirement of informed consent

21 CFR 50.20

General requirements for informed consent

What is 21 CFR Part 50.20 Subpart B?

General requirements for informed consent

21 CFR Part 58

Good laboratory practice (GLP) for non-clinical laboratory (animal) studies

ICH E6

Guidance for industry GCP

ICH S7A

Guidance for safety pharmacology studies for human pharmaceuticals.

Inclusion Criteria

Guidelines for choosing subjects with a set of characteristics that include major factors important to the research question

Use of PHI

Happens within a healthcare organization and is under the direction control of the organization

Class III (device)

Highest risk, usually requires a 510k (Pre-Market submission made to FDA) -Usually those that support or sustain human life -Important for preventing impairment of human health -Present a potential risk of illness or injury Ex. implant, used in supporting or sustaining human life

Verifying that: Risks are minimized and benefits maximized by reviewing the risk/benefit ratio Research is of sound design Subject selection is appropriate for the study Excessive compensation is not being offered

How does an IRB apply the principle of Beneficence?

Verifying that: There is equitable treatment across the study population Any benefit obtained would be accessible to the studied population (this is especially significant for drug testing in developing countries)

How does an IRB apply the principle of Justice?

Preventing undue influence Adequate informed consent Utilizing legally authorized representatives Protecting vulnerable populations

How does an IRB apply the principle of Respect for Persons?

21 CFR Part 312.40

How many days after FDA receive IND submission does the IND go into effect? 30 days unless FDA notifies sponsor of a clinical hold

Reasons that the FDA might issue a clinical hold:

Human subjects are or would be exposed to unreasonable risk for injury, the investigators named in the IND are not qualified, the investigator brochure is misleading or erroneous, the IND does not contain sufficient information to assess the risks to subjects

HDE

Humanitarian Device Exemption (HDE) application is similar to a PMA, but because a HUD is exempt from the effectiveness requirements of a PMA, an HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. However, the HDE must contain sufficient information for FDA to determine that the probable benefit to health outweighs the risk of injury

Documentation of Informed Consent

ICF must be in written form, approved by IRB Signed and dated by subject or LAR Subject receives a copy

Where are the relationship of the CRO and sponsor specified?

ICH GCP- E6, Section 5.2

When isn't an IND application needed?

IND Application is not needed if investigation does not support change in labeling.

21 CFR Part 312

IND Applications

1571

IND Cover Sheet Form used for investigational new drugs

21 CFR Part 312.32

IND Safety reports (* an SAE leads to an IND *

Continued submission to the IRB

IND safety reports (if IRB requires), SAEs, Protocol Amendments; Consent form modifications Significant protocol deviations; Notification of changes in personnel, lab or study location; Continuing review at least every 365 days.

Before starting a clinical trial, what must be filed, what does it include, and how long must one wait after filing it?

IND, results of preclinical testing. Wait 30 days after filing with the FDA

What is the difference between an IND & NDA?

IND- before start of first trial, allows shipping across state lines NDA-Phase I-II completed, request FDA to allow marketing

When are IND's and NDAs filed?

IND: after preclinical studies and before clinical trials begin. NDA: filed when phase III (primary efficacy studies) studies are complete. Must be formally approved.

21 CFR Part 314

INDA and NDA applications for FDA approval to market a new drug (New drug approval)

Investigator Training includes:

IP Training GCP Training Protocol Training Reporting Requirements Training

If the clinical investigation involves more than minimal risk and no prospect of direct benefit, children may only be involved if the ______ provides approval.

IRB

21 CFR 50.50

IRB Duties

21 CFR Part 56 Subpart C

IRB Functions and Definitions

21 CFR 56.108

IRB functions and operations

IRB disqualification

IRB has refused or repeatedly failed to comply. Will be made public. Research will end. IRB can be reinstated if found to be in compliance. FDA can proceed with judicial action if appropriate.

21 CFR 56.107

IRB membership

21 CFR 56.115

IRB records

21 CFR 56.106

IRB registration

21 CFR Part 56

IRB regulations

16.53. Certain applications for federal funding may be submitted without prior IRB approval, if the proposal does not include definite plans for involvement of human subjects. For example, human subject research would be dependent upon prior research, such as animal or laboratory research. However, prior to involving humans in research, what must take place?

IRB review approval must be obtained, and certification of such approval must be submitted by the grantee institution to the department or agency funding the research.

What is 21CFZR56.109 Subpart C?

IRB review of Research

21 CFR 56.109

IRB review of research

Who to notify after the IRB approves that exception of informed consent

IRB will notify the Investigator and sponsor. Sponsor will notify FDA

21 CFR 56 addresses

IRBs

Required Element: (All Studies):

Identification of any procedures which are experimental.*

Subpart A -

Basic HHS Policy for Protection of Human Research Subjects (Subpart A also called "The Common Rule" describes the required protections for all human subjects)

Which event led to the Belmont report?

Belmont report was published in 1974, just after disclosure of the Tuskeegee Syphilis Trial tragedy. (The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research)

The Belmont Report (1979) - Direct result of Tuskegee Syphilis Trial

Both the Declaration of Helsinki and the Belmont Report were directly influenced by the Nuremburg Code

Declaration of Helsinki

Brought about by the need for human research as opposed to human experimentation and actually better defined the criteria for consent

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.

3454

CERTIFICATION of financial interest from clinical investigators

A(n) _______________ is a printed, optical or electronic document designed to record all the protocol required information to be reported to the sponsor on each trial subject.

CRF - Case Report Form

What is a CRF

CRF Case Report Form The case report form is the tool used by the sponsor of the clinical trial to collect data from each participating patient.

What is a person or an organization (commercial, academic, or other) contracted by the sponsor of a clinical trial to perform one or more trial-related duty and function?

CRO - Contracted Research Organization

5-149 Investigators are required to retain records of each subject's case history and exposure to the device. Name 3 types of documents that would be included as case history for an investigation with a device.

Case report forms and supporting data including signed and dated informed consent forms, and medical records including progress notes of the physician, an individual's hospital chart(s) and nurses notes. 21 CFR 812.140

Exemption for Investigation of a Device Abbreviated Requirements 21 CFR Part 812.2(c)

Categories of investigations considered to have approved IDE applications, unless FDA has notified sponsor otherwise. -Those in use in accordance with its labeling & in commercial distribution before 5-28-1976 -A diagnostic device if the testing is: —-non-invasive —-does not require invasive sampling of significant risk —-does not introduce energy into subjects, and, —-is not used as a diagnostic procedure without confirmation by another medically established diagnostic product/procedure -Device undergoing consumer preference testing, modification testing, or combo of 2/more devices in commercial distribution -Device solely for veterinary use or lab animal research

Adverse reaction

Caused by the drug

CDER

Center for Drug Evaluation and research

16.14. Explain the term "certification" with respect to federally support research.

Certification is the official notification by an institution to the supporting department or agency, in accordance with the requirements of 45 CFR 46 that a research project or activity involving human subjects has been reviewed and approved by an IRB in accordance with an approved assurance.

FDA Form 3674

Certification of Compliance

Form 3454

Certification of financial interest and arrangements of clinical investigators

Exclusion Criteria

Characteristics that eliminate a potential subject from the study to avoid extraneous effects

Pre-Clinical Research

Chemical synthesis and initial chemical development conducted on animals or on cell cultures.

45 CFR Part D

Children

21 CFR 56.103

Circumstances in which IRB review is required

Class I definition

Class I devices are subject only to general controls. They typically present the lowest potential for harm and are simpler in design than Class II or Class III devices. Examples of Class I devices include elastic bandages, examination gloves, and hand-held surgical instruments.

What are the FDA device classes, and give one example of each.

Class I: Not life-supporting. Ex: gloves Class II: Special controls req'd: Ex: powered wheelchairs Class III: Higher risk, require pre-market approval - PMA). Ex: pacer or AED

21 CFR 50.53

Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition

21 CFR 50.52

Clinical investigations involving more than minimal risk but presenting the prospect of direct benefit to individual subjects

21 CFR 50.51

Clinical investigations not involving more than minimal risk

21 CFR 50.54

Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

Phase II Clinical Trial

Clinical investigations of 100 to 200 patients for effectiveness and relative safety.

Sponsor Responsibilities

Collect financial disclosure information from investigators; perform due diligence Submit summary forms to FDA in marketing applications (3454 and 3455) Store clinical investigators financial disclosure information for 2 years after the date of application approval

Coordinating Committee

Committee that a sponsor may organize to coordinate the conduct of a multicenter trial.

1991

Common Rule publication

Active treatment

Comparative treatment has a similar mechanism of action as investigational product and is considered standard of care. Used when placebo treatment for condition is unethical.

A(n) ___________________ is an investigational or marketed product, or placebo, used as a reference in a clinical trial.

Comparator, Product

Good Clinical Practice (GCP) is

Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected consistent with the principles that: Origin in the Declaration of Helsinki, and that the clinical trial data are credible.

Phase IV Clinical Trials

Concurrent with marketing approval, FDA may request sponsor conduct certain "postmarketing" studies to delineate additional information about drug's risks, benefits and optimal use. Examples: Fast-tracked drug studies that evaluate age and ethic groups, safety, pharmacoeconomic data, and it's marketing launch.

A statement regarding the ____ of a subject's study records must be included in all informed consent documents.

Confidentiality

FDA Form 1572

Contract between Investigator and FDA, documenting the Investigator is responsible for conducting the study following all FDA/USHHS regulations and keeping appropriate records.

What is the FDA definition of a CRO's potential responsibilities?

Contract research organization means a person that assumes, as an independent contractor with the sponsor, one or more of... design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the FDA. On SOCRA test: does not include accrual of subjects(?)

21 CFR 56.114

Cooperative research (IRB)

Minimal risk

Encountered in daily lives or usually standard treatment.

Humanitarian Use Device (21 CFR Part 814)

Encourages the development of HUDs and is "intended to benefit patients in the treatment of diagnosis of diseases or conditions that affect or are manifested in not more than 8,000 individuals in the US per year". Therefore CANNOT be a comparable device that is available to the intended population.

Sponsor Responsibilities: Manufacturing, Packaging, Labelling, and Coding Investigational Product

Ensure product is manufactured in accordance with any applicable GMP and coded and labelled in a manner to protect blinding Determine acceptable storage temperatures, storage conditions, storage times, reconstitution fluids and procedures and devices for product infusion and inform all involved parties Package to prevent contamination and deterioration For blinded trials include a mechanism that permits rapid identification of product in case of emergency

Investigational Product Shipping and Disposition

Ensure timely delivery of IP to the investigator. Maintain records that document shipment, receipt, disposition, return, and destruction of the IP. Maintain a system for retrieving IP and documenting this retrieval Maintain a system for the disposition of unused IP and for the documentation of this disposition.

FDA Audit

Ensures Compliance. Types include: Study Directed, Investigator Directed, For Cause, or Not For Cause (Routine Surveillance)

Quality Assurance (QA)

Ensures that the trial is performed and the data are generated, documented, and reported in compliance with GCP and regulatory requirements.

Investigator responsibilities:

Ensuring that an investigation is conducted according to the signed agreement; protecting the rights, safety, and welfare of subjects; the control of devices under investigation; ensuring that informed consent is obtained in accordance with part 50; control of investigational drug; accurate record keeping; progress reports; safety reports; final reports; financial disclosures; assurance of the IRB review.

5-132 What are the general responsibilities of investigators

Ensuring that investigations are conducted according to the signed agreement, the investigational plan and applicable FDA regulations, protecting the rights, safety and welfare of participants under the investigator's care, controlling the devices under investigation, and ensuring that informed consent is obtained in accordance with 21 CFR 50. 21 CFR 812.100

Declaration of Helsinki (1964)

Ethical principles for medical research. Well-being of subjects should take precedence over the interests of science and society. Some subjects need further protections. The benefits, risks, burdens, and effectiveness is comparable to the best known treatment.

Ethical Principles of The Declaration of Helsinki

Ethical principles for medical research. Well-being of subjects should take precedence over the interests of science and society. Some subjects need further protections. The benefits, risks, burdens, and effectiveness is comparable to the best known treatment.

List the 5 Content Areas of the SOCRA exam & % in each

Ethics /Informed Consent /Safety 20% IRB Roles and Responsibilities 10% Clinical Trial Protocol and Amendments 10% Investigator Roles and Responsibilities 30% Sponsor Roles and Responsibilities 30%

Guideline for Good Clinical Practice was developed with consideration of the current good clinical practices of

European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO

For-cause audit

Evidence that the site is out of compliance

Class III devices

Examples of Class III devices include replacement heart valves, silicone gel-filled breast implants, and implanted cerebellar stimulators.

21 CFR 50.24

Exception from informed consent requirements for emergency research

21 CFR 50.23

Exemption from informed consent general requirements

21 CFR 56.104

Exemptions from IRB requirement

FDA Form 483

Exit interview form/summary of observations. Exit interview first occurs in real time at end of audit, then FDA Form 483 is sent to audited party after legal has reviewed the language.

21 CFR Part 312 Subpart I

Expanded Access to Investigational Drugs for Treatment Use

21 CFR Part 300 (Subpart 1)

Expanded access: illness is life-threatening Benefit > risk no alternative Only apply to this 1 person Within 15days has the sponsor or physician submit written summary of expanded access to FDA after use.

Phase III:

Expanded controlled and uncontrolled studies Intended to gather additional information about effectiveness and safety Evaluate the overall benefit-risk relationship Provide adequate basis for physician labeling Include from several hundred to several thousand subjects

21 CFR 56.110

Expedited review procedures for certain kinds of research involving no more than minimal risk and for minor changes in approved research

Pilot Studies (device)

Exploratory Includes small numbers of subjects

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.

Which form is used to certify absence of financial interest?

FDA Form 3454

What form is used for the mandatory reporting of serious adverse events?

FDA Form 3500A

FDA Form 482 -what is it for?

FDA Form 482 - Notice of Inspection

5-168 What additional information is available from the FDA that applies to and supports interpretation of the FDA regulations? 21 CFR 312.145

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.

5-167 The FDA may disclose the existence of an IND, even if it has not previously been made public. True or False? 21 CFR 312.130

False. The FDA may not disclose that an IND exists if the fact has not been previously disclosed.

5-133 If the FDA has granted approval for an investigation, investigators may begin to recruit study subjects, while local IRB review is ongoing. True or False?

False. Approval from both the IRB and FDA are required prior to obtaining informed consent from prospective study subjects. 21 CFR 812.110

5-137 Upon completing or termination of a clinical investigation, the investigator may dispose of or use the remaining devices at his/her discretion. True or False?

False. The sponsor will direct the investigator on how the remaining devices must be disposed of or returned to the sponsor. 21 CFR 812.110

The Investigator must report Financial Disclosure for how long?

If any relevant changes occur during the course of the investigation and for 1 year following completion of the study.

Corrective and Preventative Action (CAPA)

If noncompliance that significantly affects or has the potential to significantly affect human subject protection or reliability of trial results is discovered, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions.

5-138 Under what conditions can the FDA issue an investigator a written notice of a complaint?

If the FDA has information indicating repeated or deliberate failure to comply with the IDE, informed consent or IRB requirements, or has repeatedly or deliberately submitted false information to the sponsor or on any required report by the investigator. 21 CFR 812.119

Non-significant risk category (NSR) for Investigational Device Exemptions

If the IRB agrees that the study is NSR, no review by the FDA is necessary before starting studies in humans. If the IRB does consider the study to be SR, the Sponsor must obtain an IDE from the FDA before proceeding with clinical studies.

Pre-Market Approval (21 CFR Part 814)

If the new device is deemed substantially equivalent to a pre-amendments devices, it may be marketed immediately and is regulated in the same regulatory class the pre-amendments device to which it is equivalent. The pre-market notification requirement for new devices and devices that are significant modifications of already marketed devices is set forth in section 510k of the act Therefore deemed "substantially equivalent" are also known as 510k devices.

SAE reported by sponsor within 7 calendar days if

If the report is about a fatal or life-threatening unexpected adverse drug reaction

Report to IRB in 5 working days

Immediate use & investigator opinion required to preserve life or no sufficient time investigator shall decide use

Justice

Implies fairness and is manifested in equitable selection of subjects for research Who should bear burdens of research? Selection based on reasons directly related to the problem being studied No systematic selection of a class of individuals due to compromised position, manipulability, etc. Who should receive benefits of research? Benefits not restricted to those who can afford it Research should not involve persons from groups not likely to benefit from application of the research

US Public Health Service: Syphilis Study at Tuskegee

In 1932, the Public Health Service, working with the Tuskegee Institute, began a study to record the natural history of syphilis in hopes of justifying treatment programs for blacks. It was called the "Tuskegee Study of Untreated Syphilis in the Negro Male."

5-150 How must an investigator store investigational drugs which are also controlled substances? 21 CFR 312.69

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.

Safety Reports

In each IND safety report, the SPONSOR must identify all IND safety reports previously submitted to FDA concerning a similar suspected adverse reaction, and must analyze the significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information. Must be reported to the Investigators and FDA within 15 calendar days

Sponsor Responsibility: Audit

Independent and separate from routine monitoring Done to evaluate trial conduct and compliance Auditors appointed by the sponsor Auditors are independent of the clinical trials Sponsor should ensure auditors are qualified by training and experience

Legally authorized representative

Individual or judicial body authorized to consent on behalf of a prospective subject to the subject participation in research

21 CFR 50 Subpart B addresses:

Informed Consent

3 Applications of The Belmont Report

Informed Consent Assessment of Risk and Benefits Selection of Subjects

21 CFR Part 50

Informed Consent Regulations

21 CFR Part 50 Subpart B

Informed Consent of Human Subjects

21 CFR Part 50

Informed consent

Which of the following are necessary to satisfy 21CFR50.23 Subpart B?

Informed consent cannot be obtained from the subject because of an inability to communicate with or obtain legally effective consent from the subject.

FDA Form 483

Inspectional Observations of an FDA audit

483

Inspectional observations

21 CFR Part 56

Institutional Review Board

21 CFR 56

Institutional Review Board (IRB)

21 CFR Part 56

Institutional Review Boards

What is 21CFR56?

Institutional Review Boards

Federal Wide Assurance

Institutional assurances are a mechanism to apply federal regulations to all human Subject research. When institutions sign federal assurances, they may also elect to apply the health and human services regulations and terms of the assurance to all research of the institution, regardless of the sources of funding. The assurance outlines the institution's responsibilities for meeting the requirements for Title 45 CFR Part 46.103 and documents how the institution will protect the welfare and rights of research Subjects based on federal regulations.

Significant Risk Device

Intended as an implant and presents a potential for serious risk to the health, safety or welfare of the subject Is purposed or represented to be for a use in supporting or sustaining human life and presents a potential serious risk Is for a use of substantial importance in diagnosing, curing , mitigating or treating disease or otherwise preventing impairment of human health.

Significant risk device is defined as an investigational device that is:

Intended as in implant, purported or represented to be for a use in supporting or sustaining human life, and/or for use of substantial importance in diagnosing, curing, mitigating or treating disease And presents a potential for serious risk to the health, safety or welfare of a subject

What does ICH stand for?

International Conference on Harmonization

ICH

International conference on harmonization

Guideline:

Interpretive Document

Phase I:

Introduction of an investigational new drug into humans Conducted in patients or normal volunteer subjects Designed to determine metabolism and pharmacologic actions in humans, side effects associated with increasing doses, early evidence on effectiveness Often conducted in in-patient setting to allow close monitoring Small numbers of subjects (20 to 80)

Secondary pharmacodynamics studies

Investigate the mode of action and/or effect of a drug substance not related to its desired therapeutic target

Primary pharmacodynamic studies

Investigate the mode of action and/or effects of a drug substance in relation to its desired therapeutic target

21 CFR 812

Investigational Device Exemption

21 CFR Part 812

Investigational Device Exemption

21 CFR 812 addresses:

Investigational Device Exemptions

21 CFR Part 812

Investigational Device Exemptions

What is 21CFR812?

Investigational Device Exemptions

21 CFR 312

Investigational New Drug Application

21 CFR Part 312

Investigational New Drug Application

What is 21CFR312?

Investigational New Drug Application

21 CFR 312 addresses

Investigational New Drug Application (IND)

21 CFR Part 312

Investigational New Drug Application (IND)

21 CFR Part 312 Subpart B

Investigational New Drug Application (IND)

21 CFR Part 312

Investigational new drug applicaiton

What is an IND

Investigational new drug application (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.

Central focus of the INITIAL IND submission:

Investigational plan and protocol

Who makes an "assessment"

Investigator

21 CFR Part 312

Investigator responsibilities

Sponsor Responsibilities: Investigator Selection

Investigators should be qualified by training and experience, and have adequate resources Provide investigators with protocol and IB and allow sufficient time for review before agreement Obtain investigator/institutional agreement: To conduct trial in compliance with GCP To comply with procedures for data recording and reporting To permit monitoring, auditing and inspection

Respect for persons

Is manifested by the informed consent process Treated as independent agents; those w/diminished autonomy are entitled to protection Subjects enter into research voluntarily and with adequate information Elements of consent: Information, Comprehension, Voluntariness

Unexpected Adverse Event or Unexpected Adverse Reaction

Is one that has not been identified in nature, severity, or frequency in the current Investigator's Brochure.

16.66. Why is the basic premise for providing additional protection to prisoners who are research subjects put into place?

It is believed that prisoners, due to their incarceration, are under constraints that may inhibit their ability to make a truly voluntary decision to participate in research.

The Nuremberg Code (1949)

Judgement by War Crimes Tribunal (for Nazi war crimes) establishing 10 research ethics principles for human experimentation. 1. Voluntary consent essential 2. Experiment to yield positive results for the good of society & not be random/unnecessary. 3. Animal experiments must first be done to justify human experiments. 4. Experiments to be conducted to avoid unnecessary physical/mental suffering and injury. 5. No experiment conducted if a priori reason to believe that death/disabling injury will occur, unless physicians are also subjects. 6. Degree of risk < humanitarian importance. 7. Preparations and facilities must adequately protect subjects. 8. Experiment only conducted by scientifically qualified persons. 9. Human subjects at liberty to quit the experiment at any point when they feel physically or mentally unable to go on. 10. Scientist in charge must be prepared to terminate the experiment at any stage when they observe that continuation would be dangerous.

Who does FDA require signature(s) from for informed consent?

Just the subject (different from WU requirements)

Regulation:

Law

Law vs. Regulation

Laws Passed by legislature Establish authority of a regulatory body Regulations Passed by regulatory authorities Have effect of law (civil and criminal penalties for non compliance)

The ______ means 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 procedure(s) involved in research.

Legally authorized representative

21 CFR 56.120

Lesser administrative actions (IRB)

FDA Form 482

Letter of Intent to Inspect

FDA Form 483

Letter of investigational observations/citation of noncompliance that specifies how long you have to respond.

Exceptions to Informed Consent

Life threatening situations Informed consent cannot be obtained Insufficient time to consent LAR No alternative approved or general recognized therapy that affords the subjects a better chance of survival.

No treatment

Long term safety studies for chronic conditions (hypertension). Meant to assess maintenance of clinical response over time and safety.

Class I (device)

Lowest risk --General controls are sufficient to provide reasonable assurance of the safety and affectiveness Ex. elastic bandages, examination gloves, hand-held surgical instruments

Sponsor Responsibilities: Trial Management, Data Handling, and Record Keeping

Maintain ability to compare original data with processed data Use unambiguous subject identification codes Retain all sponsor specific essential documents as required by country If development is discontinued: Notify all investigators/institutions and regulatory authorities Report any transfer of ownership of data to authorities Retain documents for at least 2 years of last approval Inform investigators of record retention requirements

Sponsor Responsibility: Quality Assurance and Quality Control

Maintain quality assurance with SOPs Secure agreements for direct access to source data/documents for monitoring and auditing Quality control for data handling Obtain written agreements between the sponsor and the investigator/institution

MedWatch 3500A

Mandatory reporting

Medwatch 3500A

Mandatory reporting of AEs, product problems and product use errors

3500A

Mandatory safety reporting by user facilities, distributors, and manufacturers

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.

Sponsor

May refer to a corporation, government agency, or individual who takes responsibility for and initiates a clinical investigation.

Sponsor Responsibility: Contract Research Organization

May transfer any or all sponsor trial-related duties Quality and integrity of data responsibility still sponsor's ultimate responsibility Specify transferred duty and function in writing Any duties or function not transferred retained by sponsor

Biometrics:

Method of verifying an individual's identity based on measurement of the individual's feature(s) or repeatable action(s) where those features and/or actions are both unique to that individual and measurable.

Biometrics

Method of verifying an individual's identity based on measurements of the individual's physical features or repeatable actions where those features and/or actions are both unique and measurable to that individual.

21 CFR Part 312 Subpart F

Miscellaneous

Providing a unified standard for Europe, US and Japan to facilitate the acceptance of clinical trials is the.....

Mission Statement of the GCP Guidelines.

Class II (device)

Moderate risk, usually requires a 510k (Pre-Market submission made to FDA) --General controls are insufficient to assure safety and effectiveness. --Special controls include: special labeling requirements, mandatory performance standards, post-market surveillance Ex: powered wheelchairs, infusion pumps, and surgical drapes

ICH M

Multidisciplinary

Subject Recruitment and Retention

Must be approved by IRB prior to use. No coercive wording about following Subjects for survival or about payment guidelines permitted.

5 IRB Requirements

Must have 5 members Each member has a diverse background 1 scientific member 1 non-scientific member Cannot have a conflict of interest

Labeling of an Investigational New Drug

Must have a label with the statement "Caution: New Drug—Limited by Federal (or United States) law to investigational use." Must not bear any statement that is false or misleading

Source Document Requirements

Must include all pertinent observations of each subject Should be accurate, complete, kept up-to-date, and maintained.

Action Letters

NAI = No actions indicated VAI = Voluntary action indicated OAI = Other action indicated (bad)

What is an NDA

NDA New Drug Application

Public Health Information (PHI)

Names, addresses, employer's names or addresses, relatives' names and addresses, all elements of dates related to a person except for a year, telephone numbers, fax numbers, email, SSN, MRN, certificate numbers, device serial numbers, member or account numbers, etc.

The Belmont Report (1979)

National commission for the protection of human Subjects of bio-medical and behavioral research.

NDA -

New Drug Application

21 CFR 314

New Drug application

5th principle of The Nuremberg Code

No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except perhaps, in those experiments where the experimental physicians also serve as subjects

Notice of IDE changes are to be reported no more than how many days after the change?

No more than 5 working days.

How often can a sponsor submit protocol and/or information amendments to the FDA?

No more than every 30 days

5- 149 In addition to permitting authorized FDA representative to have access to, copy, and verify study records, what information is an investigator required to divulge regarding each study subject?

No other information. The investigator may withhold subject names unless the records of particular subjects require more detailed study, or if there is reason to believe the records do not represent the actual cases, or results. 21 CFR 312.68

16.46. Informed consent should always include a statement that participation is voluntary and that refusal to participate involves what?

No penalty or loss of benefits to which the subject is otherwise entitled and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

Two reasons for inactive status of an IND:

No subjects enrolled for a period of two years or more, clinical hold for one year or more

FDA Form 482

Notice of FDA Inspection form

What is the FDA Form 482?

Notice of Inspection

FDA Form 482

Notice of establishment Inspection by FDA

482

Notice of inspection

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.

If an IRB is disbanded, how soon must the OHRP be notified?

OHRP must be notified within 30 days of cessation

Investigator Responsibilities: Communication with IRB

Obtain written IRB approval Submit the current IB to the IRB Provide IRB all documents subject to review

Expedited Review

Occurs quickly. If there is minimal risk to human subjects.

Disclosure of PHI

Occurs when PHI is given to someone who is not part of the organization

2000

Office for Human Research Protections (OHRP)

US Code of Federal Regulations (CFRs)

Official government information regarding GCP

Certification

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.

Phase IV:

Ongoing safety and effectiveness Post-marketing Address FDA requirements for additional information not in New Drug Application (NDA) Continue assessing overall therapeutic value Surveillance for less common adverse events (spontaneous reports, registries, etc.) Large number of subjects (thousands)

With respect to electronic records: what is an open system?

Open system means an environment in which system access is not controlled by persons who are responsible for the content of electronic records that are on the system.

Clinical Hold

Order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation.

21 CFR Part 56 Subpart B

Organization and Personnel

The Declaration of Helsinki

Originally adopted in June of 1964, is a set of ethical principles for medical research involving human subjects.

21 CFR Part 316

Orphan drugs

5-147 Investigators are required to maintain accurate, complete and current correspondence records within 5 entities related to his/her participation in an investigation. Name the 5 entities.

Other investigators, the IRB, the sponsor, the monitor and the FDA. 21 CFR 812.140

What is 21 CFR Part 312?

Part 312 - Investigational New Drug Application

What is 21 CFR Part 50?

Part 50 - Protection of Human Subjects

What is 21 CFR Part 56?

Part 56 - Institutional Review Board ........

What is 21 CFR Part 812 - about?

Part 812 - Investigational Device Exemptions

Double-blind Study

Participant nor the researcher knows whether the participant has treatment or the placebo

Part time site

Participate in research studies, but also maintain their regular medical practice

Emergency Use or Compassionate Use

Patient or patients to be treated have a serious or immediately life-threatening disease or condition with no comparable or satisfactory alternative therapy Potential patient benefit justifies potential risks of treatment Providing the investigational drug will not interfere with the initiation, conduct or completion of clinical investigations that could support marking approval

Direct Access

Permission to examine, analyze, verify, and reproduce any records and reports that are important to the evaluation of a clinical trial.

Investigational Device Exemption

Permits a device that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully for the purpose of conducting investigations of that device.

Conflict of Interest

Person whose study being reviewed may be present at IRB meetings to answer questions but not during the discussion leading up to the vote

16.69. Explain the DHHS definition of "children".

Persons who have not attained the legal age for consent to treatments or procedures involved in research under the applicable law of the jurisdiction where the research will be conducted.

Additional drug interaction, dose-response, and safety studies are some examples of a ______ study.

Phase 4

Additional drug interaction, dose-response, and safety studies are some examples of a ______ study.

Phase 4 (E8 Section 3.1.3.4)

How many participants are typically in different phase clinical trials?

Phase I 20-100 Phase II 100-300 Phase III 300-3000

5-153 What is 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

Physicians and patients are generally more willing to accept greater risks or side effects from drugs intended to treat severely debilitating or life-threatening illnesses.

Investigational Plan

Plan for investigating the drug product for the following year. Should include the following: (a) Rationale for the drug or study (b) the indication to be studied (c) the general approach in evaluating the drug (d) the kinds of clinical trials to be conducted in the first year following the submission (e) estimated number of patients (f) any risks of particular severity or seriousness anticipated

Quality Assurance (QA)

Planned and systematic actions that are established to ensure that the trial is performed and data are generated, documented, and reported in compliance with GCP and applicable regulatory requirements.

Difference between policy and procedure?

Policy: general strategies; Procedures: detailed, step-by-step instructions

Phase IIIb Clinical Trial

Post NDA submission Additional safety and efficacy data

Phase 4

Post-marketing Continue assessing overall therapeutic value size depends on design

Subpart B

Pregnant Women, Human Fetuses and Neonates Involved in Research

45 CFR Part B

Pregnant women and fetuses

The regulations in Subpart B are applicable to supporting research, development, and related activities involving which aspects of pregnancy?

Pregnant women, Human in vitro fertilization, and The fetus

21 CFR Part 814

Premarket Approval of Medical Devices (and Humanitarian Use Devices)

21 CFR 814

Premarket approval of medical devices

21 CFR Part 814

Premarket approval of medical devices

Investigator Meeting

Prepares sites for a study. There should be free, full, and open communication about any scientific or medical question that may arise during the clinical investigation.

What & when: PDUFA

Prescription Drug user fee act 1992

Confidentiality

Prevention of disclosure to other than authorized individuals of a sponsor's proprietary information or a subject's identity.

Sponsor Responsibilities: Allocation of Responsibilities

Prior to initiation, the sponsor should define, establish, and allocate all trail related duties and functions

45 CFR 46 Subpart C

Prisoners

45 CFR Part C

Prisoners

Regulations in subpart C are applicable to research conducted by HHS in which subjects?

Prisoners 45 CFR 46.301(a)

Suspected AR

Probably caused by the drug

Randomization

Process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignment in order to reduce bias.

Unfavorable reasons to close a study

Product was unsafe, not effective, not possible to enroll, not viable for marketing, or compliance or other problems at a site

7th principle of The Nuremberg Code

Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.

21 CFR Part 50

Protection for human subjects ( compare with 45 CFR 46 from Dept of Human Health Sevices, provision for vulnerable populations)

21 CFR Part 50

Protection of Human Subjects

Part 50

Protection of Human Subjects

What is 21CFR50?

Protection of Human Subjects

What is 45CFR46?

Protection of Human Subjects

21 CFR 50 addresses:

Protection of Human Subjects/Informed Consent

21 CFR Part 50

Protection of human subjects

45 CFR 46 Subpart B

Protections for pregnant women

Sponsor Responsibilities: Medical Expertise and Trial Design

Provide medical expertise to advise on trial related medical questions or problems (might be outside consultant) Utilize qualified individuals for design, analysis and preparing interim and final clinical reports

16.48. An IRB may approve a modified consent procedure or form, or waive the requirement to obtain informed consent for certain types of federally supported research, provided what criteria are met?

Provided that the IRB finds and documents that the research meets the exemption(s) defined in 45 CFR 46.

45 CFR 46 Subpart D

Provides for assent of minors

45 CRF 46 Subpart A (Common rule)

Provision with intent to protect vulnerable subjects

21 CFR 56.122

Public disclosure of information regarding revocation (IRB)

Treatment IND

Purpose is to facilitate the availability of promising new drugs to desperately ill patients as early in the drug development process as possible. Issued when no other comparable or satisfactory treatment is available. Risk is not unreasonable. Common in cancer and aid's treatment due to lack of treatments and need of patients.

Describe the Tuskegee Experiments

Purpose: to record natural history of syphilis Involved 600 black men, 399 with syphilis and 201 without it. (No one was purposely infected for the purposes of the study) Participants were told being treated for "bad blood" Participants examined, spinal taps were conducted. No active treatment was given. Penicillin became widely and cheaply available in the 1940s Tuskegee doctors withheld this treatment from participants until 1972 Many participants died directly due to syphilis, wives contracted syphilis, and children were born with congenital syphilis.

Investigator Responsibilities: Investigator's Qualifications and Agreements

Qualified by education, training, and experience Provide evidence through current CV Thoroughly familiar with use of the investigational product Aware of and comply with GCP and regulations Permit monitoring, auditing and inspection Maintain a list of persons who have been delegated significant trial-related duties

ICH Q

Quality

The ______ will maintain copies of all protocols pertaining to the nonclinical laboratory studies.

Quality assurance unit

3 things IP Packaging must include

Rapid identification of the product in case of emergency, but does not permit undetectable breaks of the blinding. Labeled with "Caution: New Drug—Limited by Federal (or United States) law to investigational use." Cannot have any statement that is false or misleading and does not represent that the drug is safe or effective

Declaration of Helsinki 1964

Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects Basic ethical principles reiterated principles from the Nuremberg Code "Informed consent" obtained from subject or legal guardian Design and performance of experimental procedure formulated in a clearly formulated protocol; transmitted to specially appointed independent committee for consideration, comment and guidance

21 CFR Part 56 Subpart D

Records and Reports

Record retention

Records must be kept for 2 years after the NDA is approved or investigation is discontinued and the FDA is notified.

5-142 What records must be maintained by investigators for investigational drug supplies? 21 CFR 312.62

Records of drug disposition including dates, quantities, and use by study subjects.

5-152 Describe the records an investigator must maintain related to a subject eligibility for a study and progress during the study.

Records of the condition of the participant upon entering and during the course of the investigation, including information about relevant previous medical history and the results of all diagnostic tests. 21 CFR 812.140

Drug Accountability

Records of the product's delivery to the trial site The inventory at the site The use by each subject The return of unused product

45 CFR Part E

Registration of IRBs

Subpart E

Registration of Institutional Review Boards

Food and Drug Adminstration

Regulate all Clinical Investigations

21 CFR 56.123

Reinstatement of an IRB or an instituion

What did the 1938 Food Drug and Cosmetics Act Do?

Required new drugs to demonstrate safety before marketing Established standards and safe tolerances Authorized factory inspections Regulation Basis of 21 CFR Chapter 1

Pre-Market Approval (PMA)

Required process of scientific review (usually class III) to ensure reasonable safety and effectiveness of device. *Must be FDA "approved" or NOT cleared before marketing per 21 CFR Part 814

21 CFR 50.55

Requirements for permission by parents or guardians for assent by children

What are the 8 required elements of informed consent?

Research Risk Benefits Alternatives Confidentiality Compensation Contact Voluntary

16.67. Name two of the four types of federally funded research that prisoners may be used as subjects.

Research involving: 1). Possible causes, effects, and processes of incarceration and criminal behavior. 2). Prisons as institutional structures or prisoners as incarcerated persons. 3). Conditions particularly affecting prisoners. 4). Practices aimed at improving the health or well being of prisoners.

Minimal Risk Research

Research that involves no greater risks to participants than they would encounter in their daily lives.

Belmont Report 1979

Respect for persons Beneficence Justice

21 CFR Part 312 Subpart D

Responsibilities of Sponsors and Investigators

The Nuremberg Code

Result of the Doctor's Trial Judgment

Serious adverse event

Results in death, is life-threatening, requires hospitalization, results in persistent or significant disability

21 CFR 56.112

Review by institution (IRB)

Site Initiation Visit

Review protocol, CRFs, answer questions. Monitor will review basic execution of protocol. This is conducted after the contract is executed and IRB approval is received.

Investigator's Brochure

Reviewed annually, revised as needed.

Monitors are responsible for:

Reviewing accuracy and completeness of site records (source, CRFs, eligibility, dosing, accountability, AEs, ICF, etc.)

1981

Revised FDA and HHS regulations

What is a SUSAR and how long does the sponsor have to report it?

SERIOUS UNEXPECTED SERIOUS ADVERSE REACTION Fatal or life threatening SUSARs: Not later than 7 calendar days after the sponsor has information that the case reported fulfills the criteria for a fatal or life-threatening SUSAR, with any follow up information to be reported within a further 8 calendar days. All other SUSARs: Not later than 15 calendar days after the sponsor has information that the case fulfilled the criteria for a SUSAR.

Annual Report includes:

SPONSOR must submit a brief report of the progress of the investigation that includes: Individual study information Information obtained during the previous year's clinical and nonclinical investigations Investigational plan for the coming year If the investigator brochure has been revised, a description of the revision and a copy of the new brochure. A description of any significant Phase 1 protocol modifications made during the previous year Any significant foreign marketing developments with the drug during the past year If desired by the sponsor, a log of any outstanding business with respect to the IND

What is form 1572

STATEMENT OF INVESTIGATOR: A form that must be filed by an investigator running a clinical trial to study a new drug or agent. The investigator agrees to follow the (FDA) Code of Federal Regulations, verifies that he or she has the experience and background needed, and that it will be done in a way that is ethical and scientifically sound. Also called 1572 form.

ICH S

Safety

Sponsor responsibilities

Select qualified Investigator, provide information to conduct the study, ensure proper monitoring, ensure compliance with general investigational plan and protocols, maintain an effective IND, ensure FDA regulations are being followed and Investigators are notified of significant new adverse events or risks.

Sponsor responsibilities:

Selecting qualified investigators and providing them with information to conduct the investigation, provide monitoring, ensuring that IRB review and approval are obtained, submitting an IND application to the FDA, ensuring that the reviewing IRB and FTA are promptly informed of new information, only sending drug to qualified investigators, keep records for two years

Study Endpoints

Set before the trial begins to determine what

Who needs to sign an informed consent short form and summary?

Short form: witness and subject Summary: witness and person obtaining consent

Test Article Un-blinding

Should be done only in cases to protect the safety of the Subject and should be documented and procedures followed appropriately.

Investigator Qualifications

Should be qualified by education, training, and experience Should meet all the qualifications specified by the applicable regulatory requirements Should provide a CV and/or other relevant documentation requested by the sponsor or the IRB

What must the Sponsor obtain from the Investigator prior to start of study?

Signed Investigator Statement (Form FDA 1572) CVs Phase 1: Clinical protocol Phase 2/3: Protocol outline w/approx number of subjects to get tx & number to be used as controls (sex, age, and condition) Financial Disclosure

Reporting SAEs

Sites has 24 hrs from when made aware. Report by phone or fax then follow up with written report. Sponsor has 7 calender days to report to FDA if event is live threatening or is a death. Sponsor has 15 days to provide the FDA with the written report.

Phase I Clinical Trial

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

Class II definition

Special controls identified by the agency, which may include special labeling requirements, performance standards and postmarket surveillance. Examples of Class II devices include powered wheelchairs, infusion pumps, and surgical drapes.

Exception to IND label:

Specified lots, batches, or other units of human drug product that is or will be included in a strategic national stockpile.

The Master Randomization List must be kept by the:

Sponsor

Who "Determines"

Sponsor

Who decides if something is caused by the drug

Sponsor

Who decides if something is expected or unexpected

Sponsor

Definition of a Sponsor

Sponsor means a person who initiates a clinical investigation, but who does not actually conduct the investigation

IND safety reporting

Sponsor must notify FDA and Investigator or Potential serious risks asap but no later than 15 calendar days after sponsor determines the info qualifies for reporting

Site Qualification Visit

Sponsor or CRO visits the potential site to evaluate ability to conduct the protocol. Purpose is for sponsor to decide what sites to choose and they will assess the PI and staff qualifications, availability of appropriate equipment, and adequate potential Subject population to screen/enroll from.

IND Safety Report

Sponsors must notify FDA and all participating investigators of any adverse events associated with the use of a drug that are both serious and unexpected.

Fee-for-service

Sponsors will pay for actual work performed

16.64. What laws govern the conduct of federally funded research involving a deceased fetus, fetal material, or placenta?

State and/or local laws.

Form 1572

Statement of Investigator Agree to: Conduct trial according to Sponsor Protocol Let subjects know about the study drug Obtain ICF Keep adequate records Staff is trained

1572

Statement of Investigator for the IND

16.40. What information is an IRB required to preserve in its records that it receives from investigators regarding new information for study subjects?

Statements of significant new findings provided to subjects.

3 Exemptions from IRB requirement

Studies that started before 1981 Emergency situations Taste and Food Studies

How long is the reporting period for equity interest and significant payments?

Study period plus 1 year.

16.24. The requirements permitting expedited review of research by an IRB are the same as those in 21 CFR 56. To learn these requirements, study the question mentioned on the other side of this card.

Study question 4-36.

16.21. For federally funded research, the requirements for IRB decisions are based on the members available to vote are the same as those in 21 CFR 56.108. To learn these requirements, study the questions identified on the other side of this card.

Study questions 4-23 and 4-24.

16.22. The requirements for IRB review of research in 45 CFR 46.109, are the same as those in 21 CFR 56, with the exception of requirements for waiver of informed consent in emergency research, which applies only to FDA-governed research. To learn these requirements, study the questions identified on the other side of this card.

Study questions 4-25, 4-26, 4-29, 4-30, 4-32 and 4-33.

16.26. The requirements for utilizing an expedited IRB review process for minor changes and informing the full IRB are essentially the same as 21 CFR 56. To learn these requirements, study the questions identified on the other side of this card.

Study questions 4-37 and 4-38.

16.27. The criteria for IRB approval of federally supported research is similar to that required in 21 CFR 56.112. To learn this material, study the questions identified on the other side of this card.

Study questions 4-40, 4-41 and 4-42.

16.20. The IRD membership requirements for 45 CFR 46.107 are the same as those of 21 CFR 56.107. To learn these requirements, study the questions identified on the other side of this card.

Study questions 4-9 through 4-19.

16.47. Many of the required elements of informed consent from 21 CFR 50 and 45 CFR 46 are essentially the same. To study these elements, review the questions located on the back of this card.

Study questions: 2-36 through 2-39, 2-41 and 2-42, 2-44 through 2-48, 2-51 and 2-52.

16.50. Many of the requirements for documenting informed consent are the same for 21 CFR 50 as they are for 45 CFR 46. To study these requirements, review the questions located on the back of this card.

Study questions: 2-50, 2-53 through 2-55, 2-57 through 2-59.

5 Types of Source Documents

Subject Eligibility Informed Consent Safety (AE/SAE etc.) Study Visits/procedures/assessments Discontinuation/Termination of Study Subject

When is a protocol amendment required?

Submit to both FDA and IRB: 1. Changes in protocol that affect safety of subjects 2. Increase in drug dose or duration of exposure 3. Change of design of a protocol (eg dropping control group) 4. Adding new test 5. New investigator (within 30 days) Note: eliminating a hazard implement immediately & advise FDA

Investigator IND

Submitted by Physician who both initiates and conducts investigation (Sponsor PI).

FDA Form 1571

Submitted to FDA. IND becomes effective 30 days after receipt by FDA, barring any requests for additional information, and is approved if there are none.

45 CFR Part 46 - Department of Health Human services Vulnerable Populations (sub-parts)

Subpart A - Common Rule - Provision with intent to protect vulnerable subjects Subpart B - Protections for pregnant women Subpart C - Makes prisoners a protected population due to their incarceration Subpart D - Provides for assent of minors

Belmont Report (1979)

Summarizes the basic ethical principles and guidelines for the protection of human subjects of research. (Respect for persons, beneficence and justice)

Describe in general terms the content of each of the following "Subparts:" B; C; D;

Supart B: Pregnant woman Hint:b for baby Subpart C: Prisoners Hint:c for convicts Subpart D: Children Hint:d for deliquent Note: Subpart A is the "usual" consent; others are special cases...

21 CFR 56.113

Supervision or termination of IRB approval of research

SUSAR

Suspected and Unexpected Serious Adverse Reaction

Closed system

System access is controlled by persons who are responsible for the content of electronic records that are on the system

Open system

System access is not controlled by persons who are responsible for the content of electronic records that are on the system

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

What are some of the additional elements of human consent?

That this is research, anticipated risks & benefits, alternative treatments, confidentiality, compensation (if any), that participation is voluntary, and refer to clinicaltrials.gov

Nuremberg Military Tribunals: The Doctor's Trial

The American judges pronounced their verdict on August 20, 1947. Sixteen of the doctors were found guilty. Seven were sentenced to death. They were executed on June 2, 1948.

The World Medical Association (WMA) ethical principals for medical research involving human subjects is called...

The Declaration of Helsinki

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.

5-143 If, after eliminating data from a disqualified investigator, the FDA determines that an investigation cannot continue safely, what action will the FDA take?

The FDA will notify the sponsor who will be given an opportunity for a regulatory hearing on the continuation of the investigation. 21 CFR 812.119

5-145 If the FDA makes a determination that after removal of unreliable data from the consideration, the continued clearance or approval of the marketing application of a device cannot be justified, what action will occur?

The FDA will proceed to withdraw approval or rescind clearance of the medical device, in accordance with the applicable provisions of the Act. 21 CFR 812. 119

The _______ is responsible for ensuring the adequacy of the information required in Section 50.25 (except for the information described in 50.25(a)(8)

The IRB PART 50 -- PROTECTION OF HUMAN SUBJECTS Subpart B--Informed Consent of Human Subjects Sec. 50.23 Exception from general requirements.

16.71. Whose responsibility is it to determine whether children are capable of assenting to participate in a research trial?

The IRB.

Continuing Review

The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year

What is ICH?

The International Conference on Harmonization of Technical Requirements for the registration of Pharmaceuticals for Human Use Commonly referred to as the International Conference on Harmonization (ICH)

16.65. Under what conditions can modifications related to the requirements of additional protections for research related to fetuses, pregnant women and in vitro fertilization be made?

The Secretary of Health and Human Services may waive certain requirements, only after approval of an ethical advisory board, IRB approval, an opportunity for public comment and publication of the waiver in the Federal Register.

16.23. For federally supported research, who is responsible for publishing a list of categories of research that may be reviewed by the IRB through an expedited review procedure?

The Secretary, Health and Human Services, publishes the list in the Federal Register. A copy of the list is available from the Office for Protection from Research Risks (renamed the Office of Human Research Protection)

3. The responsibility for ensuring that the investigator understands a clinical trial lies with:

The Sponsor

The responsibility for ensuring that the investigator understands a clinical trial lies with:

The Sponsor

Who designates a device study as significant risk (SR) or non-significant risk (NSR)?

The Sponsor makes the initial determination of SR or NSR and then the IRB evaluates the study. Sometimes the IRB may defer to the FDA to make the initial determination.

Who Monitors the progress of all clinical trial investigations being conducted under its IND?

The Sponsor.

Inspection

The act by a regulatory authority of conducting an 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 sponsors or the CROs facilities, or at other establishments deemed appropriate by the regulatory authorities.

45 CFR

The common rule

5-163 import of investigational new drugs into the US is permissible provided the consignee meets one of three criteria. Name the 3 criteria. 21 CFR 312.110

The consignee 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.

15-55 The FDA is required to provide the sponsor with a written assessment of its review after receiving an IDE that involves an exception from informed consent within what specific period of time?

The correct answer is 30 days.

15-42 Labeling for investigational devices may never bear any false statements, but they may suggestion that a use if potentially beneficial if previous data suggests that it is. True or False?

The correct answer is False. A label may not bear any false or misleading information.

15-26 A monitor of a clinical investigation must be an employee of the sponsor or contract research organization and may not be paid as a contracted consultant. True or False?

The correct answer is False. A monitor may be an employee or contracted consultant to either a sponsor or a contract research organization.

15-70 If a sponsor is unable to make a statement of compliance with 21 CFR Part 58 (Good Laboratory Practice, or GLP, regulations), it may omit non-clinical laboratory studies from an IDE application. True or False?

The correct answer is False. All non-clinical laboratory studies must be submitted, even if a statement of compliance with 21 CFR 58 cannot be provided.

14-19 An IRB cannot receive consulting information from anyone other than members of the IRB who have full voting privileges. True or False?

The correct answer is False. An IRB may obtain expert information from external sources when adequate expertise is not present within the IRB membership. However, external consultants may not vote on any decisions, because they are not members of the IRB.

14-26 An IRB must require that informed consent documents are compliant with the required elements of informed consent (21 CFR 50.25), but it cannot require any additional criteria. True or False?

The correct answer is False. An IRB may require additional information be given to subjects when the IRB believes that the information would meaningfully protect and enhance the rights and welfare of the subjects.

15-71 A medical device investigation cannot start until the sponsor receives written notification from the FDA. True or False?

The correct answer is False. An investigation may begin when 30 days have passed after the date that FDA received the application, unless the device is banned or the sponsor is notified it may not begin the investigation. Or, the sponsor may begin anytime following receipt of an FDA approval of the IDE.

15-64 In an IDE application, a statement describing the environmental impact of a device is an optional component, while all of the labeling and information that is provided to subjects during the consent process is a mandatory piece. True or False?

The correct answer is False. Either an environmental impact assessement or a claim for categorical exclusion must be submitted as well.

14-37 An IRB may use the expedited review process to approve or disapprove research if there is only a minor change to the research plan. True or False?

The correct answer is False. Expedited review may only be used to approve and not to disapprove the research.

13-17 Applicants who request marketing approval for drugs, biologics or devices are only required to submit the appropriate financial certification or disclosure statements to the FDA for the specific studies that the applicant sponsored. True or False?

The correct answer is False. Financial certification or disclosure statements must be submitted whether or not the applicant directly contracted for the study.

15-65 When you re-submit each new IDE application, all information that was previously submitted must be included. True or False?

The correct answer is False. It may be incorporated into the IDE application as a reference.

13-36 Applicants may dispose of records of clinical investigator financial disclosure one year following approval of an application. True or False?

The correct answer is False. Records must be retained for a minimum of two years.

15-47 An investigator is allowed to promote an investigational device as safe and effective to other clinicians during its investigation. True or False?

The correct answer is False. Representation that an investigational device is safe or effective for the purposes for which it is being investigated is prohibited.

15-21 A device that is placed in the body for a time period of less than 30 days cannot be defined by the FDA as an implant. True or False?

The correct answer is False. The FDA may define such a device as an implant to achieve the mission of protecting the public health.

14-60 The only legal action that can be undertaken by the FDA against an IRB is disqualification. True or False?

The correct answer is False. The FDA may proceed with additional civil or criminal charges, before, during or after the inspection and subsequent disqualification process. Legal actions may be filed at the local, state or federal level.

15-43 The sponsor can test market an investigational device within a relevant audience. True or False?

The correct answer is False. The FDA must have approved the device for commercial distribution before any test marketing or promotion occurs.

14-28 If an IRB waives the need for documented informed consent, the IRB may not require an investigator to give research subjects a written statement about the research. True or False?

The correct answer is False. The IRB may require investigators to provide a written statement regarding the research.

14-11 Diversity with respect to race, gender, cultural background as well as sensitivity to community attitudes are not criteria for IRB membership. True or False?

The correct answer is False. The IRB membership should include these qualifications.

14-38 The full IRB committee does not need to be informed of an expedited decision on research. True or False?

The correct answer is False. The IRB must have a mechanism in place to inform all members of expedited review decisions.

14-12 IRBs shall be able to determine the acceptability of proposed research in terms of institutional commitments, but not for regulations, applicable law or standards of professional conduct or practice. True or False?

The correct answer is False. The IRB shall be able to determine the acceptability of research for all of these criteria.

15-46 The sponsor can prolong a Class II device investigation until the collected data complies with the applicable performance standard. True or False?

The correct answer is False. The investigation may not be unduly prolonged and must be terminated if the developed data indicates that it will comply with an applicable performance standard or an amendment to that standard.

15-40 A device label may state that the device is safe or effective, provided it is the primary study objective. True or False?

The correct answer is False. The statement is prohibited on investigational device labels.

15-25 The term monitor, used as a noun, refers to a person who conducts and also reviews the data for a medical device investigation. True or False?

The correct answer is False. The term monitor, when used as a noun, refers to a person who is designated by a sponsor or contract research organization to oversee the progress of an investigation.

15-37 A previously unreported beneficial effect that is observed during a clinical investigation of a medical device is defined as an unanticipated adverse device effect. True or False?

The correct answer is False. Beneficial observations are not considered as unanticipated adverse effects.

14-52 The FDA is allowed to inspect IRB records at reasonable times and in a reasonable manner, but they cannot take any copies of IRB records. True or False?

The correct answer is False. The FDA may also copy the records.

15-74 Can a sponsor challenge an FDA disapproval order? True or False?

The correct answer is False. The sponsor may request a hearing regarding the application.

13-12 According to the FDA's financial disclosure regulations, treatment protocols, parallel track protocols and large open safety studies at multiple sites always require investigator financial disclosure. True or False?

The correct answer is False. These types of studies generally are not considered covered clinical studies.

14-23 As long as a majority of the IRB members are present at a review meeting, research may be approved without regard to the areas of primary concern represented by those who are present. True or False?

The correct answer is False. A majority of members must be present in order for research to be approved, including at least one member whose primary concerns are in non-scientific areas.

15-32 The definition of 'subject' does not include volunteers who are healthy. True or False?

The correct answer is False. A subject may present with normal health or have a medical condition or disease.

13-1 The purpose of disclosing financial information and interests in a particular clinical study is to support the FDA's evaluation of marketing applications for drugs, biologics and devices. True or False?

The correct answer is True.

13-10 The term "covered clinical study" can include any human study with a drug or device submitted to the FDA in a marketing application or reclassification petition, in which a single investigator makes a significant contribution to the demonstration of safety. True or False?

The correct answer is True.

13-11 Generally, the majority of Phase I trials are not included in the FDA's definition of covered clinical studies, as it relates to financial disclosure by clinical investigators. True or False?

The correct answer is True.

13-13 Applicants submitting marketing applications or reclassification petitions to the FDA may have discussion with the FDA as to which studies constitute "covered clinical studies". True or False?

The correct answer is True.

13-16 The term "sponsor of the covered clinical study" describes the party supporting a clinical study at the time it was carried out. True or False?

The correct answer is True.

13-18 The applicant must provide a list of all clinical investigators, who are full-time and part-time employees of the sponsor for each covered study. True or False?

The correct answer is True.

13-19 Applicants must include lists of all clinical investigators who are not full-time or part-time employees of the sponsor for each covered study. True or False?

The correct answer is True.

13-2 The FDA could consider studies or data inadequate if steps have not been taken in the design, conduct, reporting, and analysis to minimize bias. True or False?

The correct answer is True.

13-20 Clinical investigators subject to the investigational new drug or investigational device exemption regulations must provide sponsors with adequate information to enable the sponsor to comply with the financial disclosure regulations. True or False?

The correct answer is True.

13-23 Sponsors submitting marketing applications for drugs, biologics or devices are required to include Form FDA 3454, which documents the absence of financial interests and arrangements for those investigators who provided such information to the sponsor. True or False?

The correct answer is True.

13-24 The Chief Financial Officer (CFO), or another responsible corporate official of the sponsor must personally sign and date Form FDA 3454. True or False?

The correct answer is True.

13-26 Applicants are required to include a completed Form FDA 3455 in all marketing applications in which any clinical investigator has disclosed financial arrangements. True or False?

The correct answer is True.

13-31 When assessing the potential of an investigator's financial interest to bias a study, the FDA will consider the design and purpose of a study. True or False?

The correct answer is True.

13-33 The applicant is required to keep and maintain records of financial interests of clinical investigators once a marketing application has been submitted. True or False?

The correct answer is True.

13-9 When applied to the principle of financial disclosure, the term "covered clinical study" includes any human study of a drug or device submitted in a marketing application or reclassification petition that the FDA or applicant relies on to establish effectiveness. True or False?

The correct answer is True.

14-10 An IRB must be qualified through its combination of experience, expertise and diversity to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. True or False?

The correct answer is True.

14-24 In order for research to be approved, the members at the meeting must approve the research by a majority vote. True or False?

The correct answer is True.

14-3 In the FDA's Institutional Review Board regulations, the related terms of research, clinical research, clinical study, study, and clinical investigation are deemed to be synonymous. True or False?

The correct answer is True.

14-33 The IRB has the right to require that a third party be allowed to observe the consent process and the research. True or False?

The correct answer is True.

14-41 When evaluating risks and benefits, the IRB should only consider those benefits that may result from the research; they should not consider possible long range effects of applying knowledge which may be gained from the research. True or False?

The correct answer is True.

14-43 Prior to approving research, the IRB is required to ensure that the procedures for obtaining and documenting informed consent or consistent with FDA requirements. True or False?

The correct answer is True.

14-44 An institution may require reviews of research in addition to the IRB's review, but may not approve research not already approved by an IRB. True or False?

The correct answer is True.

14-45 An IRB may not approve research if it finds that they safety of the research subjects are not being adequately monitored through the review of data collected, or if subject privacy and confidentiality of data is not adequately protected. True or False?

The correct answer is True.

14-5 IRB approval is required for any drug, device, or biologic research product subject to FDA regulation unless the research project qualifies for an exemption criteria. True or False?

The correct answer is True.

14-53 If an IRB refuses to allow an inspection of records by the FDA, the FDA has the right to disallow any data from a clinical investigation reviewed by the IRB in support of an NDA. True or False?

The correct answer is True.

14-55 Generally, the FDA will direct any administrative actions imposed on an IRB against the parent institution because of the presumption that the institution is responsible for the operation of the IRB. True or False?

The correct answer is True.

14-56 In addition to disqualifying an IRB, the FDA also is able to disqualify the IRB's parent institution. True or False?

The correct answer is True.

14-57 The IRB may be disqualified if the rights or welfare of research subjects are adversely affected by the IRB's non-compliance. True or False?

The correct answer is True.

14-58 If an IRB or a parent institution are disqualified, the FDA may notify other interested parties such as sponsors or investigators. Additionally a notice of this action may be published in the FEDERAL REGISTER. True or False?

The correct answer is True.

14-6 The FDA may disallow consideration for data supporting an NDA if the data is from a study which was not approved by an IRB and a waiver of approval was not issued by FDA. True or False?

The correct answer is True.

14-8 Upon application from a sponsor, or sponsor-investigator, the FDA has the power to waive the requirement for IRB review for either a specific research activity or for a class(es) of research activities. True or False?

The correct answer is True.

15-22 The term "institution" or "facility" that appears in the regulations includes device manufacturers. True or False?

The correct answer is True.

15-24 The term 'investigation' in the IDE regulations refers only to clinical investigations of devices with human subject and doesn't include animal research studies. True or False?

The correct answer is True.

15-27 The term 'non-invasive' when used to describe a diagnostic device or procedure means that the device or procedure does not by design or intention, enter the ear beyond the external auditory canal or the nose beyond the nares. True or False?

The correct answer is True.

15-28 According to the IDE regulations, simple venipuncture is not considered to be an invasive procedure, nor is using surplus amounts of body fluids or tissue samples obtained through venipuncture and used for non-investigational purposes. True or False?

The correct answer is True.

15-31 When a person, other than an individual, uses at least one or more of its employees to conduct an investigation that it has initiated as a sponsor, the entity is the sponsor and the employees are the investigators. True or False?

The correct answer is True.

15-36 Adverse device effects that are described in the Report of Prior Investigations and included in the original IDE application are not considered to be unanticipated adverse device effects, if they recur in the same nature in a clinical study. True or False?

The correct answer is True.

15-39 A device label or other labeling must contain all relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings and precautions. True or False?

The correct answer is True.

15-44 Can a subject in a medical device investigation be charged a reasonable amount that is deemed necessary to recover the cost to manufacture, research, develop and handle the device? True or False?

The correct answer is True.

15-48 A sponsor may ask the FDA to waive any requirement of the IDE regulations along with applicable supporting documentation. True or False?

The correct answer is True.

15-51 A person must obtain the FDA's prior approval before exporting an investigational device under an IDE. True or False?

The correct answer is True.

15-54 A sponsor cannot start an investigation until they receive the IDE application approval from the FDA. True or False?

The correct answer is True.

15-56 If an IDE application will be conducted under the exception from informed consent criteria in 21 CFR 50.24, that fact must be prominently identified on the application cover page. True or False?

The correct answer is True.

15-57 When submitting an IDE application, sponsors must include a complete report of prior investigation as well as a summary of or the full investigational plan. True or False?

The correct answer is True.

15-61 When putting together the IDE application, it must contain a list that has the name of the chairperson and the address of all the IRBs that have been asked to review to investigation and certification of the action of each IRB. True or False?

The correct answer is True.

15-62 Any research location intended to be used in a device investigation that is different from the location of the reviewing IRB must be listed separately in the IDE application. True or False?

The correct answer is True.

15-73 When the FDA disapproves or proposes to withdraw an application, the sponsor will receive written notification. True or False?

The correct answer is True.

15-77 Do you need to file a separate IDE application if the sponsor wants to conduct an investigation involving an exception to informed consent under 21 CFR 50.24? True or False?

The correct answer is True.

15-41 Is IDE labeling required if an investigational device is shipped only for animal research?

The correct answer is Yes. The label must state: 'CAUTION-Device for investigational use in laboratory animals or other tests that do not involve human subjects.'

15-30 Please name at least three criteria for classifying an investigational device as a significant risk device.

The correct answer is a device that when used alone, or as follows, presents a potential for serious risk to the health, safety, or welfare of a subject: 1. Is intended as an implant. 2. Is important in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health. 3. Used in supporting or sustaining human life.

15-59 What judgment must be rendered by the FDA based on the following IDE application information: Methods, facilities and controls for manufacturing, as well as processing, packaging and storage of the investigational device and installation (if appropriate)?

The correct answer is a knowledgeable judgment about the quality control used in the manufacture of the device must be made by a person reasonably familiar with good manufacturing practices.

15-34 Please provide the term that is applied to a device that the FDA considered to be a new drug or antibiotic, prior to May 28, 1976?

The correct answer is a transitional device.

15-29 In the IDE regulations, name at least four entities that are considered as a 'person'.

The correct answer is any individual, partnership, corporation, association, scientific or academic establishment, government agency or unit of a government agency, or any other legal entity.

14-32 What is the required time interval for an IRB to conduct continuing review of previously approved research?

The correct answer is at intervals appropriate to the degree of risk, but not less than once per year.

14-16 What IRB requirements are created regarding members with scientific and non-scientific expertise?

The correct answer is at least one member must have primary expertise in a scientific area, and at least one member must have primary expertise in a non-scientific area.

14-40 The IRB must determine that the risk in procedures to be used in the proposed research are minimized. Please name the two criteria by which this is assured.

The correct answer is by using- 1. Procedures that are consistent with sound research design and which do not unnecessarily expose subjects to risk. 2. Procedures already being performed on the subject for diagnostic or treatment purposes.

15-68 When you complete the report of prior investigations, you must include information on all prior testing of the device in which three areas?

The correct answer is comprehensive reports are required on clinical, animal and laboratory testing that are adequate to justify the proposed investigation.

14-2 The FDA's Institutional Review Board regulations apply to research used in marketing applications for which categories of products?

The correct answer is drugs, including over the counter drugs; biologics; devices; color additives; additive substances affecting the characteristics of or becoming a component of food; and electronic products.

14-4 In the FDA's Institutional Review Board regulations, what is the definition of the term "emergency use"?

The correct answer is emergency use means 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 not sufficient time to obtain IRB approval.

14-7 Emergency use of a test article may occur prior to IRB approval, with the stipulation that such use is reported to the IRB within how many working days?

The correct answer is five working days.

14-9 What is the minimum number of members that an IRB must have?

The correct answer is five.

14-36 When can the IRB use an expedited review process, other than research found to involve no more than minimal risk?

The correct answer is for minor changes in research which was previously approved by the IRB during the period that the approval is active (1 year or less).

14-27 Describe the circumstances under which an IRB may waive the requirements for documentation of informed consent?

The correct answer is if the IRB finds that the research involves no more than minimal risk or harm to subjects and involves no procedures for which written consent is normally required outside of the research context, or if some or all of the subjects meet the exception from informed consent for emergency research in 21 CFR 50.24.

14-35 When the IRB publishes a list of research categories that may be reviewed using an expedited review process, where, and how often is the list published?

The correct answer is in the FEDERAL REGISTER by the FDA. This list is updated periodically, when deemed necessary by the FDA.

15-45 What should a sponsor do if the data collected from the investigation or a Class III device cannot justify a pre-market approval from the FDA?

The correct answer is promptly terminate the investigation.

15-35 The concept of 'unanticipated adverse device effect' includes any serious adverse effect on safety or health, or a life-threatening problem or death that is either caused by or associated with what?

The correct answer is that a device, if the problem, effect or death has not been previously identified in nature, severity or degree of incidence in the investigational plan or application, or is any other unanticipated serious problem associated with a device that relates to the rights, safety or welfare of subjects.

14-22 For the purpose of a routine, full review of proposals, how many IRB members must be present in order for research to be approved?

The correct answer is that a majority of the membership of the board must be present at a convened meeting.

14-15 What are the IRB membership requirements regarding differing positions?

The correct answer is that no IRB may consist of members of just one profession.

14-14 Non-discriminatory efforts should be undertaken to ensure that no IRB consists entirely of men, or of women, so long as what standard applies?

The correct answer is that no selection is made to the IRB, based solely on a person's gender.

14-17 IRB membership shall include at least one person who is not affiliated with the institution where the IRB is located. This member must also meet what additional criteria?

The correct answer is that this member cannot be an immediate family member of a person who is affiliated with the institution.

15-76 Who grants approval for a supplemental application to change an investigational plan?

The correct answer is the FDA and the reviewing IRB, when appropriate.

15-52 Who receives the applications, reports or requests for a waiver of the IDE requirements?

The correct answer is the FDA's Center for Devices and Radiological Health.

14-30 In addition to providing written notification of its disapproval of research, what additional activity must the IRB allow to occur?

The correct answer is the IRB must allow the investigator to respond in writing or in person.

14-31 If an IRB discovers that proposed research involving an exception to informed consent for emergency research does not meet the requirements of 21 CFR 50.24, or if it determines that the research is not ethical, whom must the IRB notify?

The correct answer is the IRB must promptly notify the investigator and the sponsor of the research in writing, and include the reason(s) for its finding.

14-29 Who receives the written statement from the IRB explaining its actions when a decision is made regarding approval of a research project?

The correct answer is the institution and the investigator.

14-1 What is the FDA's intention of having Institutional Review Boards strictly follow the regulations of 21 CFR 56?

The correct answer is the intention is to protect the rights and welfare of human subjects involved in investigations regulated by the FDA.

15-50 Name the two criteria that must be met for any person who imports or offers for import, an investigational medical device into the U.S.

The correct answer is the person is the agent with respect to investigations and acts as the sponsor, or ensures that another person acts as the agent of the foreign exporter and the sponsor of the investigation.

15-49 The FDA is able to grant by letter, a waiver of any IDE requirement only if it finds that what conditions are present?

The correct answer is the requirement is not required by the Act, and is unnecessary to protect the rights, safety or welfare of human subjects.

14-34 If an IRB is required to publicly disclose information according to 21 CFR 50.24, then based on its findings in the review of emergency research, whom must the IRB notify?

The correct answer is the sponsor, promptly. the sponsor shall then promptly notify the FDA.

15-33 When considering medical device investigations, what is the FDA's definition of the term 'termination'?

The correct answer is the term termination means a discontinuance, by the sponsor or by withdrawal of the IRB's or FDA's approval, of an investigation before completion.

14-51 What is the requirement for how long an IRB must retain the records for each research project?

The correct answer is three years after the completion of the research.

14-59 What does a disqualified IRB need to do in order to be considered for reinstatement by the FDA?

The correct answer is to provide a written statement from the IRB or institution explaining the corrective action that will be taken and include the language that the IRB will operate in compliance with the FDA's IRB requirements.

14-18 No IRB member may participate in the initial or continuing review process of the board for any projects that they have declared a conflict of interest except to provide what?

The correct answer is to provide information requested by the IRB.

15-75 What would be the reason for the FDA to withdraw approval of an IDE before any sponsor hearing?

The correct answer is typically the FDA will issue a proposed withdrawal of approval and permit the opportunity for a hearing prior to a withdrawal. However, if continuing the testing will result in an unreasonable risk to the public health, the FDA may withdraw approval prior to a hearing.

14-39 The FDA may terminate, suspend or restrict an IRB's use of the expedited review procedure under what circumstances?

The correct answer is when deemed necessary to protect the rights or welfare of human subjects.

15-69 Please name three specific content requirements of the report of prior investigations.

The correct answer is- 1. A bibliography of all publications, whether adverse or supportive. 2. All published and unpublished adverse information. 3. Any other significant publications requested by the FDA or an IRB. 4. A summary of all other unpublished information.

15-60 What items must appear in the IDE application with respect to investigators?

The correct answer is- 1. An example of the investigator agreement to state compliance with all investigator obligations under the IDE 2. A list of investigator names and addresses who have signed the agreement, and 3. sponsor certification that no additional investigators will be added to the investigation until they have signed the agreement.

14-25 Please list three actions that an IRB has the authority to perform.

The correct answer is- 1. Approve research 2. Disapprove research 3. Require modifications before granting approval of research.

14-50 What is the membership information that must be maintained by the IRB?

The correct answer is- 1. Certifications and licenses, sufficient to describe the primary anticipated contribution of the member. 2. Relationship between the institution and the IRB member.

14-42 The IRB is responsible for ensuring the equitable selection of subjects. Please name at least four vulnerable populations that the IRB needs to pay special attention to so as to ensure that these subjects receive additional safeguards and are selected equitably.

The correct answer is- 1. Children 2. Prisoners 3. Pregnant women. 4. Handicapped persons. 5. Mentally disabled persons. 6. Economically or educationally disadvantaged persons.

14-20 Please list at least three areas that an IRB must have written operating procedures that govern their actions and responsibilities.

The correct answer is- 1. Conducting initial and continuing review of research and reporting its actions and findings to the investigators and affiliated institutions. 2. Identifying projects required more than annual review and those that need to receive information from sources other than the investigator. 3. Establishing requirements for promptly reporting any changes in the research plan. 4. Ensuring changes in research are not initiated without IRB approval except when it may be necessary to eliminate hazards to study subjects.

14-48 How can institutions who are involved in multi-institutional studies avoid duplication of effort? Please list two ways.

The correct answer is- 1. Joint review with other institutions. 2. Reliance on the review of another qualified IRB.

15-38 There are three labeling requirements for investigational devices or their immediate package. Please name them.

The correct answer is- 1. Name and address of the manufacturer, packer or distributor. 2. Quantity of the contents, if appropriate, and 3. The statement: 'CAUTION - Investigational Device. Limited by Federal or U.S. Law to investigational use.'

15-58 The IDE application must include the full investigational plan, not only a summary, when one of three conditions exist. Please name these conditions.

The correct answer is- 1. No IRB has reviewed them. 2. The FDA has found the IRB's review inadequate. 3. Upon request by the FDA.

15-66 An investigational plan contains ten sections. Please name five of them.

The correct answer is- 1. Purpose 2. Protocol 3. Risk Analysis 4. Device description 5. Monitoring procedures 6. Labeling 7. Consent materials 8. IRB information 9. Other institutions 10. Additional records and reports

15-63 If a device will be sold, what 2 things must be detailed in the IDE application?

The correct answer is- 1. The amount that will be charged. 2. An explanation of why selling the device does not constitute commercialization.

14-47 Who must be notified when an IRB terminates approval for research?

The correct answer is- 1. The investigator 2. The appropriate institutional officials. 3. The FDA.

14-46 An IRB may suspend or terminate approval of research under what conditions?

The correct answer is- 1. The research is not being conducted in accordance with the IRB's requirements. 2. The research has been associated with unexpected serious harm to subjects.

14-49 Please name at least four items that an IRB must maintain for each research project that is approved.

The correct answer is- 1. The research proposal or protocol. 2. Approved sample consent form. 3. Investigator progress reports. 4. Reports of injuries to subjects. 5. All correspondence with investigators. 6. Statements of new findings provided to subjects. 7. Detailed minutes of the IRB meeting. 8. Records of continuous review.

15-72 What are the additional reasons that the FDA may disapprove or withdraw an IDE application, besides 1) failure to comply with any requirement of the IDE, 2) an application that contains false or omitted information and 3) sponsor failure to provide additional information within the established FDA time frames?

The correct answer is- 1. The risks to the subjects are not outweighed by the benefits. 2. The investigation is not scientifically sound. 3. The device, as used, is ineffective. 4. The Report of Prior Investigations is inadequate. 5. Manufacturing processes and installation of the device is inadequate. 6. Monitoring and review of the investigation is inadequate.

15-67 Name the three main areas that are covered in an investigational plan, which must describe and analyze all increased risks to which a subject will be exposed to during an investigation.

The correct answer is- 1. The stops taken to minimize the risks. 2. A justification for the investigation. 3. A description of the patient population, including the number, age, sex and condition.

14-21 Name at least two areas where IRB's must have written procedures which ensure prompt reporting to the IRB, the institutional officials and the FDA.

The correct answer is- 1. Unanticipated problems involving risks to human subjects or others. 2. Serious or ongoing non-compliance with federal regulations or IRB requirements. 3. any suspension or termination of IRB approval.

14-54 If the FDA finds non-compliance during an initial or a follow-up inspection of IRB records, the FDA may impose restrictions on the IRB while awaiting corrective action to address the issues. Please name two of the possible restrictions.

The correct answer is- 1. Withhold approval of new studies subject to the requirements. 2. Direct that no new subjects be added to ongoing studies. 3. Terminate ongoing studies when doing so would not endanger the safety of the subjects. 4. Notify the relevant state and federal authorities when the IRB's apparent non-compliance poses a significant threat to the rights and welfare of the subjects.

14-13 What are the IRB membership requirements when the IRB routinely reviews research that involves a vulnerable category of subjects, including children, prisoners or mentally disabled persons?

The correct answer is: The IRB must consider adding one or more people to their board who are knowledgeable about or have experience in working with vulnerable populations.

13-5 What does the phrase "compensation affected by the outcome of clinical studies" mean?

The correct answer is: "Compensation affected by the outcome of clinical studies" means compensation that could be higher for a favorable outcome than for an unfavorable outcome of a study.

13-6 What does "significant equity interest in the sponsor of a covered study" mean?

The correct answer is: "Significant equity interest in the sponsor of a covered study" refers to any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices (i.e. interests in a non-publicly traded corporation), that exceeds $50,000, during the time the investigator is carrying out the investigation and for one year following completion of the study.

13-32 If the FDA determines that the integrity of the data is in question due to the financial interests of an investigator, what are some of the steps that they might take?

The correct answer is: -initiating data audits; -requesting the applicant submit further analyses of the data; -requesting the applicant conduct additional independent studies to confirm initial results; -refusing to treat the study as providing reliable data.

13-3 Name three potential sources of bias in relation to financial matters and clinical studies.

The correct answer is: 1. Financial interest of the clinical investigator in the outcome of the study. 2. Proprietary interest in the product (e.g. a patent, trademark, copyright, etc.). 3. Equity interest in the sponsor.

5-65 Name at least two specific clinical adverse experience summary items required in a IND annual report.

The correct answer is: 1. Most frequent and most serious adverse experiences by body system. 2. IND safety reports submitted within the past year. 3. List of subjects who died with cause of death. 4. List of subjects who dropped due to an adverse experience.

13-15 Define the term "applicant" within the context of the FDA's financial disclosure regulations.

The correct answer is: A party who submits a marketing application to the FDA for approval of a drug, device or biologic product.

13-28 Besides providing financial disclosure information from investigators, what must the sponsor include in marketing applications with Form FDA 3455?

The correct answer is: A statement of any steps taken to minimize the potential for bias resulting from any of the disclosed arrangements, interests, or payments.

5-141 To whom may a investigator administer or supply investigational drug?

The correct answer is: Drug may be administered only to subjects under an investigator's supervision; drug may only be supplied to those under direct supervision of investigator for use in clinical study.

5-138 What precautions must a sponsor take regarding storage of investigational drugs that also controlled substances?

The correct answer is: Ensure the drug is stored in securely locked, or substantially constructed cabinet or other securely locked, substantially constructed enclosure, access to which is limited to prevent theft or diversion of the substance into illegal channels of distribution.

13-4 How does the FDA utilize financial disclosure information from investigators?

The correct answer is: It is used in conjunction with other information to assess the reliability of the data.

5-139 Under what conditions may a investigator dispose of an investigational drug?

The correct answer is: Only under written authorization by the sponsor; the sponsor must also ensure that the disposition method will not expose humans to risks from the drug.

13-14 How does the FDA define the term "significant payment of other sorts", as it relates to financial disclosures by clinical investigators?

The correct answer is: Payments made by the sponsor of a covered study to the investigator or institution that exceed the value of $25,000 USD, during and for one year after the completion of the study. This does not include the costs for conducting the study.

13-27 List the four situations in which clinical investigators must provide financial disclosure.

The correct answer is: Receipt of: 1. Compensation affected by the outcome of the study. 2. Significant payment of other sorts. 3. Significant equity interest in the sponsor. 4. Proprietary interest in the tested product.

13-34 How long is the applicant required to maintain financial records of clinical investigators?

The correct answer is: Records must be maintained for two years after the date of approval of the application.

5-114 When a sponsor receives information from an IRB regarding public disclosure of research being conducted under exception to informed consent, what action must sponsor take?

The correct answer is: Submit copies of the information disclosed to both the IND file and the Dockets Management Branch of FDA.

5-137 Who may inspect records of investigational drugs that also controlled substances?

The correct answer is: The FDA and the DEA (Drug Enforcement Administration) of the US Department of Justice.

13-30 If the required financial certification or disclosure information is not submitted to the FDA in a marketing application, what actions may be taken by the FDA?

The correct answer is: The FDA may refuse to file the marketing application.

13-21 What financial information does an applicant need to provide to the FDA for investigators in covered clinical studies?

The correct answer is: The applicant is required to send in either a certification that none of the financial arrangements in 21 CFR 54.2 exist, or disclose the nature of those existing arrangements for each clinical investigator.

13-22 If an applicant, using due diligence to obtain financial information required in 21 CFR 54, cannot obtain the information from a clinical investigator, what additional action must the applicant take?

The correct answer is: The applicant must certify to the FDA that despite due diligence being taken, the information was not obtainable and include the reason.

13-25 If a submitted Form FDA 3454 does not cover all clinical data in the application, what additional information needs to be sent in?

The correct answer is: The applicant shall include a list of the studies covered by the certification.

13-29 If an investigator's financial arrangements with the sponsor of a covered study change during or for one year following the completion of the study, what does the investigator need to do?

The correct answer is: The investigator must promptly update the information with the sponsor.

5-113 What is the sponsor's regulatory responsibility with respect to selecting investigators?

The correct answer is: The sponsor must select only investigators qualified by training and experience to investigate drug

13-8 What people are included in the term "clinical investigator" as defined in the FDA's financial disclosure regulations?

The correct answer is: The term "clinical investigator" includes only listed investigators or sub-investigators who are directly involved in the evaluation or treatment of research subjects. The term also includes the spouse and each dependent child of the investigator.

13-7 What term describes property or other financial interests in a product, to include a patent, trademark, copyright or licensing agreement?

The correct answer is: This refers to the term "proprietary interest".

5-135 Upon written request from FDA, the sponsor is required to submit records or reports of clinical investigations to the FDA. True or False?

The correct answer is: True

5-136 Sponsors should discontinue shipment of drug to any investigator who failed to make available, records or reports of an investigation covered by the IND regulations. True or False?

The correct answer is: True

5-140 Investigators are responsible for ensuring that a clinical investigations is conducted in full compliance with signed investigator statement and applicable regulations. True or False?

The correct answer is: True

13-35 Can the FDA request access to an applicant's financial records or clinical investigator's after the application has been approved?

The correct answer is: Yes. The FDA has authority to have access to, copy, and verify the financial records at reasonable times.

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.

15-9 Name two of the four criteria that apply to the testing of diagnostic devices that will render the device exempt from the FDA's IDE regulation.

The correct answer is: 1. It is non-invasive. 2. It does not require invasive sampling that is significant risk. 3. It does not introduce energy by design or intention. 4. It is not the sole diagnostic method used.

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.

15-6 Name at least two of the abbreviated requirements that apply to the clinical investigation of devices that re not banned, nor considered to be significant risk.

The correct answer is: 1. The device is properly labeled. 2. IRB approval is obtained and maintained. 3. Informed consent is obtained and maintained. 4. Proper monitoring is conducted. 5. Sponsors and investigators maintain appropriate records. 6. Promotion is prohibited.

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".

16.10. For federally supported research, "human subject" means a living individual with whom an investigator (whether professional or student) conducting research obtains either of which two items?

The correct answer is: 1). Data through intervention or interaction with the individual. or 2). Identifiable private information.

16.12. Regulations for federally supported research the term "private information" includes two types of information. Name them

The correct answer is: 1). Information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place. 2). Information which has been provided for specific purposes by an individual can reasonably expect to not be made public (i.e. a medical record).

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

16-1. What are the types of human drug research are required to comply with DHHS regulations?

The correct answer is: All studies that are conducted by, supported or are otherwise subject to regulation by any federal department or agency that defines this regulation as applicable.

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

15-56: 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.

16.59. True or False? Since it is an IRB responsibility, federal agencies are not allowed to impose additional conditions prior to or at the time approval of a research project, if the department or agency determines that the additional conditions are necessary for the protection of human subjects.

The correct answer is: False. Additional conditions may be imposed at the discretion of the agency.

16.34. True or False? An institution participating in a cooperative project may enter into a joint review arrangement, rely upon the review of another qualified IRB, or make similar arrangements for avoiding duplication of effort.

The correct answer is: False. Approval of the department or agency head is required prior to entering such agreements.

16-2. True or False? Is it possible for direct or indirect identification of human subjects in education research settings can be the only condition under which education research is typically subject to the requirements of 45 CFR 46.

The correct answer is: False. If disclosure of information from cognitive research could reasonably place the study subjects at risk of criminal or civil liability, or be damaging to their financial standing, employability or reputation, the research is also subject to the requirements of 45 CFR 46.

16.37. True or False? IRBs reviewing federally supported research are required to keep records of continuing review activities, only if the research is approved to continue.

The correct answer is: False. Records of all continuing review must be retained.

16.29. True or False? Determination of the adequacy of provisions to protect the privacy of subjects and to maintain the confidentiality of data, therefore, are not IRB responsibilities and do not impact approval of research.

The correct answer is: False. The IRB should determine these provisions are present in the research.

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.

15-126 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.

16.6. Unless otherwise required by law, department or agency heads may waive the applicability of some or all of the provisions of 45 CFR 46 to specific research activities which are otherwise covered by this policy, provided what is done with the waiver?

The correct answer is: Provided that advance notice is sent to the Office for Protection from Research Risks (renamed as Office of Human Research Protection), and published in the Federal Register or as otherwise provided in department or agency procedures.

16.5. For US-funded studies conducted outside of the US, a department or agency head can determine that the procedures prescribed by a local institution afford protections that are at least equivalent to those in 45 CFR 46, he/she may approve the substitution of the foreign procedures provided that what occurs?

The correct answer is: Provided the approval is published in the Federal Register or as provided in department or agency procedures.

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.

15-142 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

15-130: 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.

15-8 Devices, other than transitional devices, distributed after May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution before that date are exempted from IDE regulations, provided what condition(s) exist?

The correct answer is: The device is used or investigated in accordance with the indications in the labeling in effect at the time of the FDA made the determination of substantial equivalence.

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).

15-31: 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.

15-120: 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.

15-57: 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.

15-153 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

15-1 What is the purpose of a Investigational Device (IDE) Exemption Regulations in the conduct of clinical investigations of devices?

The correct answer is: The purpose is to encourage the discovery and development of useful devices intended for human use, while allowing freedom for scientific investigators.

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

15-2 IDE regulators provide procedures for the conduct of clinical investigations of devices. True or False?

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

15-3 Ide regulations permit a device that would otherwise be required to comply with a performance standard or to have pre-market approval to be shipped lawfully for the purpose of conducting investigations of that device. True or False?

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

15-4 A device that is either approved under or exempt from the IDE regulations is also generally exempt from certain of Food, Drug and Cosmetic Act requirements and associated regulators. True or False?

The correct answer is: True

15-5 Devices not considered as significant risk are generally considered to have approved IDEs, unless notified otherwise by FDA. True or False?

The correct answer is: True

15-7 Devices, other than transitional devices, distributed prior to May 28, 1976, and use or investigated in compliance with the requirements in effect at that time are not subject to IDE regulations. True or False?

The correct answer is: True

16.11. True or False? For research that is federally supported, the term "intervention" includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.

The correct answer is: True

16.13. True or False? Private information must be individually identifiable (i.e. the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order to obtain the information to constitute research involving human subjects.

The correct answer is: True

16.16. True or False? Federal Departments and agencies will conduct or support research covered by 45 CFR 46, only if the institution has certified to the department or agency head that the research has been reviewed and approved by an IRB, granted for in a valid assurance, and will be subject to continuing review by the IRB.

The correct answer is: True

16.17. True or False? Assurances applicable to federally supported or conducted research are required to include a statement of principles ascending the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects of research conducted at or sponsored by the institution, regardless of whether the research is subject to federal regulation.

The correct answer is: True

16.18. True or False? Assurances applicable to federally supported or conducted research are required to include specification of one or more IRBs established in accordance with the requirements of 45 CFR 46, and for which provisions are made for meeting space and sufficient staff to support the IRB's review and record keeping duties.

The correct answer is: True

16.19. True or False? Assurances applicable to federally supported or conducted research are required to include written procedures which an IRB will follow.

The correct answer is: True

16.25. True or False? A federal department or agency head may restrict, suspend, terminate, or choose not to authorize an institution's or IRB's use of the expedited review procedure.

The correct answer is: True

16.28. True or False? When appropriate, an IRB is required to determine whether or not, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.

The correct answer is: True

16.3. True or False? Research, which involves the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or indirectly, is not subject to the requirements of 45 CFR 46

The correct answer is: True

16.31. True or False? Institutions may require approvals in addition to the IRB approval, but may not approve the research if it has not been approved by an IRB.

The correct answer is: True

16.33. True or False? The IRB is responsible for ensuring that legal informed consent will be gathered for all clinical trial subjects.

The correct answer is: True

16.35. True or False? An institution, or when appropriate, an IRB, is required to prepare and maintain copies of all research proposals reviewed, approved sample consent documents, progress reports submitted by investigators, and reports of injuries to subjects.

The correct answer is: True

16.38. True or False? Maintaining copies of all correspondence between the IRB and investigators and a detailed list of IRB members that complies with federal regulations is requirement for all IRBs.

The correct answer is: True

16.39. True or False? IRBs are required to maintain written operating procedures.

The correct answer is: True

16.4. True or False? The requirements in 45 CFR 46 do not affect any state, local or foreign laws or regulations which may otherwise be applicable and which may provide additional protections for human subjects.

The correct answer is: True

16.42. True or False? Unless a federal policy permits otherwise, no investigator may involve a human being as a subject in research covered by 45 CFR 46, unless the investigator has obtained the legally effective informed consent from the subject or the subject's legally authorized representative.

The correct answer is: True

16.45. True or False? Subject matter describing the extent, if any, to which confidentiality of records identifying the subject will be maintained must be included in all informed consent documents.

The correct answer is: True

16.49. True or False? Nothing in 45 CFR 46 is meant to limit the authority of a physician to provide emergency medical care, to the extent the physician is permitted to do so under applicable federal, state, or local law.

The correct answer is: True

16.52. True or False? In some cases where the informed consent documentation requirement is waived, an IRB may require the investigator to provide subjects with a written statement regarding the research.

The correct answer is: True

16.57. True or False? Federal funds administered by a department or agency may not be expended for research involving human subjects unless the requirements of 45 CFR 46 have been met.

The correct answer is: True

16.58. True or False? A federal agency reserves the right to suspend or terminate any project if the agency head finds that the institution has materially failed to comply with the terms of 45 CFR 46.

The correct answer is: True

16.60. True or False? Although there are exceptions for obtaining a father's consent, prior to enrolling a pregnant woman into a federally-funded research project, the researcher must normally obtain bother her consent and the consent of the father.

The correct answer is: True

16.62. True or False? Federally funded research activities directed toward an in-utero fetus typically requires informed consent of both the mother and father, unless an exception applies.

The correct answer is: True

16.63. True or False? Federal regulations generally prohibit research on a viable ex-utero fetus, unless the research is planned to enhance the possibility of survival.

The correct answer is: True

16.7. True or False? Institutions which have DHHS-approved assurances on file are required to abide by the provisions of title 45 CFR part 46 subparts A-D.

The correct answer is: True

16.70. True or False? Even though a child may assent, the child's parent(s) or guardian(s) permission is required prior to enrolling children into research studies, unless a special exception applies.

The correct answer is: True

16.8. True or False? Exemptions from applicability of 45 CFR 46 do not apply to research in populations requiring additional protections which include prisoners, fetuses, pregnant women, or human in vitro fertilization.

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

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

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

16.32. True or False? An IRB shall have authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's requirements or that has been affiliated with unexpected serious harm to subjects.

The correct answer is: True. Additionally, any suspension or termination of approval shall include a statement of the reasons for the IRB's action and shall be reported promptly to the investigator, appropriate institutional officials and the department or agency head.

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.

15-16 Within the device regulations, "Act" refers to the U.S. Device Act. True or False?

The correct answer is: false. Federal Food, Drug and Cosmetic Act.

15-19 FDA means 'Federal Device Administration". True or False?

The correct answer is: false. Food and Drug Administration.

15-10 Provided subjects are not a risk, and a safety or effectiveness evaluation is made, consumer preference testing as well as testing of combinations of devices in commercial distribution is exempt from the IDE regulations. True of False?

The correct answer is: false. IF the purpose of the testing is to evaluate the safety or effectiveness of the device, it may not be exempt from the IDE regulations.

15-12 Investigations of custom devices are always exempt from IDE regulations. True or False?

The correct answer is: false. Investigations on custom devices are subject to the IDE regulations if the purpose of the research is to determine safety and efficacy for commercial distribution.

15-15 Prior to the existence of the IDE regulations on July 16, 1980, a sponsor conducting a trial with a device under the IND regulations of 21 CFR 312 was permitted to continue that investigation under the IND regulations until the product was approved for marketing by FDA? True or False?

The correct answer is: false. The sponsor was permitted to continue the investigation for 90 days; thereafter an approved IDE was required to continue the investigation.

15-11 Investigations of devices intended solely for veterinary use or for use in or on animals in research are exempt from the IDE regulations. True or False?

The correct answer is: true.

15-13 If an FDA regulation was published, or an order given for an unapproved class III device, a Premarket Approval (PMS) has been required since the date of the publication or the order. True or False?

The correct answer is: true.

15-14 If FDA has published a performance standard for a class II device, the standard is in effect regardless of the date of the initial commercial distribution of the device. True or False?

The correct answer is: true.

15-17 A 'custom' device is generally not available to or used by other physicians or dentists, nor is it available in finished form for purchase or use via prescription. True or False?

The correct answer is: true.

15-18 Customized devices deviate from generally available devices to comply with a physician's or with a dentist's order and are not offered for commercial distribution through advertising and labeling. True or False?

The correct answer is: true.

15-20 Implant generally means a device which 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. True or False?

The correct answer is: true.

16.9. Describe the definition of research in the DHHS regulation 45 CFR 46?

The correction answer is: Research means a systematic investigation, including research, development, testing and evaluation, designed to develop or contribute to generalizable knowledge.

5-142 If it is determined that an investigator is ineligible to receive investigational devices and data has been reported by this investigator, what action must occur?

The data will be examined to determine whether the investigator has submitted unreliable data that are essential to either the continuation of the investigation in question, or the approval/clearance of any marketing application. 21 CFR 812-119

6th principle of The Nuremberg Code

The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.

16.56. What decisions may a federal agency make in regard to an application submitted for funding that involves human subjects?

The department or agency head may approve or disapprove the application or proposal or enter into negotiations to develop an approvable one.

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).

IND Application

The document submitted to the FDA once adequate preclinical data has been obtained and there is reasonable justification to warrant studying the drug in humans.

Emergency use of an unapproved drug or device: what must be done afterwards

The drug must be evaluated within 5 working days after the use of the article in writing by a physician who is not participating in the clinical investigation.

What event led to the 1938 Federal Food, Drug, and Cosmetic Act?

The elixir sulfanilamide/ Diethylene Glycol incident Caused mass poisoning in the United States in 1937, resulting in the deaths of more than 100 people.

What's the TLDR for the Declaration of Helsinki?

The ends do not justify the means

8th principle of The Nuremberg Code

The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

4th principle of The Nuremberg Code

The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

3rd principle of The Nuremberg Code

The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problems under study that the anticipated results will justify the performance of the experiment.

2nd principle of The Nuremberg Code

The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.

IRB may use expedited review procedure to review either or both of the following:

The research found by the reviewer(s) to involve no more than minimal risk, Minor changes in previously approved research

16.54. What steps must be taken by institutions or investigators supported by federally funded research that is undertaken without the intention to involve human subjects, that later proposes to involve human subjects?

The research must first be reviewed and approved by an IRB, a certification submitted by the institution to the department or agency, and the final approval given to the proposed change by the department or agency.

A purpose of monitoring clinical trials is to verify that:

The rights, safety and well-being of human subjects are protected.

16.55. All applications and proposals involving human subjects submitted to a federal department or agency for funding will be reviewed by appropriate persons. What will the evaluation take into consideration?

The risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained.

Handwritten signature:

The scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form. The act of signing with a writing or marking instrument such as a pen or stylus is preserved. The scripted name or legal mark, while conventionally applied to paper, may also be applied to other devices that capture the name or mark.

Who is responsible for ensuring an investigator understands the clinical trial?

The sponsor

5-144 If the FDA determines that the unreliable data submitted by an investigator presents a danger to the public health, the agency will terminate the IDE immediately, and will notify the IRB and the sponsor who will be given an opportunity for a hearing to determine what action?

The sponsor may request a hearing to determine whether the IDE may be re=instated. 21 CFR 812.119

Who has overall responsibility for the technical conduct of a study PRECLINICAL?

The study director has overall responsibility for the technical conduct...

Pharmacokinetics

The study of bodily absorption, distribution, metabolism, and excretion of drugs

Pharmacodynamics

The study of the biochemical and physiological effects of drugs on the body and the mechanism of action

Expanded Access:

The use of INDs and approved drugs when there is no comparable or satisfactory alternative therapy (also known as compassionate use).

1st principle of The Nuremberg Code

The voluntary consent of the human subject is absolutely essential.

Fundamental principle of the declaration of Helsinki

The well-being of the human subjects should take precedence over the interest of science and society. The ends do not justify the means.

US Public Health Service: Syphilis Study at Tuskegee

There was no informed consent. The participants were not informed of all the known dangers. The participants had to agree to an autopsy after their death, in order to have their funeral costs covered. Scientists denied treatment to patients, in order to observe the individual dangers and fatal progression of the disease. Participants were not given the cure, even when it was widely known and easily available. The designers used a misleading advertisement: The researchers advertised for participants with the slogan; "Last Chance for Special Free Treatment". The subjects were NOT given a treatment, instead being recruited for a very risky spinal tap- diagnostic.

A sponsor may ship an investigational new drug to investigators named in the IND:

Thirty days after FDA receives the IND

Bellmont report: what are the 3 principles, and what are 3 areas of application?

Three core principles are identified: respect for persons, beneficence, and justice. Three primary areas of application are also stated. They are informed consent, assessment of risks and benefits, and selection of subjects

IRB audit (routine audit)

To assure that the site is managing studies correctly

5-160 For what purposes might the FDA undertake focused regulatory research? 21 CFR 312.86

To evaluate critical rate-limiting aspects of the drug development process in facilitating the development of therapies to treat life-threatening or severely debilitating illnesses.

21 CFR Part 312.34

Treatment use of an Investigational new drug.

21 CFR Part 312.34

Treatment use of investigational new drug

Describe: Nuremberg Code of 1947

Trial of nazi leaders calling for informed consent without coercion, previous animal research required, death and disability should not be expected outcomes, and other items

Principles of ICH:

Trials and should be in accordance with principles of the declaration of Helsinki and consistent with GCP and regulatory requirements

5-158 Although a full NDA is required for drugs intended to treat life-threatening diseases, special recognition of the medical risk/benefit must be given by the FDA. True or False 21 CFR312.84

True

5-159 Concurrent 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

True

5-162 All safeguards incorporated in the 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

True

True or Fale: 21CFR56 is IRB Functions and Operations

True

True or False: The object of GCP is part of the ICH mission statement

True.

True or False: When a short form is used for the Informed Consent, the patient signs the short form ONLY and receives a copy of both the summary and the short form.

True.

5-134 Investigators are always required to comply with any additional requirements imposed by the FDA or an IRB in addition to the study plan and applicable regulations. True or False?

True. 21 CFR 812.110

5-136 The clinical investigator is responsible for disclosing sufficient accurate financial information to the sponsor during and for 1 year after the study completion, to allow the sponsor to comply with the requirements of 21 CFR 54 (Financial disclosure Regulations). True or False?

True. 21 CFR 812.110

Additional elements of informed consent:

Unforeseeable risks, circumstances where participation is ended by the investigator, participant withdrawal from study, additional costs, consequences of study withdrawal, findings from the study, number of participants to be enrolled

Regulations

United States Code of Federal Regulations (CFR) FDA Regulation development occurs through publication in the Federal Register The Code of Federal Regulations (CFR) is issued annually and includes any changes made since the previous year

3 countries that make up the regulating body of the ICH:

United States, European Union, Japan

What are the three members of the ICH regulatory body?

United States, European Union, Japan

Investigator must keep records for how long?

Until 2 years after the investigation is discontinued and FDA is notified.

Emergency Use IND

Use if time does not allow submission of IND to FDA yet must be made asap. IRB approval required within 5 days of administration of the drug.

Emergency Use:

Use of a test article on a human in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval.

Examples of IND exemptions:

Use of placebo, drug tests in Vitro or lab animals, blood grouping serum

Stage II studies usually involve how many patients?

Usually involve no more than several hundred subjects (e.g. 200-300, are well controlled and closely monitored.

Sponsor Responsibilities: Trial Management, Data Handling, and Record Keeping

Utilize qualified individuals to supervise trial conduct Consider an independent data-monitoring committee Should maintain written operating procedures and meeting minutes When using electronic systems: Ensure requirements for completeness, accuracy, reliability and consistency are met (validation) Maintain SOPs Ensure documentation of data changes Prevent unauthorized access Maintain list of authorized users Maintain adequate data backup Safeguard blinding

Eligibility Criteria

Very specific inclusion/exclusion criteria outlined in protocol of the specific Subject population the Sponsor wants in the study. Requires review of potential Subjects medical record.

MedWatch 3500

Voluntary reporting

MedWatch 3500

Voluntary reporting of AEs, product problems and product use errors

3500

Voluntary safety reporting of adverse events and product problems

21 CFR 56.105

Waiver of IRB requirement

Nuremberg Military Tribunals: The Doctor's Trial

War crimes and crimes against humanity: to perform medical experiments upon concentration camp prisoners and other living human subjects, without their consent, in the course of which experiments the defendants committed murders, brutalities, cruelties, tortures, atrocities, and other inhuman acts

21 CFR 50.56

Wards

Phase II:

Well controlled clinical study Evaluate the effectiveness of the drug for a particular indication Determine common short-term side effects and risks Closely monitored Conducted in relatively small number of patients, usually no more than several hundred subjects

Respect for Persons Beneficence Justice

What are the 3 major principles of the Belmont Report?

21 CFR Part 312.23

What information a general IND application include: Cover letter Reg documents (form 1571, 1572, 2674) Introductory statement & general inv plan IB (PT, BD &PK, SE) Protocol related: protocol &amendments, previous human experience Non-protocol related: Animal PT, CMC (chemistry, manufacturing, control) Has to include info on: Preclinical data (animal PT), manufacturing, protocol & investigator info

Informed Consent

What is the practical application for "Respect for Persons"?

Assessment of Risk and Benefits

What is the practical application of "Beneficence"?

Selection of Subjects

What is the practical application of "Justice"?

Human subjects should not be harmed; research should maximize possible benefits and minimize possible harms

What is the principle of "Beneficence"?

The benefits and risks of research must be distributed fairly

What is the principle of "Justice"?

Individuals should be treated as autonomous agents; persons with diminished autonomy are entitled to protection

What is the principle of "Respect for Persons"?

IRBs

What kind of organization gets its guidelines almost directly from the Belmont Report?

The National Research Act of 1974

What law created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

The Tuskegee Experiments

What prompted the creation of the Belmont Report?

Study objectives

What researchers hope to answer through their research

21 CFR Part 312.42

What steps must be taken if IND is put on clinical hold? - Proposed study: subjects mustn't be give drug - Ongoing study: no recruiting & subjects receiving drug must discontiue unless specifically permitted by FDA in interest of patient safety What are the reasons for clinical hold? - Unqualified investigator - Exposure of unreasonable risk to suject - Misleading IB - IND doesn't contain sufficient information about risk assessment

A group of physicians, theologians, ethicists, and attorneys They were charged with creating guidelines for research involving human subjects

What was the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research ?

Lasagna's law

When a number of potential patients have been identified and waiting, but as soon as the study opens they disappear.

Site evaluation

When a sponsor representative (CRA) visits a site to evaluate for investigator's experience, expertise, interest in trial, staff, facility, competing studies, and potential patient population available.

SAEs are reported in 15 days when:

When it fits all SAE criteria (serious, unexpected, and definitely related), but is not life threatening and does not result in death.

21 CFR Part 312.31

When must an IND amendment be submitted? -if changes to protocol affects safety of subject, quality and scope of research -if new investigator added -chemistry/microbiology, PT

New Drug Application (NDA)

-Formal request to allow marketing of a drug -Submitted once phase III studies are completed

ICH E2A

-Guidance for clinical safety data management -Definitions and standards for expedited reporting

Sponsors and other regulated entities should use a risk-based approach for validating electronic systems. What is a risk-based approach?

a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities to oversee a study effectively. For example, the guidance specifically encourages greater use of centralized monitoring methods where appropriate.

Investigational new drug:

a new drug or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms "investigational drug" and "investigational new drug" are deemed to be synonymous for purposes of this part.

Contract Research Organization (CRO)

a person that assumes, as an independent contractor with the sponsor, one or more obligations of a sponsor.

Contract research organization (CRO):

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 Food and Drug Administration.

Define "Sponsor" per the CFR.

a person who initiates, but who does not actually conduct, the investigation

Sponsor:

a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.

Research means

a systemic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge

biologic

a virus, vaccine, toxin, antitoxin, blood product, therapeutic serum or similar material for the prevention, treatment or cure of disease or injury in humans

6. Informed consent documents must include the following:

a. A statement that the study involves research. b. A statement of the possible risks. c. A discussion of possible alternative treatments. d. All of the above.

Required Element: (All Studies):

An explanation of whom to contact in the event of a research-related injury to the subject.

Monitor

An individual designated by a sponsor or CRO to oversee the progress of an investigation.

According to 45CFR46, who is defined as a legally authorized representative?

An individual or judicial or other body authorized under applicable law to consent on behalf of a subject.

Sponsor-Investigator

An individual who both initiates and actually conducts alone or with others a clinical investigation

Sponsor-Investigator

An individual who both initiates and actually conducts, alone or with others, a clinical investigation

Guardian

An individual who is authorized under applicable state or local law to consent on behalf of a child to general medical care including research.

Medical Device Definition

An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar article, including any component, part, or accessory which is: Recognized, in the official National Formulary, or the United States pharmacopeia, or any supplement to them Intended for use in the diagnosis of disease or conditions, or in the cure, mitigation, treatment, or prevention of disease in man or other animals Intended to affect the structure or any function of the body of man or other animals

Device

An instrument, apparatus, machine, implant, contrivance, in vitro reagent, or other similar article, including any component, part or accessory.

Comparator (Product)/ Active Control

An investigation or marketed product or placebo used as a reference in a clinical trial

IRB Waiver

An investigator may use and disclose PHI for research without authorization from each individual if the investigator has a waiver from an IRB.

Significant payments of other sorts that greater than $______ must be reported.

$20,000

Equity interest in publicly traded company greater than $______ should be reported?

$50,000

Exemptions from IRB Requirement

& (b) Any investigation which commenced before July 27, 1981... (c) Emergency use of a test article, provided that such emergency use is reported to the IRB within 5 working days. Any subsequent use of the test article at the institution is subject to IRB review. (d) Taste and food quality evaluations and consumer acceptance studies, if ...

Exempted Investigations

(1) A device, other than a transitional device, in distribution before May 28, 1976, when used according to labeling (2) A device, other than a transitional device, in distribution after May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution before May 28, 1976, when used according to labeling (3) A diagnostic device, if the sponsor complies with applicable requirements -

Retention Period

An investigator or sponsor shall maintain the records during the investigation and for a period of 2 years after the latter of the following two dates: The date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product development protocol.

"Additional elements" to informed consent, which sometimes might be applicable

(1) Risks which are currently unforeseeable; (2) When research may be terminated by the investigator (3) Any additional costs to the subject (4) The consequences of a subject's decision to withdraw (5) A statement that significant new findings developed during the course will be provided to the subject; and (6) The approximate number of subjects involved in the study.

How often is the IND updated and what info must be included?

Annual IND update: what was learned about the drug and clinical plan for the next year

When must an IND amendment be submitted and which section outlines this?

(21 CFR Part 312.31) -If there are changes to the protocol that affects safety of subjects, scientific quality of study, or scope of investigation -If a new Investigator is added to the study -Information amendments must be submitted for chemistry/microbiology, pharm/toxicology, or clinical Other submissions: --IND safety reports --Response to clinical hold --Response to FDA request for information --IRB Annual report

How many days after FDA receives IND submission does the IND go into effect? 21 CFR 312.40

(Administrative Actions) An IND goes into effect 30 days after the FDA receives the submission unless the FDA notifies the Sponsor of a clinical hold.

Continuing Review

Annual report to the IRB to ensure that documents are still appropriate and that the risk vs benefit assessment is still acceptable

CRO

(Contract Research Organization) Company contracted by Sponsor to run some aspects of the study such as monitoring, contract negotiations, payments, etc.. FDA requires delegated trial responsibilities in writing from the Sponsor because FDA and IRB consider the CRO to be the same as "Sponsor".

21 CFR Part 54

(Financial Disclosure) Disclosure from Investigators/Sponsors of any potential or actual conflicts of financial interest which could affect the conduct of the study and/or study outcome. All personnel listed on FDA Form 1572 must complete one (includes immediate family).

SMO

(Site Management Organization) Company contracted by the Sponsor to find and manage the sites conducting the study.

Monitor Responsibilities

(VERIFY) Report the subject recruitment rate Verify source documents and trial records are accurate, complete, up-to-date Verify investigator provides all the required reports, notifications, applications and submissions - accurate, complete, timely, legible, dated, and identify the trial Check the accuracy and completeness of CRF entries, source documents and trial records against each other

Monitor Responsibilities

(VERIFY) Verify the protocol is followed Verify consent is obtained Ensure investigator receives current IB Ensure investigator and staff are adequately informed about the trial Verify study staff are performing trial functions according to protocol/contract Verify only eligible subjects are enrolled

Noninvasive

(applied to a diagnostic device or procedure) Does not: (1) Penetrate or pierce the skin or mucous membranes of the body, the ocular cavity, or the urethra, or (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.

Definition of a Sponsor-investigator

(f) Sponsor-investigator means an individual who both initiates and actually conducts, alone or with others, a clinical investigation

Exempted Investigations

(i) Is noninvasive (ii) Does not require an invasive sampling procedure that presents significant risk (iii) Does not by design or intention introduce energy into a subject (iv) Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure (all must be true)

8 Elements of Informed Consent

*Explanation of Purpose/Description of Procedures/Any Experimental Procedures *Potential Risks *Potential Benefits *Alternative Options *Confidentiality of Info *Compensation/Injury *Contact Info *Voluntary

What are some typical FDA meetings?

- End of phase II - Pre NDA meeting (may be same thing: NDA is when Phase I-II completed, request FDA to allow marketing)

Exceptions to informed consent

- Life threatening situations. - Informed consent cannot be obtained from subjects. - Insufficient time to consent LAR. - No alternative approved or general recognized therapy that affords the Subjects a better chance of survival.

PI doesn't have time to consult with another physician

- Must have information reviewed and evaluated in writing by a physician who is not participating in the research within 5 working days. - Submit to the IRB within 5 working days of using test article. - Can be waived when requested by the secretary of defense when an IND is sponsored by the department of defense. - DOD request for the waiver of IC must be limited to a specific military operation involving combat or the immediate threat of combat

Medical Safety Officer Responsibilities

- Providing advice on medical matters - Advising on medical waivers for eligibility - Review of SAEs - Continuance/ discontinuance of trial subjects in light of medical facts

SAE collection and reporting

- SAE collection is done on CRFs- prepped by sponsor/ CRO and reported to CRO by site WITHIN 24 HOURS - Sponsor prepares IND SAFETY REPORT ON MEDWATCH 3500A FORMS and submits to FDAm when receive SAE - Copies of IND safety report sent to CRO, which will then be distrubted to sites, and then submits to IRB as external SAEs (if belong to other sites)

FDA Form 3455

Disclosure

FDA Form 3455

Disclosure of Financial Interests and Arrangements of Clinical Investigators

Form 3455

Disclosure of financial interest and arrangements of clinical investigators

5-154 What are the criteria for life-threatening diseases or conditions to which special IND regulations apply? 21 CFR 312.81

Diseases or conditions: -Where the 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 56.121

Disqualification of an IRB or an institution

Subjects "Lost to Follow Up"

Document attempts to contact subject such as 'at least two phone calls'; return of certified letter.

21 CFR 50.27

Documentation of Informed Consent

Audit Trail

Documentation that allows reconstruction of the course of events.

5-150 Specifically, what records must an investigator retain related to the obtaining of informed consent from study subjects?

Documentation that informed consent was obtained prior to participation for each study subject. For any use of a device without prior informed consent, the investigators records must include the written concurrence of a licensed physician, and a brief description of the circumstances that justify the failure to obtain informed consent. 21 CFR 812.140

Essential Documents

Documents that individually and collectively permit evaluation of the conduct of a study and the quality of the data produced

Essential Documents

Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced.

21 CFR Part 312 Subpart E

Drinks intended to treat life-threatening illnesses and severely-debilitating illnesses

Which act in what year was a result of thalidomide?

Drug amendments of 1962. Thalidomide caused phocomelia . Now safety testing was required

21 CFR Part 201

Drug labeling

21 CFR Part 312 Subpart G

Drugs for investigational use in Laboratory Research Animals or in In Vitro Tests

5-161 For what type of studies do FDA officials intend to monitor study progress and evaluation to facilitate appropriate progress of the study trials! 21CFR 312.87

Drugs intended to treat life-threatening or severely debilitating illnesses.

During which phases is a treatment protocol usually made available?

During Phase 3 but if data is compelling, may be available during Phase 2, OR, after all clinical trials have been completed and Sponsor of trials is awaiting/pursuing marketing approval.

9th principle of The Nuremberg Code

During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.

10th principle of The Nuremberg Code

During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe in the exercise of the good faith, superior skill and careful judgement required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

16.15. What information must each institution participating in federally supported research covered by 45 CFR 46 provide to the department or agency head?

Each institution must either submit a written assurance, or provide documentation of the existence of a current federal wide assurance that is appropriate for the research in question that is on file with the Office of Human Research Protection (OHRP)

Crossover Study

Each subject acts as their own control (each pt gets placebo and treatment at some point)

ICH E

Efficacy

21 CFR Part 11

Electronic Medical Records; Electronic signatures

21 CFR 11

Electronic Records/Signatures

21 CFR 11 addresses:

Electronic Records/Signatures

What is 21CFR11?

Electronic Records; Electronic Signatures

21 CFR Part 11 Subpart B

Electronic records

21 CFR Part 11

Electronic records, electronic signatures

21 CFR Part 11 Subpart C

Electronic signatures

21 CFR 50.25

Elements of Informed Consent

Expanded Access to Investigational Drugs for Treatment Use, Also known as

Emergency Use or Compassionate Use

Significant risk device is defined as an investigational device that is:

a. Intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject. b. Purported or represented to be for a use in supporting or sustaining human life and presents a potential risk to the health, safety, or welfare of a subject. c. 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. d. All the above

5. A purpose of monitoring clinical trials is to verify that:

a. The rights, safety, and well-being of human subjects are protected

Financial Disclosure Reporting based on study outcome or Proprietary interest in tested product must disclose:

all amounts, anytime

IND amendments

amendments to the IND that contain new or revised protocols should build logically on previous submissions and should be supported by additional information, including the results of animal toxicology studies or other human studies as appropriate.

placebo

an inactive substance designed to resemble the drug being tested

Legally Authorized Representative (LAR)

an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject's participation in the procedures involved in the research.

Define "Investigator" per the CFR.

an individual who actually conducts a clinical investigation

Investigator means

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.

Define "Sponsor-Investigator" per the CFR.

an individual who both initiates and actually conducts, alone or with others, an investigation

Sponsor-Investigator:

an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those applicable to an investigator and a sponsor.

Human Subject means

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.

IRB means

an institutional review board established in accord with and for the purposes expressed in this policy.

Investigation New Drug (IND)

an investigational new drug application, aka a notice of claimed investigational exemption for a new drug.

comparator

an investigational or marketed product (i.e. active control), or placebo, used as a reference in a clinical trial

adverse drug reaction

an unintended reaction to a drug taken at normal doses

IRB means

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.

Test article means

any drug for human use, 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 or 354-360F of the Public Health Service Act.

test article

any drug, biologic, or device being tested for use in humans

Clinical Investigation:

any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.

Clinical investigation means

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 FDA under section 505(i) or 520(g) of the act, or is not subject to requirements for prior submission to the FDA under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the FDA as part of an application for a research or marketing permit.

Applicant - means

any person who submits an application or abbreviated application or an amendment or supplement to them under this part to obtain FDA approval of a new drug or an antibiotic drug and any person who owns an approved application or abbreviated application.

PMA means

any premarket approval application for a class III medical device, including all information submitted with or incorporated by reference therein.

Unanticipated Adverse Device Event

any serious adverse event 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.

Serious Adverse Event

any untoward medical occurrence at any dose that results in death, is life-threatening, requires hospitalization (or a prolongation of hospitalization in a patient who is already hospitalized), results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect

adverse event

any untoward medical occurrence in a study subject administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment

Class II devices

are more complicated and require special controls for labeling, guidance, tracking, design, performance standards, and postmarket monitoring. Most require Premarket Notification 510(k). Examples: powered wheelchairs, CT scanners, contact lens care products, endolymphatic shunts

Intervention includes

both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes

8. Which of the following would require the breaking of a randomization code in a blinded study?

c. A participant experiences a serious adverse experience, the etiology of which cannot be explained.

9. The responsibility for ensuring that the investigator Understands a clinical trial lies with:

c. The Sponsor

CI

clinical investigator

CRA

clinical research associate (sponsor monitor)

Interaction includes

communication or interpersonal contact between investigator and subject

CRO

contract research organization

DHHS

department of health and human services

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for

designing, conducting, recording and reporting trials that involve the participation of human subjects

essential documents

documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced

beneficence

doing no harm, maximizing benefits while minimizing risks

EDC

electronic data capture

What types of events require safety reporting per 21 CFR part 312?

events that are both serious and unexpected with possible attribution to drug, findings from other studies that would suggest a significant risk in humans exposed to the drug, findings from animal or in vitro testing that may suggest an increased risk in humans, increased rate of suspected serious adverse events

Each IRB shall have at least

five members, with varying backgrounds, Not entirely of one gender, not entirely of one profession At least one member with primary concern in scientific areas; one non-scientific member (must be on the roster and attend every meeting.) Each IRB shall include at least one member not affiliated with the institution (often called a community member) No one with a conflict of interest - they cannot be part of the immediate family of a person who is affiliated with the institution

The US FDA adopted the ICH only as a

guidance. The ICH guidelines do not have the force of law in the US and are not regulations. Compliance is voluntary, but compliance with ICH is considered part of Good Clinical Practice.

Investigator can weigh in on

if the event is serious or not

Report SAEs

immediately to sponsor unless otherwise specified in protocol

Audit

independent

IEC

independent ethics committee

Private information includes

information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place

IDE

investigational device exemption

Closed system

means an environment in which the systemaccess is controlled by persons who are responsible for the content of electronic records that are on the system-

Legally authorized representative (LAR) means

means 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 procedure involved in the research

Sponsor-investigator

means 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 person other than an individual, e.g., it does not include a corporation or agency. The obligations of a sponsor-investigator under this part include both those of a sponsor and those of an investigator.

Significant equity interest in the sponsor of a covered study

means any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices (generally, interests in a nonpublicly traded corporation), or any equity interest in a publicly traded corporation that exceeds $50,000 during the time the clinical investigator is carrying out the study and for 1 year following completion of the study.

Compensation affected by the outcome of clinical studies

means compensation that could be higher for a favorable outcome than for an unfavorable outcome, such as compensation that is explicitly greater for a favorable result or compensation to the investigator in the form of an equity interest in the sponsor of a covered study or in the form of compensation tied to sales of the product, such as a royalty interest.

Significant payments of other sorts

means payments made by the sponsor of a covered study to the investigator or the institution to support activities of the investigator that have a monetary value of more than $25,000, exclusive of the costs of conducting the clinical study or other clinical studies, (e.g., a grant to fund ongoing research, compensation in the form of equipment or retainers for ongoing consultation or honoraria) during the time the clinical investigator is carrying out the study and for 1 year following the completion of the study.

A Non Significant Risk (NSR) device does not

meet the definition for a significant risk device. The sponsor makes the initial risk determination of SR or NSR, then IRB evaluates the study. FDA is also available to help the sponsor, clinical investigator, and IRB in making the risk determination.

Biometrics

method of verifying an individuals 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 measureable

Financial certification

negative disclosure

NDA

new drug application

NAI

no action indicated

Inspection

official

OAI

official action indicated

Phase 1 Clinical Trials

-Initial introduction of investigational new drug into humans. -Closely monitored, may include patients/normal Subjects -Designed to determine metabolism and pharmacologic actions of drug in humans, side effects with increasing doses to gain early evidence on effectiveness. -Also includes studies of drug metabolism, structure-activity relationships, and mechanism of action in humans, and studies in which investigational drugs are used as research tool to explore biological phenomena or disease processes -Total number of Subjects = 20-80 -Data collected: pharmacodynamics, pharmacokinetics, bioavailability, bioequivalence, dose proportionality. (Safety, vital signs, plasma and serum concentrations, side effects).

Phase IIIB Studies

-Initiated and conducted while NDA is pending -Purpose is to gather additional safety data or to gather additional information on indications for the drug or to assess use in special patient populations

IRB

-Institutional Review Board -Responsible for safety and well-being of all trial subjects -Any board, committee, or other group formally designated by an institution to review biomedical research involving human subjects to approve the initiation of and conduct of periodic reviews of such research.

What should drug accountability records include?

-Inventory of product/drug -Dispensation records -Batch information/expiration dates, etc

Once all standard criteria is met, IRB reviews

-Investigator qualifications -Study protocol -Supporting documents -Proposed content -Any subject compensation or ads

Sponsor means

person or other entity that initiates a clinical investigation, but that 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 an individual (e.g., a corporation or agency) that uses one or more of its own employees to conduct an investigation that it has initiated is considered to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators.

PhRMA

pharmaceutical research and manufacturers of america

Financial disclosure

positive disclosure

PMS

post market surveillance

Class I devices

present a low risk of harm to the user and are subject to general controls that are sufficient to protect the user. Most are exempt from the regulatory process. Examples: non-powered breast pumps, elastic bandages, tongue depressors, examination gloves, most hearing aids, arm slings, microbial analyzers, keratoscopes

unanticipated event

problems involving risks to human subjects or other participating in a clinical research study, e.g. breach of confidentiality, incarceration of subject, suicide attempt, incorrect labeling of study drug.

Financial Disclosure

requires that sponsors certify the absence of certain financial interests or certify the information wasn't obtainable.

see the list of CFR codes for clinical trials pg 25 in CRA's guide

see the list of CFR codes for clinical trials pg 25 in CRA's guide

SMO

site management organization

SoCRA

society for clinical research associates

pre-clinicial testing

studies conducted on animals to determine that the drug is safe to use in studies on humans

open label study

study in which the subjects and the investigator are aware of the drug that is being administered

An approved investigational device exemption (IDE) permits a device

that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully for the purpose of conducting investigations of that device.

The objective of this ICH GCP Guideline is to provide a unified standard for

the European Union (EU), Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.

double blind

the design of a study in which neither the investigator nor the subject knows which treatment the subject is receiving

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 other institutional and federal requirements.

Minimal risk means

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

blinding

the process through which study subjects, the investigator and/or other involved parties in a clinical trail are kept unaware of the treatment assignments of study subjects

Unexpected fatal or life-threatening suspected adverse reaction reports

the sponsor must notify FDA of any Unexpected fatal or life-threatening suspected adverse reaction asap but no case later than 7 calendar days after the sponsor's initial receipt of the information

Emergency use means

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 not sufficient time to obtain IRB approval.

No informed consent, whether oral or written, may include any exculpatory language

through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.

Humanitarian Use Devices (HUD)

to encourage the discovery and use of devices intended to benefit patients in the treatment or diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the United States per year

Class III devices

usually sustain or support life, are implanted, or present potential unreasonable risk of illness or injury. They have the toughest regulatory controls. Most of these devices require Premarket Approval because general and special controls alone cannot reasonably assure their safety and effectiveness. Examples: pacemakers, implanted weight loss devices, non-invasive glucose testing devices, medical imaging analyzers, cochlear implants, breast implants

VAI

voluntary action indicated

Report a hospitalization

within 15 calendar days

Devices are in _______ Days

working days (because a device needs to work)

Compliance

-Adherence to all the trial related requirements, GCP requirements and the applicable regulatory requirements. -International effort to harmonize the technical requirements for product registration.

Test Article Accountability (logs, etc)

-Adherence to storage requirements via temp and freezer logs -Proper dispensing/dosing administration, including calculations -Retrieval of medications or containers from subjects (drug diary) -Monitoring of adequate supplies -Maintenance of randomization orders -Maintenance of accountability logs at both Subjects and study level -Implementation of DEA controlled substance storage (double lock required by Class V) -Preparation of emergency use reports in case test article is used under emergency conditions -Use of appropriate un-blinding procedures

What information must the general IND include? (21 CFR Part 312.23)

-FDA Form 1571 -FDA Form 1571 cover sheet -Table of contents -Investigative Plan -Investigator's brochure -Protocol -Chemistry/Manufacturing information -Pharmacology/Toxicology -Previous human research/literature information -Additional information (drug dependence and abuse potential)

No action needed (NAI)

-Best audit results -No significant deviations, investigator not required to respond

FDA audit

-Bioequivalence inspections are done when one study is the sole basis for the drugs approval -Study related and investigator related Almost always done on studies that are important to an NDA or product license application that has been submitted to the agency. -Sites are selected bases on if they are high enrollers or have multiple studies

IRB deliberations consist of

-Board will review all submitted materials and discuss the proposed research followed by a vote -Board will approve, request changes or additional information, or disapprove it -Study cannot open until IRB approval letter is received.

Regulatory Authorities

-Bodies that have the power to regulate in the ICH GCP guidelines. -Include the authorities that review submitted clinical data.

Required signatures for consent

-CFR requires only the subject to sign -ICH requires the subject + person obtaining consent to sign

Closure procedures

-CRA will perform study close out visit -CRFs need to be reviewed, submitted, and corrected -Drug accountability -Investigator will submit final reports to the sponsor

Short form written consent

-Can be used with IRB approval and is most often used for Subjects who cannot read. -Needs an impartial witness to consent process -Study consent form should be read and explained to subject -Needs oral consent -Witness signature -Person obtaining consent signs

510K clearance

-Established in 1976 with medical device amendments -Must be cleared prior to marketing, has short review time

Declaration of Helsinki of 1964

-Ethical standard that the ICH is based on -Provides ethical principles for the World Medical Association (WMA) -Allows legal guardians to grant permission, and requires review and prior approval of a protocol by an IRB.

Phase III Clinical Trials

-Expanded controlled and uncontrolled trials. -Performed after preliminary evidence suggests effectiveness of drug has been obtained. -Intended to gather additional information about effectiveness and safety needed to evaluate benefit-risk relationship to provide adequate physician labeling. -Total number of Subjects between several hundred to several thousand.

What are the reasons for clinical hold?

-Exposure of unreasonable/significant risk/injury to subjects -Unqualified Investigators (lack of scientific training/experience) -Investigator brochure is misleading, erroneous, or incomplete -IND does not contain sufficient information to assess risk to subjects of proposed studies

Sponsor Intitiated IND must contain

-Form 1571 -Table of contents -Introductory statement -IB -Protocol -Chemistry and manufacturing information -Pharmacology and toxicology information -Previous human experience with investigational drug -Additional information

When will the FDA permit use of an investigational drug in widespread use?

-If the criteria for expanded access are met ( benefits outweigh risk, illness is life threatening, or if no alternative treatments are available) -If drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for the expanded use or all clinical trials are completed.

Waiver of signed informed consent

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

Expedited Review

-Includes minor changes in previously approved research -Reviewed by IRB chairperson -Never used when there is increased risk

Respect for Persons

-Individuals to be treated as automous agents & acknowledged as such -Persons w/diminished autonomy are entitled to & need protection

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 r specific purpose by an individual and which the individual can expect will not be made public.

Phase II clinical trial

-Initial demonstration of efficacy in patients -Short-term information -Subjects should have target disease but no other illnesses -Usually consists of double-blind studies using placebo, comparator drug or both -Purpose to examine efficacy at dose levels from phase I trials

Academic site

-Located in universities and teaching hospitals -Uses specialists in their fields

Class I Device

-Low risk -Bandages, exam gloves, q-tips, etc.

Phase 2 Clinical Trials

-Usually no more than several hundred subjects -Multi-centered sites

Class II Device

-Medium Risk -Usually requires 510k and might require PMA -Powered wheelchairs, infusion pumps, surgical drapes

IRB Membership Requirements

-Minimum 5 members -Must be experienced, experts, and diverse in race, gender, cultural background, etc. -One member with a scientific background (i.e. physician) -One member with a non-scientific background -One member not affiliated with the institution

Study Start-up Activities (9)

-Negotiate contract/budget -Establish billing prices for procedures -Compile essential regulatory docs (FDA Form 1572, FDFs, etc.)) -Complete IRB application and Consent -Obtain IRB approval (IBC, if applicable) -Attend Site Initiation visit (investigator(s)/site staff -Prepare/create source docs -Ensure site has all study materials, including study drug(s) -Ensure all appropriate parties have completed protocol specific training -Ensure Sponsor has effective IND so trial can begin once IRB approval

Independent, central, or national IRB

-Not affiliated with a particular institution -Can be used by any research who is not constrained by institutional policy to the use of a particular IRB. -Frequently used for multicenter studies in non-hospitalized patients -Tend to act quickly and are preferred

IRB Progress Reports should include:

-Number of Subjects entered -Number if subjects withdrawn and reasons why -Summary of experiences -Research results thus far -Current risk/benefits assessment

Coordinating Organization

-Variation of SMOs -Group of experienced study coordinators who have formed a business in recruiting investigators to do trials

Who signs Short forms and who gets copies

-Short Form to be signed by Subject or LAR -WITNESS signs both Short Form & Copy of summary -Person obtaining consent shall sign a copy of summary -Copy of Summary shall be given to the subject or LAR in addition to copy of short form

Pre-Study Documents (Essential Documents)

-Signed FDA Form 1572 (drug) or signed Investigators Agreement (devices), correlating credentials for those listed on it -Fully-executed contract and budget Protocol signature sheet -Approved informed consent -Lab credentials: CLIA, MD CV/ML, CAP/COLA, lab normal values -IRB membership and Federal Wide Assurance number -IRB approval

Phase I clinical trial

-Small trials with healthy subjects (20-100 subjects) -Purpose is to determine pharmacokinetics and maximum tolerated dose.

Vulnerable Subjects

-Special population that the IRB must pay special attention to. -Includes employees under direct supervision of clinical investigator -Includes children, pregnant women, prisoners, handicapped or mentally disabled, people with acute or severe mental illness, people who are economically or educationally disadvantaged and those institutionalized.

Clinical Research Coordinator (CRC)

-Specialized research professional working with or under the direction of the clinical investigator. -Must conduct all trial related activities according to the appropriate federal and state regulations. -Must help ensure the safety and well-being of all study subjects throughout the trial.

Benefit vs Risk assessment

-Study is scientifically valid -Minimal risk to subjects -Benefits compare favorable to risks -Subject selection process must be equitable

Common informed consent problems

-Study procedures being done before the consent is signed. -Proper signatures are not always obtained -Poorly written consent -Missing required elements

Interim Monitoring Visits

-Study sponsor or their CRA visits the site to review and verify data against source documentation. "Pull the Data" -Meet with the PI and other study staff to answer any questions. -Regulations nor ICH-GCP say how often. Sponsor may have SOP but regulations do not. -Person should be qualified by training and experience to monitor the investigation.

Exceptions to informed consent

-Subject is unable to consent (unable to communicate) -Life-threatening condition -Insufficient time to obtain consent -No available alternative therapy

Emergency research waiver

-Subjects are in a life-threatening situation and available treatments are unproven or unsatisfactory. -Obtaining consent is not feasible, due to medical condition, no time for LSR, no way to prospectively identify subject. -Research must hold a prospect of direct benefit. -Research could not be practically carried out without the waiver. Protocol defines length of participants and attempts will be made to consent the subjects or LAR within that time. -Emergency research waiver is a waiver of time not necessity.

Circumstances/conditions required for informed consent

-Sufficient opportunity and time to consider participation -Minimal coercion or influence

(21 CFR Part 20) Other elements of consent

-Termination by agents -Pregnancy language -Patient's costs associated with protocol -Withdrawal from the protocol -Total Number of Subjects to be screened/enrolled -Important Study Findings

FDA criteria for IRB Board Members?

-They must have varied backgrounds. -At least one member must have scientific expertise. -At least one member whose primary concern is non-scientific. -At least one member not affiliated with the institution. -No conflicts of interest.

A study protocol contains

-Title -Protocol Number, IND number, Version date, sponsor, medical monitor, principal investigator -Purpose, including expected benefits, study objective/population, duration of treatments, methods and materials, anticipated number of subjects -Results from previous related research -Subject inclusion/exclusion criteria -Study design/research methods -Description and schedule of procedures -Provisions for managing AEs -Financial relations for subjects -Compensation for injuries -Privacy of subjects -Extra costs of participating -Extra third part costs

Emergency use

-Use of a test article on human subjects in a life-threatening situation in which no standard acceptable treatment is available and in which there is no significant time to obtain IRB approval. -Requests for emergency use to the FDA by telephone or other rapid communication means. -IRB notified of emergency within 5 working days

Short Form consent

-Used when it is the most appropriate way for a subject to comprehend the consent, in the best judgement of the investigator and with concurrence of the IRB -Form must state all elements have been presented orally to subject or LAR -Must have a witness -IRB must approve written summary of what is to be said -Only short form should be signed by subject or LAR -Witness is to sign short form and copy of written summary

Phase III clinical trial

-Uses a large number of patients (thousands) -For long term safety information

Phase 1 Clinical Trials

-Usually 20-80 subjects -Meant to assess initial safety and efficacy -Usually single center sites

Serious Averse Event or Serious Suspected Adverse Reaction definition

An adverse event/suspected adverse reaction is considered "serious" if, by either the Investigator or Sponsor if it results in any of the following: -Death -Life-threatening adverse event (any untoward medical occurrence associated with use of a drug in humans, whether drug-related or not) -In-Patient hospitalization or prolongation of existing hospitalization -Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions -A congenital anomaly or birth defect Medical events that may not result in death, be life-threatening, or require hospitalization may also be considered serious when medical judgement determines they may jeopardize the Subject and may require medical/surgical intervention to prevent any outcome listed above. Examples: allergic bronchospasm

Marketing Applications

An application for a new drug submitted under section 505(b) of the act or a biologics license application for a biological product submitted under the Public Health Service Act.

Investigational Device Exemptions

An approved IDE permits a device that otherwise would be required to comply with a performance standard or to have pre-market approval to be shipped lawfully for the purpose of conducting investigations of that device. Unlike the IND, the sponsor must receive written notification that the IDE is approved by FDA before proceeding with the trial.

IDE (Investigational Device Exemption)

An approved IDE permits device to be shipped lawfully.

What is the purpose of the ICH?

An attempt to streamline the process for developing and marketing new drugs internationally

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.

Digital Signatures:

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.

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

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.

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.

Open System

An environment in which system access is not controlled by persons who are responsible for the content of electronic records that are on the system.

Open System:

An environment in which system access is not controlled by persons who are responsible for the content of electronic records.

Required Element: (All Studies):

An explanation of how to contact someone independent of the research team for questions, concerns, or complaints about the research; questions about the subjects' rights; to obtain information; or to offer input.

Required Element: (All Studies):

An explanation of how to contact the research team for questions, concerns, or complaints about the research.

Required Element: (All Studies):

An explanation of the expected duration of the subject's participation.

Required Element: (All Studies):

An explanation of the purposes of the research.

1571

Cover sheet for IND application

The National Research Act of 1974

Created national commission for the protect of human subjects of biomedical behavioral research

21 CFR 56.111

Criteria for IRB approval of research

Common study designs

Crossover (bioquivalence) Dose escalation (tolerance) Parallel Group (efficacy and safety) Dose range (multiple doses of investigational product) Uncontrolled (long term extension studies)

NSR (Non-significant risk category) examples for Investigational Device Exemptions

Crutches, braces (something that cannot penetrate skin, etc.)

3455

DISCLOSURE of financial interest from clinical investigators

5-151 If an investigator is disqualified by the FDA, what impact might that for the sponsor? 21 CFR 312.70

Data from the disqualified investigators may be eliminated from the NDA consideration, and ultimately result in the FDA's failure to approve the NDA., Further, for approved drugs, data from the disqualified investigators could result in withdrawal of marketing approval by the FDA.

Drug Accountability Records must include:

Dates Quantities Batch/serial numbers Expiration dates Unique code numbers assigned to the IP and trial subjects.

% of something =

Decrease dose

Dedicated site

Dedicated to only conducting trials

CRO responsibilities

Delegated study responsibilities transferred from Sponsor to CRO that are listed in the agreed contract between Sponsor-CRO both parties have signed and provided to FDA.

HHS stands for..

Department of Health and Human Services

45 CFR 46

Department of Human Health Services Vulnerable Populaitons

Post-market Studies

Design improvement Expansion of safety and effectiveness data Development of new uses

Pivotal Studies (device)

Determine safety and effectiveness Include most of overall subject numbers

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.

Conditions for use of a test article in an emergency that must be documented in writing:

The human subject is confronted by a life-threatening situation Time is not sufficient to obtain consent from the subject's legal representative or Informed consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from the subject

5-139 If a investigator receives a written notice of a compliance complaint, what are the first options the investigator will be given to address the complaint?

The investigator may explain the matter in writing, or at the option of the investigator, in an informal conference. 21 CFR 812.119

5-146 Once an investigator is determined to be ineligible to receive investigational devices, the FDA may rescind the action only if the investigator does what?

The investigator must present adequate assurances that the investigative devices will be used solely in compliance with the requirements of the IDE, informed consent and IRB regulations. 21 CFR 812.119

5-135 What responsibilities does the investigator have regarding the supervision of the use of a device?

The investigator shall permit the device to be used only with subjects under the investigator's supervision and shall not supply the device to any person not authorized to receive it. 21 CFR 812.110

5-141 If an investigator is found to have repeatedly or deliberately been non-compliant with the applicable regulations, to whom will the FDA issue disqualification notices?

The investigator, sponsor and the reviewing IRB. The notification will include a statement of the basis on which disqualification was determined. 21 CFR 812-119

16.44. Name the requirements for informed consent regarding language.

The language must be understandable to the subject or the representative and may not include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence.

Minimal risk

The likelihood of harm is no greater than that encountered in daily life or during routine PE.

Investigational Device Exemptions (IDE) 21 CFR Part 812

The non-significant risk category was created to avoid delay and expensive where the anticipated risk to human Subjects did not justify the involvement of the FDA.

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.

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.

Sponsor Companies

The pharmaceutical, medical device, and biotechnology companies that sponsor the conduct of clinical trials.

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.

What is meant by "minimal risk"

The probability and magnitude of physical and psychological harm that is normally encountered in the daily lives of healthy persons

1980

The publication of FDA regulations

16.41. How long must an IRB retain its records, and to whom does the IRB provide access to the records?

The records shall be retained for at least 3 years and records relating to research which is conducted shall be retained for at least 3 years after completion of the research. All records shall be accessible for inspection and copying by authorized representatives of the department or agency at reasonable times and in a reasonable manner.

Contract

Written, dated, and signed agreement between two or involved parties that sets out any arrangements on delegation and distribution of tasks, obligations, and financial matters.

DOD has explained" -- requirements for IRB for DOD

[The IRB] must include at least 3 nonaffiliated members who shall not be employees or officers of the Federal Government (other than for purposes of membership on the IRB) and shall be required to obtain any necessary security clearances.

April 18, 1979

When was the Belmont Report released?

Medical Device Definition

Which does NOT achieve its primary purposes through chemical action within or on the body of man or other animals and which is NOT dependent upon being metabolized for the achievement of its intended purposes.

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. (Shorter duration up to FDA discretion)

Termination

a discontinuance of an investigation before completion by the sponsor, IRB, or FDA

control group

a group of subjects who are not treated with the investigational product. This group is used as a comparison to the treatment group

Human Subject means

a living individual about whom an investigator (whether professional or student) conducting research obtains

randomization

a method in which study subjects are randomly assigned to treatment groups. It helps to reduce bias in a trial by ensuring that there is no pattern in the way subjects are assigned to treatment groups

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Who created the Belmont Report?

21 CFR Part 312.38

Withdraw an IND: a sponsor can withdraw from IND any time without prejudice by: notifying FDA Stop all studies and notify investigators return all the drug or destroy drugs as instructed by sponsor If the study is withdrawn for safety reasons, IRB and investigators must be notified.

Serious event report

Within 24 hours to investigator

What is the necessary follow-up after making an exception to informed consent?

Within 5 working days, a physician not associated with the clinical trial should review the use and make a written evaluation and then that documentation must be submitted to the IRB.

Time frame for a sponsor to submit an annual report to the FDA:

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

Short Form

Written Consent document stating that the elements of consent required have been presented orally to the subject or subjects LAR. There shall be a witness for the oral presentation.

Clinical Trial/Study Report

Written description of the trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations and analyses are fully integrated into a single report.

What are a sponsor's responsibilities if they choose to withdraw and IND?

Written notice to the FDA and all further investigations are put on hold. If for safety reasons, the sponsor needs to inform the FDA and all participating investigators of the reason.