SOCRA Practice 1

No-treatment

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

No treatment

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

Action Letters

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

Action Letters

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

FDA Guidance: legally binding?

NO (just the agencies current thinking on the issue)

reasons for study site termination

low enrollment, unsatisfactory performance, other site/sponsor -specific issue

IND includes:

refer to 21 CFR 312.23

How might audit reports be available to the reg authorities?

reg authorities should not shouldn't routinely request audit reports but may seek access in legal proceedings or in evidence of serious GCP non-compliance

Closed system definition

system access is controlled by people who are responsible for the content of the records on the system

Phase IIa

to compare drug dosing and dose regiment

IRB must have written SOPs

true

45 CFR Part 46

Protection of Human Subjects

21CFRpart50

Protection of human subjects

45 CFR 46

Protection of human subjects

How long should study sponsor/investigator keep documents upon completion of a trial?

2 years

45CFR Parts

46

Life-threatening

- disease/condition where likelihood of death is high unless course of the disease is interrupted - potentially fatal outcomes - end-point of study is survival

Subjects "Lost to Follow Up"

- document attempts to contact subject such as 'at least two phone calls'; return of certified letter.

In-vitro diagnostic development class II

- general controls + special controls - pose moderate risk - may require 510(k) clearance

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

Labeling of IND 21 CFR 312

"Caution: New Drug - Limited by Federal (or United States) Law to Investigational Use"

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

When must an IND amendment be submitted and which section outlines this?

(21 CFR 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 --Annual report

21 CFR 312.145 Subpart F

Guidance documents

Five

How many years must an IND be in active before it is terminated

21CFRpart312.68

Make study records available for inspection

IRBs can be audited by the FDA

True

45CFRpart46.122

Use of federal funds

Sponsor

Who informs the fda of disapproved research?

Abbreviated NDA

generic drugs

21 CFR 50.20 Subpart B

General requirements of informed consent

21 CFR 312.60 Subpart D

General responsibilities of investigators

21 CFR 812.100 Subpart E

General responsibilities of investigators

21 CFR 312.50 Subpart D

General responsibilities of sponsor

21 CFR 812.40 Subpart C

General responsibilities of sponsors

FDA expanded access charging for IND must

not interfere with drug development

What is the FDA form 482

notice of inspection

What does it take for an IND to become inactive? (2)

- If no subjects are entered into a study for a period of 2 years - If all investigators remain on hold for 1 year or more

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.

FDA 483

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

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.

Phase 3 investigation 21 CFR 312

(a)-expanded controlled and uncontrolled trials -performed after preliminary evidence of effectiveness of drug -intended to gather additional information about effectiveness and safety --> needed to evaluation overall benefit-risk -provide information for labeling -total number of subjects: several hundred to several thousand -several years (b)- once regulatory package submitted to begin cost effectiveness analysis, etc.

FDA Form 3454

*Certification* - Financial Interests and Arrangement of Clinical Investigators

FDA Form 3455

*Disclosure* - Financial Interests and Arrangement of Clinical Investigators

Contents of Investigator's Brochure ICH GCP E6 (R1)

*must be reviewed annually 1. Summary 2. Introduction 3. Physical, Chemical, and Pharmaceutical Properties and Formulation 4. Nonclinical studies 5. Effects in Humans 6. Summary of Data and Guidance for the Investigator

IND Labeling (3)

- "Caution: New Drug - Limited by Federal (or US) Law to Investigational Use" - Shall not bear any statement that is false or misleading - Shall not represent the IND as safe or effective

Requirements of the military IRB 21 CFR 50

- 3 nonaffiliated members who shall not be employees or officers of the Federal government -one member whose primary concerns are nonscientific areas -if feasible, a majority of the non-affiliated members

What needs to happen when an IND becomes inactive? (4)

- All stocks of drug must be returned or disposed of - Annual reports no longer required - Resuming study requires submission of a protocol amendment to the FDA - IND or inactive status for 5 or more years may be terminated

IND Phase 2 (3)

- Controlled clinical study conducted to evaluate the effectiveness of drug for particular indication in patients with the disease or condition - Used to determine common short term side effects and risks - Relatively small number of subjects, no more than several hundred

Direct costs for making IND available (3)

- Cost per unit to manufacturer of drug - Cost to acquire drug from another manufacturing source - Cost to ship and handle

IND Phase 3

- Expanded controlled and uncontrolled clinical trials - Performed after preliminary evidence suggests effectiveness - Intended to gather additional information about effectiveness and safety, needed to evaluate overall benefit/risk relationship - Provide adequate basis for labeling - Several hundred to thousands of subjects

If disqualification of an IRB is appropriate, FDA Commissioner will issue order explaining basis and actions to be taken regarding ongoing studies. FDA notifies (4):

- IRB - Parent Institution - Sponsors - Investigators

IND Phase 1 (4)

- Initial introduction of an IND into humans - May be conducted in patients of volunteer subjects - Designed to determine metabolism and pharmacologic actions of the drug in humans, side effects, early evidence on effectiveness - Range 20-80 subjects

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.

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

IND Application Requirements

- Preclinical data (Animal pharmacology or toxicology) - Manufacturing information - Clinical protocols and investigator information

FDA Inspection - Warning Letter (WL)

- a formal notification that allows prompt voluntary corrective action to be taken - sponsor/CRO must provide formal respond to WL within a specified time allowed - WL is public information that will be posted on FDA website

In-vitro diagnostic development class I

- devices that are general controls - lowest risk category - exempt from IDE process

FDA Inspection - No Action Indicated (NAI)

- no objectionable conditions or practices were found or the significance of the documented objectionable conditions found does not justify further actions

FDA Inspection - Voluntary Action Indicated (VAI)

- objectionable conditions or practices were found that do not meet the threshold of regulatory significance

IRB changes regarding the following must be reported

- review of new types of FDA regulated products or discontinue review of clinical investigation - reported within 30 days - disbanding-30 days of permanent cessation. All other changes at time of renewal.

FDA Inspection - Official Action Indicated (OAI)

- significant objectionable conditions or practices were found - regulatory action is warranted to address the establishment's lack of compliance with statutes or regulations

In-vitro diagnostic development class III

- subject to IDE application - pose highest risk - premarket approval required

Justice

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

Progress reports should include

--# subjects entered --#withdrawn and reasons --summary of experiences --research results thus far -current risk/benefits assessment

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

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.

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 and witness signature -Person obtaining consent signs

Children can participate in a clinical trial if:

1. The IRB determines that the clinical trial does not involve greater than minimal risk.

What are the requirements for expanded access? 21 CFR 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)

Nuremberg Trials (1947)

1st set of principals outlining professional ethics for clinical research

Phase 4 21 CFR 312

-Conducted post regulatory approval -prove safety and efficacy in new indications -test new dosage strengths and formulations (sustained release capsule, flavored solution for children) -confirm cost-effectiveness or improved QoL -Collect and analyze long term safety data

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

5 days deviations are in place to protect life or physical well-being

What is the criteria for IRB 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

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

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.

Required signatures for consent

-CFR requires only the subject to sign -ICH requires the subject + person obtaining consent to sign

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

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 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.

Phase 2 investigation 21 CFR 312

-Determine effectiveness and dose response relationship -evaluate effectiveness of drug for a particular indication -well controlled, closely monitored -total number of subjects: 100-200 (subjects inflicted with disease) -Duration: 1 to 2 years

Exemptions from IDE 21 CFR 812

-Device is noninvasive -Does not introduce energy into body -Not used as a diagnostic procedure without confirmation by an approved device or procedure

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.

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

Expanded access submission must include: 21 CFR 312

-FDA 1571: rationale for intended use method of administration facility description chemistry, manufacturing, and controls clinical procedures

information which needs to be obtained from the investigator by the sponsor 21 CFR 312

-FDA 1572 -curriculum vitae -Financial disclosure information

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)

What information must the general IND (Investigational New Drug) include? (21 CFR 312.23)

-Form 1571 -Table of contents -Investigative Plan -Investigator's brochure -Protocol -Chemistry/Manufacturing information -Pharmacology/Toxicology -Previous human research- literature review -Additional information (drug dependence and abuse -potential

IND Application 21 CFR 312

-Form 1571 (Cover sheet) -Table of Contents -Introductory Statement -General Investigational plan -Investigator Brochure -Protocol -Chemistry, Manufacturing & Control Information -Pharmacology & Toxicology -Previous Human Experience with Drug -As Applicable: Drug Dependence/Abuse Potential, Radioactive drugs, pediatric studies

What information must the general IND include? (21 CFR 312.23)

-Form 1571- cover sheet -Table of contents -Investigative Plan -Investigator's brochure -Protocol -Chemistry/Manufacturing information -Pharmacology/Toxicology -Previous human research- literature review -Additional information (drug dependence and abuse -potential

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.

When must an IND amendment be submitted and which section outlines this?

-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. (21 CFR 312. 31)

Respect for Persons

-Individuals to be treated as automous agents & acknowledged as such -Persons w/diminished autonomy are entitled to & need protection

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).

What should drug accountability records include?

-Inventory of product/drug -Dispensation records -Batch information/expiration dates, etc

Significant Risk (SR) Device 21 CFR 812

-Must have IDE number from FDA prior to IRB approval -IDE application submitted by the Sponsor -Sponsor makes initial determination of Significant risk after consultation with FDA (IRB can change risk rating)

IRB Membership 45 CFR 46

-at least 5 members -1 scientific -1 nonscientific -1 nonaffiliated

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

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

Phase 1 protocols 21 CFR 312

-Phase 1 protocols are less detailed and more flexible than phase 2 and 3 studies - Should be directed primarily at providing an outline of the investigation

Four types of controls

-Placebo -Active treatment -Dose comparison -No treatment

What are the requirements for expanded access? 21 CFR 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)

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)

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.

45 CFR Part 46 (aka The Common Rule)

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

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]

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

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.

What are the reasons for clinical hold

-Subjects are/would be exposed to increased risk/injury -investigators are not qualified -investigators brochure is inaccurate or misleading -IND does not contain sufficient informaiton to assess risk to subjects

(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.

Phase 1 Clinical Trials

-Usually 20-80 subjects -Meant to assess initial safety and efficacy -Usually single center sites

Phase 2 Clinical Trials

-Usually no more than several hundred subjects -Multi-centered sites

Treatment IND Clinical holds 21 CFR 312

-alternative treatment drug now commercially available -sponsor not diligently pursuing marketing approval -Administrative oversights by Sponsor (sponsor fails to provide requested additional information)

Premarket approval application (PMA) 21 CFR 812

-apply to Class II devices -FDA regulations provide 180 days to review PMA and make a determination -IRB makes final determination that device presents potential significant risk to subjects.

Belmont report contains

-boundaries between biomedical and behavioral research -role of assessment of risk-benefit criteria in determining appropriateness of research -guidelines for selection of human subjects -definition of informed consent

Serious adverse event 21 CFR 312

-death -life threatening -prolonged hospitalization -persistent or significant incapacity -disruption of ability to conduct normal life functions -congenital anomaly/birth defect

Phase 2 and 3 protocols 21 CFR 312

-detailed protocols describing all aspects of study -designed so if a deviation occurs, contingencies are built into the protocol

Phase 1 investigation 21 CFR 312

-determine safety -initial introduction of new drugs into humans -determine metabolism and pharmacokinetics -side effects associated with increasing doses -pharmacologic effects -drug metabolism -total number of subjects: 20-80 (healthy individuals) -Duration: 6 months to 1 year

Beneficence Belmont Report

-do no harm -maximize possible benefits and minimize possible harms

End of Phase II 21 CFR 312

-facilitates planning for later studies -determine the safety of proceeding to phase III -sponsor to submit Phase III plan at least 30 days prior to scheduled meeting with FDA

Pre-NDA or Pre-BLA (biologic license app.) 21 CFR 312

-facilitates preparation and review of NDA or BLA -Acquaints FDA with proposed marketing applicaiton -discuss statistical analysis

IRB Membership requirements 21 CFR 56

-have at least 5 members -inclusion of one or more individuals who are knowledgeable about subjects -nondiscriminatory effort on basis of gender -no IRB can consist of entirely one profession - one member scientific and one member non-scientific -one member not affiliated with institution -no member can participate if have conflict of interest -may invite individuals with competence in special areas but they cannot vote

Respect for Persons Belmont Report

-individuals should be treated as autonomous agents -persons with diminished autonomy are entitled to protection

General Principles Declaration of Helsinki

-physician shall act in patients best interest -promote and safeguard heath, well-being and rights of patients -medical progress is on research involving human subjects -purpose is to understand causes, development and effects of diseases and improve preventative, diagnostic and therapeutic interventions -ensure respects for all human subjects -goal can never take precedence over rights and interests of subjects -protection of subjects rests with physician or heath care professionals -minimize harm to environment -performed by qualified individuals -regulations are met -underrepresented groups given opportunity to participate -participation will not adversely affect health of patients -appropriate compensation for subjects harmed

Nonsignificant Risk Device 21 CFR 812

-prior IRB approval necessary -Sponsor or IRB makes determination -no prior FDA approval needed to begin examples: Assays, Gauze, Orthopedic equipment, dental braces

Additional elements for ICF 45 CFR 46

-procedure may involve risks to subject which are unforeseeable -circumstances where subjects participation may be terminated -any additional costs to subject -consequences for subjects decision to withdraw -new findings which may affect willingness to participate will be provided -approximate number of subjects

Waiver of consent 45 CFR 46

-research involves no more than minimal risk -waiver will not adversely affect rights or welfare of subjects -research could not practicably be conducted without waiver -subjects will be provided with additional information after participation (as appropriate)

IRB shall determine 45 CFR 46

-risks to subjects (from research) are reasonable in relation to anticipated benefits -selection of subjects is equitable -informed consent will be sought from each prospective subject to the extent required by 46.116 -informed consent will be properly documented -adequate provision for monitoring the data collected -protect the privacy of subjects

Criteria for IRB approval 21 CFR 56

-risks to subjects are minimized -risks to subjects are reasonable in relation to anticipated benefits -selection of subjects is equitable -Informed consent will be obtained to extent required in part 50 -Informed consent documented -monitoring data to ensure safety of subjects -protect privacy and confidentiality

Basic Elements for main ICF 45 CFR 46

-statement that study involves research -risks or discomforts -possible benefits to subject or others -disclosure of appropriate alternative procedures -how confidentiality will be maintained -who to contact for questions -participation is voluntary

Elements of informed consent 21 CFR 50

-statement that study involves research, purposes, duration of participation, description of procedures, identifying experimental procedures -risks or discomforts -benefits to subject or others -confidentiality of records -compensation and if medical treatment is available for injury

Justice Belmont Report

-to protect each person an equal share -to each person according to individual need -to each person according to individual effort -to each person according to societal contribution -to each person according to merit Justice - "Fairness in distribution"

Unexpected adverse event 21 CFR 312

-unexpected if not listed in investigator's brochure or not consistent with the listed risk information provided

2.2 lbs = ___ kg

1

2.53 cm = ___ inch

1

2.54 cm = how many inches?

1 Inch

Test Calculations

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

IRB will determine if study is morally justified and demonstrates what 4 key items?

1. Adequate Design. 2. Favorable Risk/Benefit ratio. 3. Equable selection of subjects. 4. ICF of subjects.

Possible job function of a CRP (12)

1) Clinical Investigator 2) Sub investigator 3) Clinical Researcher 4) Research Nurse 5) Pharmacist 6) Administrator 7) Coordinator 8) Consultant 9) Data Manager 10) QA Manager 11) Regulatory Affairs Manager 12) Educator in clinical trial Management

Possible CRP Duties (15)

1) Collect data 2) Analyze or monitor data 3) Manage cases or protocol participants 4) Recruit and enroll human subjects 5) Protect subjects and their rights 6) Develop ICFs 7) Prepare AE Reports 8) Construct CRFs 9) Maintain drug accountability records 10) Develop grants and budgets 11) Prepare reports 12) Educate other healthcare professionals, patients, or families about clinical trials 13) Develop protocols 14) Program administration 15) Auditing of a research program

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

What must a sponsor do if they determine that the investigational product presents significant and unreasonable risk to subjects?

1) Discontinue all studies that present a risk. 2) Report to FDA and IRB 3) Assure return and accounting for all investigationl products/devices

SOCRA Exam certification based what 6 documents

1) ICH E6 2) ICH E2A 3) CFR 4) Nuremberg Code 5) Belmont Report 6) Declaration of Helsinki

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

Documents regarding ethical principals (3)

1) Nuremberg Code 2) Belmont Report 3) Declaration of Helsinki

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

What are the clinical development stages for devices?

1) Pilot Study: 2) Pivotal Study 3) Post-market studies 4) device studies usually have 100's subjects

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

IRB changes to contact information or Chairperson must be reported to HHS within...

90 days of change

Why does the form 1572 need to be completed by an investigator?

1) To provide the sponsor with information about the investigator's qualifications and clinical site. 2) To inform the investigator of his/her obligations and obtain the investigator's commitment to follow pertinent FDA regulations. Making willfully false statement is a criminal offense.

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

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 conducted in accordance with GCP and protocol

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)s verify that study is conducted in accordance with GCP and protocol

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

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

What are the contents of an IND application?

1. 1571. Name of sponsor, phase of study, will wait for IND approval, IRB responsible, Name of people monitoring, who is evaluating safety, statement of any transferred responsibilities, signature. 2. Table of contents. 3. Intro statement. 4. IB. 5. Protocol. 6. Chemistry, manufacturing, control info. 7. Pharmacology, toxicology info.

Descirbe the membership and reporting requrements of IRBs?

1. 5 members with varying backgrounds. 2. Mix of gender and professions. 3. Include at least (1) primary concern is scientific (1) whose primary concern is non-science 4. Include at least (1)not affiliated with institution or immediate family. 5. No member participation in initial or CR of any project in which there is conflict of interest. 6. At discretion they can invite people with competence in special areas for complex issues.

Investigational Brochure (IB)

1. A compilation of the clinical and non clinical data on the investigational product that are relevant to the study of the products in human subjects. Purpose: to provide the investigators and others involved in the trial with the info to facilitate their understanding.

Miscelaneous

1. A duly constituted IRB must include at least 3 non-affiliated members who shall not be employees or officers of the federal government. 2. If use of the investigational device, in the opinion of the investigator required to preserve the life of a subject and time is not sufficient, the determination of the investigator shall be made within 5 working days after the use of the device - written certification is required to the FDA - IRB by the investigator within 5 days (working) after the use for the device.

What makes a device exempt from IDE regulations?

1. A legally marketed device that does what it's label says 2. A Diagnostic device that is noninvasive and complies with labeling requirements 3. A Device that does not require invasive sampling procedures presenting significant risk 4. A Device that Does not introduce energy into subject 5. A Device that Is not used as a diagnostic procedure without confirmation by a medically established diagnostic product or procedure

Selecting Investigators and Monitors (CRO or Sponsor) Pt 312

1. A sponsor should select only investigators qualified by training/experience. 2. Drug must only be shipped to investigator on trial. 3. Must obtain from investigator: 1572/FDFs/CV

What are the 8 basic elements of the informed consent?

1. A statement that study involves research explanation of procedures, purpose, participation. 2. A description of risks. 3. A description of benefits. 4. A description of alternative procedures/treatments. 5. Confidentiality. 6. If involves more that minimal risk - medical treatment/compensation involved. 7. Study contact questions. 8. Participation is voluntary.

Basic parts of informed consent

1. A statement that: - the study involves research - duration of the subjects participation - the purpose of the study - description of the procedures - which if any procedures are experimental 2. Foreseeable risks 3. Potential benefits 4. Disclosure of Alternative Procedures 5. Confidentiality (FDA[they'll inspect records] vs. ICH [regulatory authorities, sponsor & reps, IRB]) 6. Compensations that may be available if injury occurs 7. who to contact for pertinent questions 8. Participation is voluntary, no penalty for refusal to participate, may discontinue at any time.

The IRB will determine if a study is morally justified and demonstrates what key 4 items?

1. Adequate design 2. a favorable risk/benefit ratio 3. equitable selection of subjects 4. informed consent by subjects

What is the criteria for multicenter trials?

1. All investigators conduct the trial in strict compliance with the protocol agreed to. 2. CRFs are designed to capture the required data at all multi-sites. 3. Responsibilities of coordinating investigators are documented prior to the start of tx 4. are given instructions on following protocol, on complying with a uniform set of standards for assessment of clinical and lab findings. 5. communication between investigators is facilitated.

What is the Role/Purpose of IRB

1. Assure Protection of Human subjects, rights, and well being 2. Determine if research is a benefit to participants, does not cause harm, and promotes good clinical practice

FDA Inspections

1. Bioresearch monitoring program conducts. 2. Usually occurs when NDA has been submitted for marketing approval. 3. Involve interviewers with research personel, review of reg. records, data, FDA/GCP guidelines. Study Oriented: Review of data that supports NDA, PMA, bioequivilance. Investigator Oriented: usually due to complaints, misconduct, fraud

What is included in the IB?

1. Brief description of drug substance/formulation. 2. Pharmacological/toxicological effects in animals. 3. Package/biological disposition in animals, humans as known 4. Summary of safety/effectiveness. 5. Possible Risks/side effects

What two categories does the FDA place all approved IDE's?

1. Category A(Experimental): Absolute risk has not yet been established. 2. Category B (Investigational; non-experimental): Involves device types to be in classes I or II or in class III where incremental risk is the primary risk.

IRB Records (7 documents)

1. Copies of all research proposals reviewed, scientific evaluations, approved sample ICF, progress reports, reports of injury 2. Minutes of IRB meetings 3. Records of continuing review 4. Copies of all correspondence 5. List of IRB members 6. Written procedures 7. Statement of significant new findings provided to subject

IND - Investigational New Device Content

1. Cover Sheet form 1571 2. A table of contents 3. Introductory statement and general investigational plan 4. (reserved) 5. Investigator's Brochure 6. Protocol 7. Chemistry, manufacturing, and control information 8. Pharmacology and toxicology information 9. Previous Human experience with drug

Serious Adverse Event

1. Death 2. Life-threatening 3. Inpatient hospitalization or prolongation 4. Persistent or significant incapacity or substantial disruption of ability to conduct normal life 5. Congenital anomaly/birth defect 6. Important medical event

What are the 4 criteria for an SAE?

1. Death. 2. Life threatening adverse event. 3. Inpatient hospitalization or prolonged of existing hospitalization. 4. Persistent or significant incapacity to conduct normal life functions. 5. Congenital anomaly/birth defect.

Pre-Market Approval (PMA)

1. Demonstrates safety and effectiveness 2. Valid scientific evidence 3. includes clinical data 4. detailed lengthy application 5. Longer Review time 6. Must be approved

Investigator's Brochure

1. Description of the drug substance and the formulation 2. Summary of the pharmacological and toxicological effects of the drug in animals and to the extent known, in humans 3. Summary of PK and biological disposition of the drug in animals and if known in humans 4. Summary of info relation to safety and effectiveness in humans 5. Description of possible risks and side effects to be anticipated

Prompt Reporting to the IRB

1. Deviations from or changes of the protocol to eliminate immediate hazards to the trial subjects. 2. Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial. 3. All adverse drug reactions (ADR) that are both serious and unexpected. 4. New info that may affect adversly the safety of the subjects or the conduct of the trial.

IDE application is required when?

1. Device is intended to treat or diagnose a serious or life threatening disease. 2. No comparable or satisfactory alternative device. 3. Device is under investigation in controlled clinical trial. 4. Sponsor is pursuing marketing approval of device.

What is the sponsor responsible for in terms of electronic data systems?

1. Ensure and document electronic system is complete, accurate, and consistent. 2. Maintain SOPs for system. 3. Data changes are documented, no deletion of data. 4. List of authorized individuals.

What does a Phase III study entail?

1. Expanded controlled and uncontrolled studies. 2. After preliminary evidence of drug effectiveness. 3. Gather additional information (effectiveness or safety) 4. Evaluate overall benefit-risk relationship. 5. Provide adequate basis for MD labeling. 6. Several hundred to several thousands of patients.

IND study - sponsor must obtain information from all investigators including: (5)

1. FDA 1572 Investigator Statement 2. A commitment by investigator to run study according to the regulations and protocol 3. A list of names of sub-investigators 4. CV 5. Financial disclosure information

The FDA will not disclose the existence of an IDE unless:

1. FDA determines that information has been previously disclosed to public. 2. FDA approves a PMA for a device subject to an IDE or. 3. A notice of completion of a product development protocol (PDP) is in effect.

IND Application Content

1. FDA form 1571 - cover sheet 2. Table of contents 3. Introductory statement and general investigation plan - drug information - previous human experience - if drug has been withdrawn from foreign markets - brief description of overall plan for following year 4. Investigator's Brochure 5. Protocols 6. Chemistry, manufacturing and control information 7. Pharmacology and toxicology information 8. Previous human experience 9. Additional information 10. Relevant information requested by FDA

If IRB is acting out of compliance the FDA may...

1. FDA inspector present oral or written summary of observations 2. FDA may subsequently send letter to parent institution where IRB is based 3. IRB responds to letter and describes corrective actions

Reporting Time Frames

1. Fatal or Life threatening unexpected ADRs - Qualify for rapid reporting - ASAP - no later than 7 days - follow up report no later than 8 additional days. 2. All other serious, unexpected ADRs must be filed asap - but no later than 15 calendar days.

Declaration of Helsinki (1964) Ethical principles for medical research addressed primarily to physicians

1. Health of patient is 1st consideration. 2. Duty of physicians to provide and safeguard health and well being. 3. Number 1 purpose of research is to understand causes, development, effect of disease and improve prevention, diagnoses and interventions. 4. new research knowledge is never greater rights of interests of subjects. 5. Duty of physicians to protect health, life, dignity, integrity, privacy and confidentiality. 6. Research should be done so as to minimize possible harm.

Public Discolsure with INDs

1. IND will not be disclosed unless previously done. 2. FDA will disclose upon request to an individual given an IND has been given copy of report on how it relates to use.

FDA commissioner may disqualify an IRB if it is determined...

1. IRB has refused or repeatedly failed to comply with regulations 2. Noncompliance adversely affects rights/welfare of subjects

Annual Report Contains:

1. Individual study info 2. summary information 3. general investigational plan for the upcoming year 4. investigator brochure 5. any phase 1 protocol changes not previously reported 6. summary of foreign marketing developments 7. log of any outstanding business

Belmont Report: Respect for persons

1. Individuals should be treated as autonomous agents. An autonomous person is a capable individual of deliberation about personal goals. 2. Persons with diminished autonomy are entitled to protection (give weight to an autonomous person) - considered opinions and choices while refraining from obstructing their actions.

What does a Phase I study entail?

1. Initial introduction of investigational drug into humans. 2. Closely monitored 3. Patients or normal volunteers. 4. Designed to determine metabolism and pharmacologic actions of drugs in humans. 5. Side effects and increasing doses 6. Gain early evidence on effectiveness 7. drug metabolism structure activity 8. research tools. 9. 20-80 patients.

Sponsor Responsibilities

1. Maintain an effective IND or IDE 2. Ensure studies are conducted according to the general investigational plan and protocols in the IND/IDE 3.

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

IDE - Investigational Device Exemption

1. Name of sponsor 2. Report of prior investigations and investigational plan 3. Description of the methods, facilities and controls used for the manufacture, processing packaging, installing (proves GMP) 4. list of all investigators 5. Certification that all investigators have signed agreement 6. List of chairpersons of each IRB 7. Name of any institution 8. amount to be charged for device 9. claim for categorical exclusion or environmental assessment

What should sponsor obtain from investigator regarding IRB?

1. Name/Address of IRB 2. Statement from IRB that it is organized and complies with GCP 3. Documented approval of ICS and Protocol

What all does the 1572 contain?

1. Name/Address of investigator 2. Name and protocol # 3. Name and address of every facility where clinical investigations will take place 4. Name/Address of any clinical lab 5. Name/Address of IRB 6. A commitment by the investigator

Confirmation of review by IRB/IEC. The sponsor, should obtain from the investigator/institution?

1. Name/Address of investigator/institution. 2. A statement obtained from the IRB, that it is organized and operates according to GCP and the applicable laws and regulations. 3. documented IRB/IEC approval. Protocol and ICS.

IDE exempt Devices

1. No invasive sampling > minimal risk. 2. Does not introduce energy. 3. Will not be used to diagnose without another approved device or procedure.

What should a protocol contain?

1. Objectives and purpose of study. 2. Investigators information - address, name, etc. 3. Criteria for pt. selection and # of pts. 4. Description of study design. 5. Method of determining dosage - max dose/duration. 6. Observations and measurements. 7. Description of clinical procedures.

Investigational Plan for Drugs

1. Overall plan for the following year 2. rationale for the drug/study 3. indications 4. general approach to evaluating 5. Kinds of clinical trials for first year 6. Number of patients 7. Risks of particular severity or seriousness

Expanded Use Criteria

1. Patient has life threatening diagnosis or condition. 2. Benefit outweighs risks. 3. Providing investigational drug for requested use.

Assent for Children

1. Permission of each child's parents must be granted. Might be one or both. Must be documented. 2. Assent should be obtained unless. Capacity of child is limited so they can't understand. Intervention of trial is beneficial and only available through trial. 3. Or if IRB feels: No more than minimal risk. Waiver will not affect subject rights. Research couldn't happen without assent. Additional info provided as needed.

Requirements for Expanded Access

1. Population to be treated has a serious or life-threatening condition 2. no comparable or satisfactory alternative therapy 3. benefit justifies the risk; risks are not unreasonable 4. will not interfere with completion of studies that could support marketing approval

2 common routes for a device to go to market

1. Premarket notification (SIO). FDA determines device is equivalent to device already allowed on market. Can enter market without clinical trials. 2. Pre-market approval (PMA) - similar to NDA. FDA reviews all clinical investigations.

What are General Controls in regards to device development

1. Prohibit adulterated or misbranded devices 2. Pre-market notification 510K requirements 3. Good Manufacturing Practices (GMPs) 4. Registration of manufacturing facilities 5. Listing of device types

Charging for a drug under and IND (5)

1. Provide evidence has potential clinical benefit, provide significant advantage 2. Demonstrate data from trial would be essential to establish safety and effectiveness 3. Demonstrate trial could not be conducted without charging because of cost of drug 4. Sponsor must justify amount and obtain written authorization from the FDA 5. A sponsor may recover only the direct costs of making investigational drug available

Investigational Plan for medical devices

1. Purpose - name and intended use of device 2. Protocol 3. Risk analysis 4. description of device 5. monitoring procedures 6. labeling 7. consent materials 8. IRB Information 9. Other institutions 10. Additional records and reports

Children who are wards of the state can be included in clinical investigations under CFR 50.53 or CFR 50.54 only if clinical investigations are...

1. Related to their status as a wards 2. Conducted in schools, camps, hospitals, etc. in which majority of children involved are not wards

What are procedures for when ICF cannot be obtained? (E6)

1. Requires Assent when possible. 2. Normally ICF must be obtained for all non-therapeutic trials.

IRB review of research

1. Review/Have the authority to approve, require modifications or disapprove research. 2. Require ICF information follow 116. 3. Require documentation of ICF. 4. Notify investigators/institutions of decision in writing. If disapproved, must give reasons. Give inv. opportunity to respond. 5. Conduct continuing review no less than 1x per year.

If clinical trial involves greater than minimal risk and no prospect of direct benefit:

1. Risks represent a minor increase over minimal risk. 2. Intervention is commensurate with those inherent in their actual or expected medical situation 3. intervention is likely to yield generalizable knowledge about disorder

Criteria for IRB Approval

1. Risks to subjects are minimized 2.Risks are reasonable in relation to benefits. 3. Selection of subjects is equitable. 4.ICF is obtained from each subject or LAR. 5.ICF is appropriately documented. 6.Research plan includes monitor data collected to ensure subject safety 7.Adequate protection of privacy and confidentiality of data -> additional safeguards for vulnerable populations.

Responsibilities of sponsors ( CFR pt 312)

1. Select Qualified Investigators 2. Provide investigator with info they need to conduct trial. 3. Proper monitoring. 4. Maintain IND (amendment/renewals). 5. Notify FDA and all investigators of significant AEs or updated risk information of drug. 6. Protocol/investigational plan is followed. (Some of these can be transferred to the CRO)

General responsibilities of sponsors (for running IND studies)

1. Selecting qualified Investigators 2. Provide Information to conduct an investigation 3. Ensure proper monitoring of the studies 4. Ensure investigation conducted in accordance with investigational plan/protocol 5. Maintain an effective IND application/document 6. Ensuring the FDA and all investigators are promptly informed of significant new adverse events or risks

Promotion of Investigational Drugs (4)

1. Shall not promote IND as safe or effective 2. Precludes commercialization of the drug before it is approved for commercial distribution 3. Sponsor may not commercially distribute or test market and IND 4. A sponsor shall not prolong an investigation after finding that the results appear to establish sufficient data to support a marketing application

IRB can use expedited reviews when?

1. Some or all of research involved no more than minimal risk. 2.Minor changes in previously reviewed research during period of 1 year or less for which approval is authorized. 3. Can be carried out by IRB chairperson or by one or more experienced reviewers. Reviewer cannot disapprove on their own.

When can the IRB use expedited review?

1. Some or all research appears on the list and found by the reviewers to involve no more than minimal/risk. 2. minor changes in previously approved research during the period (1 yr or less) for which approval is authorized.

IND Annual Reports and Withdraw

1. Sponsor shall within 60 days of when IND went into effect, submit brief report of progress of investigation. Study info-status of each study. Summary of information. Protocol modification. IB Updates. SAEs/Deaths/Enrollment. 2. Sponsor may withdraw IND at any time without prejudice. FDA notified. Clinical investigators notified. 3. If W/D for safety, FDA should be told, also IRB

what is included in Trial Design?

1. Sponsor utilizes qualified individuals throughout all stages of trial process. 2. Designing protocol. 3. Designing CRFs. 4. Planning Analysis. 5. Planning/preparation interim and final reports.

GCP (Good Clinical Practices)

1. Standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials in a way that provides assurance that the data and reports results are credible and accurate. 2. Rights/safety/welfare of patients are protected. 3. GCP included review/approval from (IEC) independent ethics committee, before initiating a study, CR, obtaining consent. 4. GCP does not require consent in life threatening situations.

Basic Elements of the ICF 1 of 8

1. Statement that the study involves research, explanation of purposes and expected duration, description of procedures to be followed, and identification of any procedures which are experimental

General Requirements for ICF (CFR 46) (Basic Elements)

1. Study Involves research (People, duration, experimental parts). 2. Risk or discomforts to subject. 3. Benefits. 4. Alternative Procedures. 5. How records that identify subject will be kept confidential. 6. If research is greater then minimal risk -> compensation /treatment for injury. 7. Who to contact for questions/injury. 8. Participation is voluntary.

Clinical Hold Criteria

1. Subjects are exposed to a significant risk 2. Investigators not qualified 3. Investigators brochure is incomplete or misleading 4. IND is incomplete 5. (phase 2 and 3) The protocol is deficient in design to meet its stated objectives

Clinical Hold May be given if:

1. Subjects are exposed to an unreasonable and significant risk of illness or injury. 2. Investigators are not qualified 3. The investigator's brochure is not qualified 4. The IND does not contain sufficient information 5. Men/women are excluded 6. (in phase 2/3) The plan or protocol for investigation is deficient to meet objectives.

If clinical trial involves greater than minimal risk but has a monitoring procedure that ensures the well-being of the subjects or a direct benefit for the patients

1. The risk is justified by anticipated benefit 2. The anticipated benefit to risk relationship is at least as favorable to the subjects as that presented by available alternative treatments.

The sponsor should obtain the investigators agreement for a new trial based on what 4 criteria?

1. To conduct the trial in compliance with GCP, with the applicable reg requirements, and with the protocol agreed to by the sponsor. 2. to comply with procedures for data recording/reporting. 3. to permit monitoring, auditing, and inspection. 4. to retain trial related essential documents until sponsor informs investigator these are no longer needed.

Belmont Report: Beneficence

1. To secure patient well being. 2. To cover acts of kindness or charity that go beyond strict obligation. 3. Do not harm. 4. Maximize possible benefit - minimize possible harm.

What is the purpose of monitoring?

1. To verify that the rights and well being of human subjects are protected. 2. The reported trial data are accurate, complete, and verifiable from source documents. 3. The conduct of the trial is in compliance with the currently approved protocol/amendments with GCP, and with the applicable reg requirements.

Additional Elements of ICF that should be provded (CFR 46)

1. Treatment may involve risks which are currently unforeseeable. 2. Subject protection may be terminated by investigator. 3. Additional costs that may result from participation. 4. Consequences of withdrawing or termination. 5. New findings will be provided when they may offset willingness to participate. 6. Number of subjects involved.

Humanitarian Use Device

1. Treatment of diagnosis in condition affecting fewer than 4000. 2. FDA responds in 45 days. 3. HDE not equal to IDE. Only needs to address safety.

General responsibilities of investigators

1. Trial is conducted according to signed investigator statement. 2. Protect rights, safety, welfare of subjects. 3. Control of investigational drug. Maintain adequate records of drug disposal, (dates, quantity, use by subjects). 4. Record Keeping. Case histories. Record retention (2 years). 5. Reporting. Progress reports. Safety Reports. PDFs. Final Reports. 6. Assurance of IRB review and compliance.

FDA Criteria for widespread treatment with investigational drug

1. Trial status a. Drug being investigated under Clinical Investigation b. All clinical investigations have been completed 2. Marketing status: a. Sponsor actively pursing marketing approval 3. Evidence a. Sufficient clinical evidence of safety and efficacy

Prompt Reporting Guidelines

1. Unanticipated. 2. Indicate that the research places subjects or others at greater risk of harm (including, physical psychological, economic, or social harm) that was previously known or recognized. (Think any "new risk".).

What are prompt reporting guidelines?

1. Unanticipated. 2. Research places subjects or others at greater risk of harm. Examples: Deviations or changes to protocol to eliminate immediate hazards to trial subjects. Changes that increase risk to subjects or affect conduct of trial. Adverse Drug reactions (serious/related/unexpected). New info that could affect safety of subjects.

Additional Elements of Informed Consent

1. Unforeseeable risks 2. Circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent. 3. Any additional costs to the subject 4. Consequences of the subject's decision to withdrawal 5. Significant new findings discovered during the course will be provided to the subject. 6. Approximate number of subjects involved 7. Clinicaltrials.gov

Grounds for Clinical Hold (IND)

1. Unreasonable and significant risk to the subjects 2. Investigators in IND not qualified 3. Investigator Brochure is misleading, erroneous, or incomplete 4. IND application does not contain sufficient information to assess risk 5. Study excludes subjects due to reproductive toxicity in studies to treat a life-threatening disease or condition 6. In phase 2 and 3 studies - if protocol clearly is deficient in design

Elements of Nuremberg code

1. Voluntary consent 2. research will yield results for good of society 3. anticipated results will justify performance of experiment 4. avoid all unnecessary physical and mental suffering and injury 5. no experiment with a priori reason to believe that death or disabling injury may occur 6. risk never exceeds benefit 7. protect subject against remote possibilities of injury, disability, death 8. conducted by qualified persons 9. human subject can stop at any time 10. scientist must stop experiment if determines continuation would result in injury, disability or death

When is it ok to test a new intervention against a Placebo and not against best proven intervention? (Declaration of Helsinki)

1. When no proven intervention exists. 2. Sound methodical reasons requires it to determine efficacy or safety of an intervention. 3. Subjects that receive placebo will not be subject to additional risks due to not receiving best option

Investigator Commitments on 1572 (CFR 312)

1. Will conduct study according to protocol and only make adjustment if sponsor is notified or to protect health of subjects. 2. Comply with all CFR pt 312. 3. Will inform subjects that drugs are used for investigational purpose and requirements for IRB and ICF are met. 4. Will report AEs to sponsor. 5. Will ensure all associates, colleagues, employees are informed of commitments to study. IRB will do initial/ongoing approvals of study and investigator will report and changes or unanticipated problems. 6. IRB will be used and complies.

If IRB is acting out of compliance the FDA may schedule a reinspection. Until IRB takes corrective action, FDA may...

1. Withhold approval of new studies 2. Direct that no new studies be added 3. Terminate ongoing studies that would endanger subjects 4. When there is significant threat to rights/welfare, FDA may notify state and Federal agencies.

What corrective actions can be taken on the IRB?

1. Withhold approval of new studies. 2. no new subjects added to trials. 3. Terminate ongoing studies or notify institutions for corrective actions.

21 CFR 54.6

21 CFR 54 Financial disclosures Recordkeeping and record retention For any application submitted for a covered product an applicant shall retain records as we strive for two years after the date of approval of an application

What are responsibilities of the monitor?

1. communicator b/t PI and sponsor 2. verify PI qualifications 3. investigational products stored, administered, handled, returned, used, and disposed correctly 4. ensure PI follows protocol, only enrolls eligible subjects 5. IC obtained for all Pts 6. PI receives investigator brochure and all other documents need for trial 7. ensure staff are completing tasks as stated in protocol 8. reporting recruitment rate 9. verifying source docs and CRFs correct and updated 10. informing PI of errors 11. Determine AE reported adequately 12. PI maintaining essential documents 13. communicate deviations

FDA will permit use of IND in widespread treatment if:

1. criteria for expanded access are met 2. 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 3. Sufficient clinical evidence of safety and efficacy to support expanded access use - results of phase 3 studies or compelling evidence from phase 2 studies 4. For immediately life-threatening disease or condition, the scientific evidence provides a reasonable basis to conclude use would not expose patients to unreasonable and significant risk of illness or injury. 5. sponsors must monitor the study, and physicians must comply with the protocol and obligations of investigators.

Treatment Protocol/IND is made available:

1. during phase 3, but as early as phase 2 2. after all trials are completed and the sponsor for the controlled clinical trial is actively pursuing marketing approval of the drug with due dilligence

Expanded access clinical hold if... (8)

1. it was not designed to be adequate and well-controlled 2. impending enrollment in a well-controlled study 3. Insufficient quantities of drug 4. Other studies show a lack of effectiveness 5. Another drug demonstrates better potential 6. Drug has been approved 7. Not actively pursuing approval 8. Would not be in public interest

What are the abbreviated requirements for an NSR investigation

1. label device 2. maintain records 3. ensure investigators maintain records and make reports 4. Obtain IRB approval for NSR designation 5. consent is obtained (IRB can waive if minimal risk). 6. Submit reports 7. Monitor the study 8. Refrain from promotion and other practices

Exceptions to Informed Consent

1. life-threatening situation necessitating the use of the test article 2. inability to communicate with subject or obtain legally effective consent from the subject. 3. insufficient time to obtain consent from the subject's legal rep 4. no available alternative therapy that has equal or greater likelihood of saving the subjects life

IND Form 1571 Cover Sheet

1. name, address and phone number of the sponsor 2. identification of phase 3. commitment to not being investigations until IND in effect 4. Commitment to compliant IRB 5. Commitment to conduct investigation in accordance with reg requirements 6. Name and title of monitor 7. name and title of person

A sponsor may withdraw an IND at any time without prejudice by:

1. notify FDA 2. stoping all studies and notifying investigators 3. getting back all drug or destroying all drug 4. if for safety reasons, the sponsor must notify the investigators and the IRBs of those reasons

Primary Responsibilities of an investigator

1. oversee conduct of trial 2. protect the rights safety and welfare of subjects 3. control the use of investigational product

Expanded Access for Individual Patients

1. physician determines that risk is not greater than the risk from the disease 2. FDA determines patient cannot obtain drug under another IND or protocol 3. The physician or sponsor must explain how expanded access requirements are met and agree to written summary within 15 days 3. FDA authorizes treatment by telephone if there is not sufficient time for written submission

Investigation plan under 812 should include:

1. purpose 2. protocol 3. risk analysis 4. description of device 5. monitoring procedures 6. labeling 7. consent materials 8. IRB info 9. Other institutions 10. Additional records and reports

Define the special controls that Class II devices are subject to, in addition to general controls

1. special labeling requirements 2. mandatory performance standards 3. post-market surveillance

Required components of a Protocol (IND app/312)

1. statement of objectives/purpose. 2. Name/address/statement of qualifications of each investigator. 3. criteria for patients selection/inclusion and # of patients enrolled. 4. Description of study design. 5. method for determining dose to be administered, planned max dose and duration of exposure. 6. description of observations and measurements. 7. clinical procedures, lab tests to monitor effects of drug.

Exceptions to ICF in emergency setting. The IRB determines:

1. the subjects are in life-threatening situations 2. Available treatments are unproven or unsatisfactory. 3. Collection of valid scientific evidence is necessary to determine the safety and efficacy of particular interventions 4. Obtaining ICF is not feasible because the suibject's condition does not allow -- and the intervention must be administered before consent can be obtained from the subject's legal representative 5. there is no reasonable way to prospectively identify individuals likely to become elifible for the clinical trial 6. participation in the study holds out the prospect of direct benefit to the subject. 7. risks are reasonable for the medical condition and risk/benefit of standard therapy 8. the clinical trial could not be carried out practically without the waiver. Additional: -a therapeutic window has been identified based on scientific evidence - investigator commits to attempting to contact the subject's legal rep within the window and attempt to contact another family member if the legal representative cannot be reached. - community consultation and public disclosure of expected risks and benefits - continued efforts to reach the subject's legal rep or another family member if the subject remains incapacitated - establishment of a data safety monitoring board (DSMB) - study conducted under separate IND - If the IRB cannot approve the study, the IRB must promptly notify the investigator and sponsor - sponsor then must notify FDA and all other investigators who were participating or were asked to participate in a substantially equivalent study.

21 CFR 54 (all)

21 CFR 54-- financial disclosure by clinical investigators 54.4-- certification and disclosure requirements 54.5-- agency evaluation of financial interests 54.6-- record keeping and record retention

Grounds for termination of a study that is part of an IND (12)

1. unreasonable and significant risk 2. IND does not contain sufficient information to assess safety 3. Method for manufacturing/packing inadequate 4. Investigation conducted in a manner different from protocol 5. Drug being promoted or distributed for commercial purpose 6. IND/reports/amendments contain untrue statements or omit material 7. Sponsor fails to investigate and inform the FDA of serious and unexpected adverse experiences or fails to make reports 8. Sponsor fails to comply with requirements 9. Sponsor fails to comply with requirements 10. IND remains inactive status for 5 years or more 11. Sponsor fails to delay a proposed investigation or suspend an investigation on hold For phase 2 and 3... - plan or protocol is not reasonable as a bona-fide scientific plan - convincing evidence that the drug is not effective

What would initiate the need for a protocol amendment?

1. znre protocol 2. Changes in protocol 3. New investigator 4. Content and format

for MEDICAL DEVICE trials the P.I. should submit to the sponosr & IRB a report of any unanticapted adverse asap but no later than___

10 days

Nuremberg code

10 ethical principles set out at the end of WWII - 1947. 1. consent of human subjects is essential 2. Experiment must yield results good to society. 3. Experiment should be designed based on animal experiments that justify experiment. 4. Should avoid all unnecessary physical and mental suffering. 5. No a priori reason that death or disabling injury will occur. 6. Risk should not be greater than humanitarian importance of problem. 7. preparations/facilities proposed to protect against injury, death. 8. Only conducted by qualified people. 8. Subject can end experiment at anytime. 9. Scientist in charge must terminate experiment if needed.

For medical device trials, the sponsor is required to report an unanticipated adverse device effects within how many days?

10 working days after the sponsor first received the information

21CFR Parts

11 50 56 312 812

In case of SAE sponsor notifies FDA and all participating investigators in an IND safety report of potential serious risks, but not later than...

15 calendar days

The sponsor must notify the FDA and investigators of potential serious risks ASAP - But no later than how many days?

15 calendar days (After sponsor determins info qualifies for reporting)

After receiving IND Safety Report, FDA may request additional information. Sponsor must submit the information within how many day?

15 calendar days after receiving the request

Follow-up IND Safety Report. Such report should be submitted without delay, as soon as the information is available but no later than __calendar days after the sponsor receives the information.

15 days

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

15 days

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

15 days

Unexpected serious suspected adverse reactions and observations from animal studies suggesting significant risk to human subjects must be reported to FDA as soon as possible but no later than within __ calendar days following the sponsor's initial receipt of the information.

15 days

sponsor must submit saftey report in ___after knowing of an event that meet reporting criteria

15 days

Federal Food, Drug, and Cosmetic Act

1938 Established FDA's jurisdiction over cosmetics and medical devices

When was the Federal Food, Drug, and Cosmetic act established?

1938-- meant to establish the FDA's jurisdiction over cosmetic and medical devices.

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 estabilshed?

1947

What year was The Nuremburg Code established?

1949

What year was the Declaration of Helsinki estabilished?

1964

What year was the Declaration of Helsinki established?

1964

What year was the National Research Act passed by Congress?

1974

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 did they amend the Federal Food Drug and cosmetic act specifically for medical devices?

1976

510K Clearance

1976 1. Substantially Equivalent devices will be cleared for marketing 2. comparison to predicate device 3. might contain clinical data 4. shorter review time

Medical Device Amendments

1976 First major amendment specifically for devices

What year was the Belmont Report established?

1979

Calculations - on test

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

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

2 years

Record retention time for a drug sponsor

2 years after approval OR 2 years after last shipment and delivery of the investigational product and FDA was notified

IND Study Record Keeping - sponsor must retain records and reports for...

2 years after approval or until 2 years after shipment is discontinued

Record retention time for a device sponsor

2 years after study termination/completion OR 2 years after the date that the records are no longer required for a PMA or after the date on the notice of completion of protocol's requirements

If a sponsor discontinues the clinical development of an investigational product (i.e.) for any or all indications, routes of admin, dosage forms) the sponsor should maintain all sponsor specific essential documents for at least how many years?

2 years.

how long should essential clinical trial records be retained at site?

2 yrs after FDA approval or 2 years after study ended

1 kilogram (kg) = ___ lbs

2.2

1 kg equals how many pounds?

2.2 lbs

1 inch = ___cm

2.53

Phase I

20 to 100 healthy volunteers or people with the disease/condition. Length of Study: Several months Purpose: Safety and dosage

Significant payments of other sorts greater than $______ must be reported

20,000

21 CFR 312.2

21 CFR 312 - investigational new drug application Applicability/exemption Exemption 1) The investigation is not intended to be reported to the FDA has a well controlled study in support of a new indication for use nor is intended to be used to support any other significant change in the label of a drug 2) if the drug that is undergoing investigation is lawfully marketed as a prescription drug product investigation is not intended to support a significant change in the advertising of the product 3) The investigation does not involve a route of a ministration or dosage level or use in a patient population or other factor that significantly increases the risk associated with the use of the drug 4). In vitro diagnostic biological products such as blood grouping serum, reagent red blood cells, and anti-human globulin 5) A drug tested in vitro or in lab research on animals is exempt 6) A clinical investigation involving the use of a placebo and does not require submission of an IND On request FDA would advise applicability of a drug to a plan clinical investigation

21 CFR 312

21 CFR 312 - investigational new drug application This part contains procedures and requirements governing the use of investigational new drugs including procedures and requirements for the submission to review by the FDA of investigational new drug application IND's An investigational new drug for which an IND is in effect in accordance with this part is exempt from the pre-marketing approval requirements that are otherwise applicable and maybe shipped to lawfully for the purpose of conducting clinical investigations of that drug

21 CFR 50

21 CFR 50 (A) Protection of Human subjects

21 CFR 50 B (all)

21 CFR 50 B -- Informed consent of human subjects 50.20--general requirements for informed consent 50.23-- exception from general requirements 50.24 --exception from consent requirements for emergency research 50.25 elements of informed consent 50.27 documentation of informed consent

21 CFR 50.56D

21 CFR 50D Wards (children of the state) Children who are wards of the state or any other agency can be included in a clinical investigation The Avenue a kit will serve in addition to any other individual acting on half of the children as guardian IRB must require appointment of an advocate navigate must not be associated with the clinical investigations or investigators

sponsor must discontinue the use of any investigational product that causes unreasonable risk to subjects and notify the FDA in

5 days

21 CFR 56 (all)

21 CFR 56-- institutional review boards A--general provisions 56.103 A --circumstances in which r view is required 56.104 A- exemptions from IRB requirements 56.105 A -- waiver of IRB requirements 56.106 A -- registration B- organization and personnel 56.107 B-- IRB membership C- IRB functions and operations 56.108C -- IRB functions and operations 56.109C -- IRB review of research 56.110C-- expenditure review procedures of research involving no more than minimal risk and for minor changes in approved research 56.111C-- criteria for IRB approval of research 56.112C -- review by institution 56.113C -- suspension or termination of IRB approval of research 56.114C -- cooperative research D- records and reports 56.115D -- IRB records and reports E -- administrative actions and non compliance 56.120-124E

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

After initial registration an IRB must renew every...

3 years

How long are IRB registrations effective?

3 years

How long does the IRB have to keep records of studies after their completion ?

3 years

How long does the IRB maintain records for exception from informed consent for emergency research 21 CFR 50

3 years

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

3 years

IRB records are to be retained for at least ________ years after completion of the research.

3 years

The records required by this policy shall be retained for at least _____and records relating to research which is conducted shall be retained for at least ___ years after completion of the research.

3 years

IRB is required to maintain adequate documentation of activities and should be retained for ______

3 years after completion of the research

How long does the IRB have if they want to change from reviewing drugs to reviewing food? or if they want to permanently stop reviewing research ?

30 days

How long does the sponsor have to notify the FDA about a protocol amendment for an investigator change?

30 days

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

30 days

how long does a sponsor have to notify the FDA of the addition of a new PI?

30 days

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

30 days.

Notify FDA within ___ of completion or termination of investigation

30 working days

What is the difference between titles 21 CFR 312 VS. 812:

312 includes a 1572 and serious adverse even. 812 includes an investigational agreement and unanticipated adverse device effects.

312 vs 812

312= 1572 812= Investigational agreement 312= serious adverse event 812=unanticipated adverse device effects

This form is used for the voluntary reporting of adverse events and product problems

3500

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

3500A

sae form

3500a

How many Board Members must an IRB have?

5

How many members must IRB have?

5

What is the MINIMUM amount of members needed for an IRB committee ?

5

Within how many working days must a physician not otherwise involved in the trial review the use and make a written evaluation?

5 WORKING days

IRB exemptions can be made If immediate use of the test article is, in the investigator's opinion, required to preserve the life of the subject, and time is not sufficient to obtain the independent determination use of the test article, must be submitted to the IRB and FDA in

5 days

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

5 days deviations are to protect life or physical well-being

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.

Withdrawal of IRB - investigator to report to sponsor within

5 working days

under 812, if emergency changes need to be made to the investigational plan, how long should the sponsor take to notify FDA

5 working days

Device deemed significant risk by IRB, sponsor notifies FDA within---

5 working days of learning that it is significant risk

21 CFR 50 D all

50 D-- additional safeguards of children in clinical investigations 50.50-- IRB duties 50.51-- clinical investigations not involving greater than minimal risk 50.52-- clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects 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 subjects disorder or condition 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 50.55--Requirements for permission or guardians and for assent by children 50.56 Wards

Equity interest in publicly traded company greater than $______ should be reported?

50,000

final report to FDA _____ after completion

6 months

A sponsor should submit a brief report to the investigator within how many days after the IND went into effect?

60 days. Containing: 1. Individual study info. 2. Summary information. 3. Description of general investigational plan. 4. IB has been revised. 5. Significant protocol modifications.

Any unexpected fatal or life-threatening adverse reaction must be reported in no later than...

7 calendar days

Sponsor must notify FDA of any unexpected fatal or life-threatening suspected adverse reaction within how many days?

7 calendar days after the sponsor's initial receipt of the information

The sponsor shall notify the FDA by telephone or fax any unexpected fatal or life-threatening experience associated with the use of the drug as soon as possible but no later than _____ after the sponsor's initial receipt of the information

7 days

the sponsor must notify FDA of any UNEXPECTED FATAL LIFE THREATENING SUSPECTED adverse reactions ASAP but no later than __calendar days following the sponsor's initial receipt of the information

7 days

How long does the IRB have to submit changes to FDA if any changes occur ? i.e. contact or chair persons change

90 Days

How many days must the IRB revise its registration information?

90 Days

45CFRpart46 D

Children

Contract Research Organization

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

510 Application 21 CFR 812

A 510K is a premarket submission made to FDA that is not subject to premarket approval Exempt and non significant risk devices

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.

Assent (definition)

A child's affirmative agreement to participate in research.

21CFRpart50 D

Children in clinical investigations

IND/IDE

A research permit under section 505 of the act is usually known as an investigational new drug application While a research permit under section 520 of that is usually known as an investigational device exemption

What is an IND?

A research permit under the FFDCA is known as an (IND) ivestigationa new drug application.

What is a research protocol?

A research protocol is a detailed written plan for a given clinical research study. The protocol describes how and why a trial is to be performed and defined the specific data to be collected. It must be a thorough buy concise reflection of the clinical development plan.

Short Form Written Consent Document

A short form written consent document stating that elements have been presented orally to subject. When used a witness is required. Also, the IRB shall approve a written summary of what is to be said. Only short form to be signed by subject. The witness must sign both the short form and copy summary and the person obtaining consent shall sign a copy of the summary. Copy of the summary and short form provided to subject.

What are the steps for withdrawing an IND? 21 CFR 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 IRB

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.

What are information amendments (312, IND)

A sponsor must report information on the IND that is not within scope of protocol amendment. Ex: 1. Toxicology, chemistry technical info. 2. Report for discontinuation of investigation.

changes in protocol

A sponsor shall submit a protocol amendment describing 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.

Protocol Amendments (sponsor can amend as needed the protocol to ensure investigations are conducted according to protocol in application)

A sponsor shall submit an amendment when there is any change that affects patient safety. 1. Increase in drug dosage or exposure. 2. Increase in number of subjects in study. 3. Addition of any new test or procedure (must submit to FDA and must be IRB approved). 4. Change in design of protocol. If change in protocol has to be done immediately to protect subjects they can be notified ASAP. New investigator -> sponsor must notify FDA within 30 days.

IND may be used in a clinical investigation if (A) (2)

A) 1. Sponsor submits an IND to the FDA 2. Each investigator complies with CFR Part 50 and 56

What are the abbreviated requirements for device studies? 21 CFR 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 -monitor study -refrain from promotion

What investigations are Exempt from IRB review?

A) Investigation before July 27, 1981 B) Emergency use of a test article -reported within 5 days. C) Taste and food Quality evaluations

What information does an IRB have to register?

A) Name, address,phone,fax, email of the Senior officer at the institution who is responsible for overseeing activities performed by the IRB B)Name, address, phone, fax, email(if different from above). C) Number of active protocols involved. D). Description of the types of products.

FDA Form 3454

Absence of Financial Interest

45 CFR 46 subparts

A- Basic policy for protection of human research subjects B- Addtl protections for pregnant women, human fetuses and neonates involved in research C- Addtl protection for prisoners D- Addtl protections for Children

ADME

Absorption, distribution, metabolism, execration

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.

21CFRpart312 C

Administrative actions

IDE (Investigational Device Exemption)

An approved IDE permits device to be shipped lawfully.

Clinical Hold (IND)

An order issued by the FDA to a sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation

21 CFR 312.33 Subpart B

Annual reports

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

When can a sponsor withdraw an effective IND without prejudice?

ANYTIME. 1. If withdrawn, FDA must be notified. 2. All study procedures end. 3. Investigators and IRB notified.

Reporting timeframe for other serious, unexpected ADR

ASAP but no later than 15 calendar days after first knowledge by sponsor

21 CFR 56.103 Subpart A

Circumstances in which IRB review is required

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

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.

Circumstances in which IRB review is required

A: Any clinical investigation which must meet the requirements for prior submission to the FDA shall not be initiated unless reviewed and approved and is continually reviewed by an IRB B: The FDA may decide not to consider in support of an application any data derived from a clinical investigation that does not have IRB oversight C: Does not render other laws inapplicable

Exemption from IRB requirement

A: Any clinical investigation which started prior to July 27th, 1981 and was subject to IRB review under FDA regulations before that date and remains subject to that IRB B: Any clinical investigation which started prior to July 27th, 1981 and was not required to have IRB review C: Emergency use of test article, such use is reported to IRB within 5 working days D: Taste and food quality evaluations and consumer acceptance studies

Requirements for permission by parents/guardians and for assent by children

A: IRB must determine that adequate provisions are made for assent when in the judgement of the IRB children are capable of providing assent B: When determining capacity for assent, IRB must take into account: Age, maturity, psychological state Judgement may be made for all children in a study or for each child C: Assent not necessary if IRB determines: 1) Capability of some or all children is so limited that they cannot be consulted 2) Intervention/procedure holds out a prospect of direct benefit and is only available in the clinical investigation D: IRB may still waive assent if it finds and documents that: 1) Clinical investigation involves no more than minimal risk 2) Waiver will not adversely affect rights and welfare of subject 3) Clinical investigation could not be carried out without waiver 4) Subjects will be provided with additional information after participation E: IRB must determine that permission is to be obtained by each child's parents 1) IRB may determine that permission of one parent is sufficient 2) For clinical investigation under CFR 50.53 or 50.54, permission is to be obtained by both parents, unless one is deceased, unknown, incompetent, or not available or only parent has legal responsibility. F: Permission must be documented G: When assent is required, IRB determines whether and how permission is documented.

Definition of Monitoring

Act of overseeing progress of trial and ensuring it is conducted, recorded, reported in accordance with protocol, SOPs, GCPs. Sponsors. Assume compliance on ongoing basis.

21 CFR 56.124 Subpart E

Actions alternative or additional to disqualification

21 CFR 312.87 Subpart E

Active monitoring of conduct and evaluation of clinical trials

21 CFR Subpart D

Additional Safeguards for Children in Clinical Investigation

21 CFR Part 50 SubPart D

Additional Safeguards for Children in Clinical Investigations

21 CRF 50 Subpart D

Additional Safeguards for Children in Clinical Investigations

What is 21 CFR Part 50 Subpart D?

Additional Safeguards for Children in Clinical Investigations

What is 21CFR50 Subpart D?

Additional Safeguards for Children in Clinical Investigations

Some risks are unknown Termination by PI Additional costs Consequences of withdraw New info provided Approx number of subjects

Additional elements of informed consent

45CFRpart46 B

Additional protection for pregnant women, fetuses, neonates

45 CFR Part 46 SubPart D

Additional protections for children

45 CFR Part 46 SubPart B

Additional protections for pregnant women, human fetuses and neonates involved in research

45 CFR Part 46 SubPart C

Additional protections pertaining to biomedical and behavioral research involving prisoners as subjects

21 CFR 50D

Additional safeguards for children in clinical investigations

21 CFR 812.19 Subpart A

Address for IDE correspondence

21 CFR 312.140 Subpart F

Address for correspondence

Nuremberg 1949 (1)

Adhere to the principles of beneficence and morality at all times. These codes were set as a results of the Nuremberg trials. For the good of society, voluntary consent, avoid unnecessary physical and mental suffering and injury. Protects subjects.

Test Article Accountability (logs, ect)

Adherence to storage requirements - temp and freezer logs Proper dispensing and dose 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 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.

21 CFR 312 Subpart C

Administrative Actions

21 CFR 56 Subpart E

Administrative Actions for Noncompliance

21 CFR 312. C

Administrative actions 312.40 General requirements for use of an investigational new drug in a clinical 312.41 comment in advice on an IND 312.42 clinical holds a request for modification 312.44 termination 312.45 inactive status 312.47 meetings 312.48 dispute resolution

21CFRpart56 E

Administrative actions for noncompliance

Definition of IRB approval

Affirmative decision of IRB that clinical trial has been reviewed and may be conducted at the institution site with in constraints set forth by IRB, institution and GCP

Med device: significant risk (3)

All below must also present a potential for serious risk to health, safety, or welfare of a subject - intended as an implant - is purported or represented to be for use supporting or sustaining human life - is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health

Adverse drug reaction(ADR)

All noxious and unintended responses to a medicinal product related to any does should be considered drug reactions Must be at least "reasonable possibility

Adverse Drug Reaction (ADR)

All noxious and unintended responses to a medicine/product related to any dose. Relationship between medicinal product and AE's is a reasonable possibility. (the relationship cannot be ruled out)

21CFR314 New Drug Application

All research complete and they want to market the new drug.

21 CFR Part 314 New Drug Application

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

How many days after FDA receives IND submission does the IND go into effect? 21 CFR 312.40

An IND goes into effect 30 days after the FDA receives the submission unless the FDA notifies the sponsor of a clinical hold.

When is an IND (Investigational New Drug) application needed?

An IND is required when a drug is involved in a clinical investigation that is not exempt from the regulations.

IND Safety Reports (21 CFR 312.31)

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 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.

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

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

60

Annual reports made by the sponsor to the FDA including updates on steady progress should be made within how many days of the anniversary date that the IND went into effect?

Serious Averse Events

Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, life-threatening experience, hospitalization or prolongation thereof, persistent or significant disability, a congenital anomaly or birth defect, any medically significant event (Event if not related, sponsor to be notified in 24 hours).

Adverse Event (Definition)

Any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug related. It can therefore be any unfavorable and unintended sign, symptom, or diagnosis associated with the use of a medicinal investigational product whether or not related.

Adverse event

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmalogical product and which does not necessarily have a causal relationship with this treatment Whether or not considered related to the medicinal product

SAE (Definition)

Any untoward medical occurrence that at any dose results in the criteria for an SAE

21 CFR 312.2 Subpart A

Applicability

21 CFR 812.2 Subpart A

Applicability

21 CFR 812.20 Subpart B

Application

21 CFR 812 Subpart B

Application and Administrative Action

21 CFR Part 812 SubPart B

Application and Administrative Action

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

As drug development progresses who's responsibility is it to submit informational amendments to the FDA regarding the drug?

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

As soon as possible but later than 10 days after investigator learns of the effect.

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 1st learns of the effec

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.

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

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.

A. Will conduct study according to protocol B. Will comply with requirements of PI C. Will personally conduct or supervise investigation D. Inform subjects that drugs are investigational, adhere to informed consent and IRB review and approval are met E. Will report adverse experiences to sponsor F. Read and understands investigator brochure G. All staff informed of duties and obligations H. Complied with initial and continuing review and prompt reporting to IRB

Aside from contact and basic info, what is the PI saying when submitting a 1572?

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.

21 CFR 312.66 Subpart D

Assurance of IRB review

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

At any time

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

At any time.

How long should essential documents be retained?

At least 2 years after the last approval of a marketing application in an ICH regim and until there are non pending.

How often should IRB records be retained?

At least for 3 years after completion of research.

IRB Minutes must show...

Attendance Actions taken Voting with numbers The basis for requiring changes or disapprovals

21 CFR 312.130 Subpart F

Availability for public disclosure of data and information in an IND

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.

IND may be used in a clinical investigation if (B) (1)

B) 1. IND goes into effect - 30 days after FDA receives IND - earlier with FDA notification

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

Clinical holds and requests for modifications in an ongoing study with subjects enrolled and taking drugs must be discontinued and no drug should be dispensed.

Respect for persons, justice, beneficence

List the three ethical principles of the Belmont report

Includes all of the normal plus: Sponsor may recover costs associated with monitoring expanded access protocol, complying with IND reporting, and administrative costs directly associated with the expanded access

Claiming costs for expanded access IND

Class I device classification 21 CFR 812

Class I (Exempt) devices are deemed to be low risk and subject to the least regulatory controls (i.e. dental floss)

21 CFR 600

Biological Products and Development.

45CFRpart46 A

Basic HHS policy

45 CFR Part 46 SubPart A

Basic HHS policy for protection of human subjects

Nuremberg 1949 (2)

Basic principles must be observed in order to satisfy moral, ethical, and legal concepts. Voluntary consent Good of society Designed and based on the results of animal experimentation Avoid all unnecessary physical and mental suffering and injury.

Involves research Risks/discomforts, Benefits Alternates to participation Confidentiality Compensation Contact info Injury Voluntary

Basic required elements of informed consent

Signed investigator statement (form 1572) CV Clinical protocol Financial Disclosures

Before permitting an investigator to begin participating in an investigation what must the sponsor obtain from them?

Three parts of Belmont Report

Boundaries between research and practice, Basic ethical principles (respect for persons[consent], beneficence [do not harm, max benefits], and justice [fairness of distribution of research], applications - informed consent, systematic assessment of risks and benefits, equitable selection of subjects.

Annual report for IND

Brief report of progress of the investigation must be submitted within 60 days of the anniversary date of the IND's effective date

How to go from Celsius

C -> F is (F -32)/1.8. F->C is (C x 1.8) + 32

IND may be used in a clinical investigation if (C) (2)

C) Sponsor may ship product to investigator named in IND: 1. 30 days after FDA received IND 2. earlier with FDA notification

3455

DISCLOSURE of Financial Interests/Arrangements of Clinical Investigator

Class II device classification 21 CFR 812

Class II (Non-significant) devices are higher risk and require greater regulatory controls to provide reasonable assurance of safety and effectiveness (i.e. condoms)

% of something =

Decrease dose

Class III device classification 21 CFR 812

Class III devices are generally the highest risk (Significant risk) devices and are therefore subject to highest level of regulatory control Class III devices must typically be approved by FDA before they are marketed (i.e. replacement heart valves) -Support or sustain human life -important in preventing impairment of human health -potential risk of illness or injury

21CFRpart312.42

Clinical hold

21 CFR 312.42 Subpart C

Clinical holds and requests for modification

document describing objective, design, methods, statistics, and organization of trial. Gives background and rationale for trial.

Define Protocol

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

Clinical holds and requests for modifications in an ongoing study subjects currently taking drug must discontinue and in no drug should be dispensed.

detailed written instructions to achieve uniform performance on specific task

Define SOP

21 CFR 50.55 Subpart D

Requirements for permission by parents or guardians and for assent by children

3454

CERTIFICATION - Financial Interests/Arrangements of Clinical Investigator

Required signatures for consent

CFR requires only the subject to sign ICH requires the subject + person obtaining consent to sign

Required Signatures CFR vs ICH

CFR requires only the subject to sign, ICH reuqires the subject the the person conducting the consent process

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

FDA form 3454

Certification - Financial Interests and Arrangements of Clinical Investigators "As the sponsor (or party submitting on behalf of the sponsor) of the submitted studies, I certify that I have not entered into any financial arrangement with listed clinical investigators..."

What is FDA form 3454

Certification Financial Interests and Arrangements of Clinical Investigators

FDA Form 3674

Certification of Compliance

Form FDA 3674

Certification of compliance

Form 3454

Certification-Financial Interests and Arrangements Clinical Investigators

FDA Form 3454

Certification. This is for financial disclosure certification for any clinical investigator who has no disclosable financial interests.

A. Initial intro of an investigational new drug into humans With an emphasis on identification and control of raw materials and drug substance B. Understand metabolism and pharmacological of drug, side effects associated with increased doses, and gain early evidence on effectiveness in humans D. Obtaining info about drugs pharmacokinetics and pharmacological effects in order to move to a phase to study D1. Protocols are less detailed and more flexible serving as an outline of the investigation E. Number of participants range from 20 to 80

Characteristics of phase 1 IND studies

A. Controlled and closely monitored clinical study to evaluate effectiveness of drug for a particular indication B. Aims to determine the common short term side effects and risks associated with drug C. Involves no more than several hundred subjects

Characteristics of phase 2 I n D studies

A. Expanded controlled and uncontrolled trails B. Conducted after preliminary evidence suggesting effectiveness of drug has been obtained C. Intended to gather additional information of effectiveness and safety D. Evaluates overall benefit risk relationship and to provide adequate basis for physician labeling E. Includes several hundred to several thousand subjects

Characteristics of phase 3 Ind studies

21CFRpart312.8

Charging for drugs

21 CFR 312.8 Subpart A

Charging for investigational drugs under an IND

Pre-Clinical Research

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

Pre-Clinical Research

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

Children: Clinical investigation not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting health or welfare of children

Clinical investigation may proceed if IRB deems study not under scope of CFR 50.51-53, only if A: IRB finds and documents that clinical investigation presents a reasonable opportunity to collect data B: Commissioner of FDA determines: 1. Clinical investigation satisfies conditions of CFR 50.51-53 2. Following conditions are met: i) clinical investigation presents reasonable opportunity ii) clinical investigation conducted in accordance with sound ethical principles iii) adequate provisions for assent and permission of parents to enroll child subject

Requirements for an IND exemption

Clinical investigation of product marketed in US that also: 1. Is NOT to be reported to FDA in support of a new indication or support of change in labeling. 2. No significant change in advertising. 3. Does not change dose, route, patient population that significantly increases risk. 4. Drug intended for invitro or lab tests in animals. 5. Blood grouping serum/ reagent RBCs/Anti-HGB

21 CFR 50.53 Subpart D

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

21 CFR 50.51 Subpart D

Clinical investigations not involving greater than minimal risk

21 CFR 50.54 Subpart D

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

ICH E2A series

Clinical safety data management

21 CFR 312.41 Subpart C

Comment and advice on an IND

45CFR46

Common Rule (Vulnerable populations)

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

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.

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.

Compensation affected by the outcome of clinical studies

Phase 2 and 3 Clinical Holds 21 CFR 312

Concern about safety or efficacy

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.

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

Any untoward medical occurrence associate it with use of a drug in humans whether or not considered drug related

Define adverse event

21 CFR 812.38 Subpart B

Confidentiality of data and information

Phase 3 Clinical Trials

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

Phase 3 Clinical Trials

Confirmation of short-term efficacy and establishedd long term efficacy. Establish benefit-risk relationship Provide adequate basis for labeling Several hundred to several thousands

Life threatening circumstances deem use of test article necessary, inability to communicate or get legally affective consent, time not sufficient, no alternative method to saving life

Consent is Feasible unless all of following are true:

What is a CRO?

Contract Research Organization. A person that assumes, as an independent contractor with the sponsor, one or more of the obligations of the sponsor. Ex: Design of protocol, selection of monitors of investigators, evaluation of report, prep of materials to be submitted to the FDA.

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.

1572

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

A person that assumes as an independent contractor with the sponsor one or more of the obligations of a sponsor for example design of a protocol, selection or monitoring of investigations, evaluation of reports, in preparation of materials to be submitted to the FDA

Contract research organization (cro)

CRO

Contract research organization - runs some aspects of the study such as monitoring, contract negotiations, payments, ect. Duties must be transferred in writing from the sponsor.

21 CFR 312.61 Subpart D

Control of the investigational drug

21 CFR 56.114 Subpart C

Cooperative research

45CFRpart46.114

Cooperative research groups

Experiment that involves a test article and one or more human subjects - does not include experiments which are nonclinical lab studies

Define clinical investigation

FDA Form 1571

Cover page for an IND application

1571 = IND Application (Expanded Use)

Cover sheet for expanded access submissions includes: 1. Rationale of intended use of drug. 2. Criteria for client selection. 3. Method of administration. 4. Description of facility where drug-manufactured. 5. chemistry...strength of investigational drug. 6. Pharmacology/toxicity

Declaration of Helsinki

Created June 1964 set of ethical principles for medical research involving human subjects

21CFRpart56.111

Criteria for IRB approval and research

21 CFR 56.111 Subpart C

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.)

An adverse event or suspected adverse reaction which places the patient or subject at immediate risk of death

Define life threatening adverse event

IND may be used in a clinical investigation if (D) (2)

D) An investigator may not administer an IND until the IND application goes into effect

Form FDA 3455

Disclosure: Financial Interests and Arrangements of Clinical Investigators

Form 3500

For Voluntary Reporting of AEs and Product Problems

FDA Form 3500

For Voluntary Reporting of Adverse Events and Product Problems

And adverse event which results in any of the following: death, a life-threatening adverse event, inpatient hospitalization or prolonged existing hospitalization, a persistent or significant incapacity or disruption of the ability to conduct a normal life, or a congenital anomaly/birthday fact

Define serious adverse event or serious suspected adverse reaction

Any equity interest in a publicly traded corp. that exceeds 50k during time clinical investigator is carryign out study and for 1 year following completion of study or value can't be determined through reference to public prices

Define- Significant equity interest in the sponsor of a covered study

property or other financial interest in the product including a patent, trademark, copyright or licensing agreement

Define- proprietary interest

21 CFR 56.102 Subpart A

Definitions

21 CFR 812.3 Subpart A

Definitions

21 CFR 312.3 Subpart A

Definitions and interpretations

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.

Basic Elements of the ICF 3 of 8

Description of any benefits which may be reasonably expected

Basic Elements of the ICF 2 of 8

Description of any reasonably foreseeable risks or discomforts

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

Pivotal Studies (device)

Determines safety and effectiveness, includes most of overall subject numbers

3500A

Device adverse event report

Medical Device

Device is NOT dependent on chemical action or being metabolised -also must be recognized in official national formulary or US pharmacopeia -intended for use in the diagnosis, treatment, mitigation or prevention of disease in man or other animals

Medical Device

Device is NOT dependent on chemical action or being metabolized, and; -also must be recognized in official national formulary or US pharmacopeia -intended for use in the diagnosis, treatment, mitigation or prevention of disease in man or other animals

Device studies

Device studies do not have phases per the regulations, but many sponsors may refer to their protocols in terms of phases. Devices are divided into classes: Class: general controls; Class Ii: performance standards Class III: premarket approval.

FDA Form 3455

Disclosure

FDA Form 3455

Disclosure - Financial Interests and Arrangements of Clinical Investigators

FDA Form 3455

Disclosure - Financial Interests and Arrangements of Clinical Investigators Each investigator completes for each study separately

FDA Form 3455

Disclosure of Financial Interests and Arrangements of Clinical Investigators

Basic Elements of the ICF 4 of 8

Disclosure of appropriate alternative procedures

Form 3455

Disclosure-Financial Interests and Arrangements Clinical Investigators

Severely Debilitating

Disease/condition that causes major irreversible morbidity

21 CFR 312.59 Subpart D

Disposition of unused supply of investigational drug

21 CFR 312.48 Subpart C

Dispute resolution

21 CFR 312.70 Subpart D

Disqualification of a clinical investigator

21 CFR 812.119 Subpart E

Disqualification of a clinical investigator

21 CFR 56.121 Subpart E

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 Part 50.27

Documentation of informed consent

21CFRpart50.27

Documentation of informed consent

What cirical question must be answered by the IRB?

Does the sum of benefits and importance of knowledge gained from research outweigh risks to partipants?

What critical question must be answered by the IRB?

Does the sum of the benefits and the importance of the knowledge gained from research outweigh the risks to the participants.

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 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.

21 CFR 312 Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating illness

21 CFR 312 Subpart G

Drugs for Investigational Use in Laboratory Research Animals or In Vitro Tests

21CFRpart312 G

Drugs for investigational use in lab research animals and in vitro tests

21 CFR 312.160 Subpart G

Drugs for investigational use in laboratory research animals or in vitro tests

21CFRpart312 E

Drugs intended to treat life threatening / severely debilitating illnesses

What legal document defines the investigator's obligational for conduction a clinical trial?

Drugs: FDA 1572, Devices: the investigator agreement.

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.

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.

ICH E series

Efficacy

Drug development Phase II

Efficacy (proof of concept) (n = 100-200)

21 CFR 11 Subpart B

Electronic Records

21 CFR 11

Electronic Records; Electronic Signatures

21 CFR 11 Subpart C

Electronic Signatures

21 CFR 312.82 Subpart E

Early consultation

What does the FDA operate under?

FD&C Act and other federal laws

21CFRpart11 B

Electronic records

21 CFR Part 11

Electronic records; considered equivalent to handwritten records & signatures. These maybe used in lieu of handwritten (unless there's an exception).

21CFRpart11 C

Electronic signatures

21 CFR 50.25 Subpart B

Elements of informed consent

21CFRpart50.25

Elements of informed consent

21 CFR 812.47 Subpart C

Emergency research

21 CFR 312.54 Subpart D

Emergency research under 50.24 this chapter

21CFRpart312.36

Emergency use IND (not emergency setting)

Minimal risk

Encountered in daily lives or usually standard treatment.

Humanitarian Use Device 21 CFR 814.124

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 fewer than 4,000 individuals a year in the US". Therefore CANNOT be a comparable device that is available to the intended population.

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.

FDA Audit

Ensure Compliance, Study-directed, Investigator directed, For cause audits, Not for cause - routine surveillance.

What do audits, inspections, and monitoring visits have in common?

Ensure human subject protection, data integrity, and product accountability

FDA Audit

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

510K clearance

Established in 1976 (90%) of devices are marketed as 510(k)s- meaning that the sponsor can provide data that device is comparable to an already approved device -Mostly class I and II devices

510K clearance

Established in 1976 -Most devices (90%) are marketed as 510(k)s- meaning that the sponsor can provide data that device is comparable to an already approved device -Mostly class I and II devices -FDA applies "clearance" NOT approval

Declaration of Helsinki 1964

Ethical principles for med 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.

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.

How often does an IRB have to renew its registration?

Every 3 years

How often should an IRB renew registration?

Every 3 years.

21 CFR 50.23 Subpart B

Exception from general requirements

21 CFR 50.24 Subpart B

Exception from informed consent requirements for emergency research

21 CFR Part 50.23

Exceptions of obtaining consent (DOD stuff)

21 CFR Part 50.24

Exceptions to consent 2/2 emergency research. Protocols involving an exception to the consent must be performed under a separate IND or IDE clearly stating some maybe unable to consent.

Exemption for Investigation of a Device...21 CFR 812.2 (c)

Exempt Investigation of a Device -Those that are used in accordance with its labeling -Does not present significant risk -Not used a diagnostic product or procedure

21 CFR 56.104 Subpart A

Exemptions from IRB requirement

Form FDA 483

Exit interview form- summary of observations. Exit interview 1st happens in real time then form comes later after legal has reviewed the language

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 312 Subpart I

Expanded Access to Investigational Drugs for Treatment Use

21CFRpart312 I

Expanded access

21 CFR 56.110 Subpart C

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

Basic Elements of the ICF 7 of 8

Explanation of whom to contact for answers to questions and in event of injury

Pilot Studies (device)

Exploratory Includes small numbers of subjects

Pilot Studies (device)

Exploratory and includes small numbers of subjects

Pre-Study Documents (Essential Documents)

FDA 1572 (drug) or signed investigators agreement (devices) CVs, licenses, ect Fully executed contract and budget Protocol signature sheet Approved informed consent LAB certificates (Clia and CAP) and normal values Lab director's CV IRB membership and assurance # IRB approval

What must the sponsor obtain from the investigator prior to start of study?

FDA Form 1572 (statement of investigator) CVs Protocol Financial Disclosure

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

21 CFR 812.309 Subpart B

FDA action on applications

21 CFR 812.42 Subpart C

FDA and IRB approval

FDA 483

FDA form issued form to an institution when conditions are observed that in their judgement may constitute violations of the FDA. The form notifies the company's management of objectionable conditions. Investigator responds with in 15 days. Describes any observations that represent deviations from applicable statues and regulations. Inspector also prepares EIR -> goes to FDA with 3 outcomes: 1. No action required. 2. Voluntary Action required (response recommended generally for minor deviations). 3. Official Action indicated - major deviations)

FDA jurisdiction for devices

FDA has jurisdiction at international sites where investigator is under an IDE

Pre-IND submission meeting 21 CFR 312

Facilitates planning for IND

Common Deficienceis of FDA inspections

Failure to follow protocol, Deviations, Inadequate record keeping, Inadequate accountability, ICF issues/subject protections

Justice

Fairness of distribution

The IRB determines whether or not a device study is SR or NSR.

False

The sponsor is responsive for selection of an IRB

False

If an IRB regularly reviews research involving prisoners, a prisoner representative should be included on the board (True/False)

False - Consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with those subjects (21 CFR 56.107a).

An IRB must be composed of five(5) members (True/False)

False - Must have at least 5 members (21 CFR 56.107a)

The ICF must be signed and dated by the Principal Investigator (True/False)

False - Not Specified by FDA Regulation or Guidance but sometimes required by IRB

The ICF must be signed and dated by the person obtaining consent (True/False)

False - Specified by ICH GCP (4.8.8)

Each subject's case history should document that informed consent was obtained prior to participation in the study (True/False)

False - Specified in both 21 CFR 312.62b and 812.140a. "Case histories" include CRFs, signed and dated consent forms, and medical records (physician progress notes, individuals hospital chart and the nursing notes).

An IRB must have at least one female member (True/False)

False - The FDA Regulations (21 CFR 56.107b) specify: "Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the institution's consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of gender."

The ICF must be signed by a child subject if the IRB determines that assent is required (True/False)

False - The method of documenting assent is determined by the IRB (21 CFR 50.55) and does not necessarily have to be by child signature.

If a site uses electronic medical records as source documents the EMR system must be compliant with 21 CFR part 11 (True/False)

False - There is currently no FDA Regulation or Guidance specifying this. However, a recent FDA Draft Guidance does indicate: "For those who use electronic signatures based upon the use of identification codes in combination with passwords, the clinical site must employ controls to ensure the security and integrity of the authorized user names and passwords (21 CFR 11.300a)."

It is prohibited to use CRFs (other than questionnaires) directly as source documents (True/False)

False - There is no regulation preventing this practice of from using copies of CRFs as source documents

All source documents must be signed by the completer (True/False)

False - There is no requirement for this but several FDA Guidance's do specify that data should be "attributable".

An IRB member that has a conflicting interest in a project under review may not participate in the IRB's review proceedings (True/False)

False - These individuals can participate in order to provide information requested by the IRB (21 CFR 56.107e).

When a short form is used for informed consent the witness must sign the short form or the summary?

False-they must sign both

True or False Investigators are responsible for periodically requesting updates regarding new information gleaned by a sponsor during the course of a clinical investigation.

False. The sponsor must provide relevant new information about the drug, particularly with respect to adverse effects and safe use, Via revisions to an Investigator Brochure, reprints of published studies, or reports, or through other appropriate means. 22 CRF 313.55

True or False The terms "treatment protocol" and "treatment IND" are interchangeable and mean the same thing.

False. A treatment protocol is sponsored by a sponsor, while a treatment IND (Investigational New Drug) is sponsored by a licensed medical practitioner who becomes a sponsored investigator. 21 CRF 312.35

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.

Humanitarian Device Exemption

Faster. A devices manufacture must submit an HED application to the FDA that includes a description, all data and experience with the product. FDA will only approve if manufacture proves the device is safe and have probably benefit in the intended patient population. This is marking approval and therefore the devices is not considered investigational. IRB approval is still required, full board, doesn't require informed consent but IRB can require it. No data collected as it not research, not required but can collect data.

Federal Regulations and ICH GCP - Differences

Federal Regulations are the legal requirements for the conduct of clinical research established and monitored by federal authorities. GCP is the international ETHICAL and scientific quality standard for designing , conducting, recording, and reporting trials that involve the participation of human subjects.

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.

ICH Clinical Safety Data Management: Definitions and Standards fro Expedited Reporting- E2A Guideline

Finalized 27 October 1994

International Conference on Harmonization (ICH) Guideline for Good Clinical Practice E6 (R1)

Finalized May 1996

21 CFR 54

Financial Disclosure - disclosure any potential or actual conflicts of interest which could affect the conduct of the study and/or study outcome. All personnel listed on 1572 must complete (includes immediate family).

21 CFR Part 54

Financial Disclosures

21CFR54

Financial Disclosures

3455

Financial certification form

21 CFR 54

Financial disclosure by clinical investigators Reason- minimize bias, One a potential source of bias in a clinical studies is a financial interest in the outcome of the study because of 1)Payment is arranged (royalty- sales of a product) 2)or proprietary interest in a product( patent) 3)or equity interest in a sponsor (stock e.g.) exceeds $50,000- reporting during the clinical trial plus one year after the trial 4) significant payments of a sponsor to an investigator or institution to support activities have a value of more than 25,000 (excludes grants equipment etc) Clinical investigator definition only a listed or identified investigator or sub investigator who is directly involved in the treatment or evaluation of research subjects. The term also includes the spouse in each dependent child of the investigator Applicant The party who submits a marketing application to FDA for approval of a drug device or biological products the applicant is responsible for submitting appropriate certification and disclosure statements required in this part

3454

Financial disclosure form

Should financial records be filed along with the regulatory files?

Financial disclosure reports and financial aspects 9budget0 of the clinical trial are typically filed separately from the clinical/regulatory documents.

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!

Phase II

First to use patients with disease or condition, define dose of drug, establish safety and some efficacy, well defined patient eligibility criteria.

21 CFR 312.86 Subpart E

Focused FDA regulatory research

Products covered by 21 CRF 50 (7 products)

Foods Dietary supplements (with claims) Infant formula Food and color additives Drugs for human use Medical devices for human use Electronic products

FDA Form 3500

For *Voluntary* Reporting of Adverse Events and Product Problems

Form 3500A

For Use by User-Facilities, Distributors and Manufacturers for Mandatory Reporting

FDA Form 3500A

For Use by User-Facilities, Distributors, and Manufacturers for Mandatory Reporting

FDA Form 3500A

For Use for User-Facilities, Distributor, and Manufacturers for *Mandatory* Reporting

The investigator shall promptly update this information if any relevant changes occur in the course of the investigation or for 1 year following completion of the study.

For how long should an investigator update the sponsor of financial disclosures and changes?

until 2 years after date of approval of application

For how long should the sponsor retain financial information of investigators?

FDA form 3500 A

For use by User-facilities, Distributers, and Manufacturers for mandatory reporting

21 CFR 312.120 Subpart F

Foreign clinical studies not conducted under an IND

IND Safety Reporting Form 21 CFR 312

Form 3500 A

NDA application form

Form 356H

What does SOCRA certification mean/imply

Foundation of knowledge and practice in research regulations and GCP

21CFRpart56 C

Functions and operations

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

Declaration of Helsinki

GCP has it's origins in what?

21 CFR 312.300 Subpart I

General

Class 1 Device

General Controls are sufficient to provide reasonable assurance of the safety and effectiveness

21 CFR 11 Subpart A

General Provisions

21 CFR 312 Subpart A

General Provisions

21 CFR 50 Subpart A

General Provisions

21 CFR 56 Subpart A

General Provisions

21 CFR 812 Subpart A

General Provisions

21 CRF 50 Subpart A

General Provisions

class I

General controls bandages, gloves, tongue depressors

21 CFR 312.22 Subpart B

General principles of the IND submission

What is 21 CFR Part 50.20 Subpart B?

General requirements for informed consent

21 CFR 312.40 Subpart C

General requirements for use of an investigational new drug in a clinical investigation

21 CFR 312 A

General scope 312.1 Scope 312.2 applicability 312.3 def and interpretations 312.6 labeling of an investigational new drug 312.7 promotion of investigational drugs 312.8 charging for investigational drugs under IND 312.10 waivers

Any of the conditions under phase 1 study are met or investigational plan is not reasonable as a scientific plant to determine whether or not drug is safe and effective, evidence that the drug is not effective for purpose for which it has been investigated is discovered,

Grounds for termination under CFR 312 four phases two and three studies

ICH E6 series

Guidance for industry

IRB registration is reviewed and accepted by

HHS

21 CFR 312.69 Subpart D

Handling of controlled substances

1964

Helsinki Declaration

Class III (device)

Highest risk, premarket approval usually reqiured -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

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

Class III (device)

Highest risk: premarket approval usually required. 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

Sponsors can transfer responsibility for any or all of the obligations in and investigation but it must be described in writing If transfer of obligations is in effect the CRO is held to same standards as sponsor

How are duties transferred under CFR 312 between a sponsor and a contract research organization?

If no subjects enrolled for two years or more or Investigation on clinical hold for 1 or more years Annual reports need not be submitted to FDA under this status

How does an IND get put onto in active status

For two years after the date a marketing application is approved or two years after the investigation is discontinued and FDA's notified

How long are investigators mandated to retain records under 21 CFR 312?

3 years after completion of clinical investigation

How long is the IRB required to retain records from a clinical investigation?

Must be performed under a separate IND or IDE that clearly includes subjects who are unable to consent

How must protocols with exceptions to informed consent proceed under IND or IDE applications?

Someone who is or becomes A participate in research either as a recipient of the test article or as a control

Human subject is:

21 cfr part b

ICF

ICH E2A also called

ICH Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

Significant Risk Device

IDE must be submitted. 1.Implant or serious risk to health, safety, well-being 2.Supports/sustains human life 3.Importance for diagnosis, treatment, or curing diseases. Could be class II or class III. IRB makes determination when FDA hasn't already.

When isn't an IND application needed?

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

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

21CFR312

IND Applications

21 CFR 312.31

IND Safety Reports

21CFRpart312

IND application

21CFRpart312 B

IND application steps

21 CFR 312.23 Subpart B

IND content and format

21CFRpart312.23

IND content and format

21CFRpart312.22

IND general

21 CFR 312.32 Subpart B

IND safety reporting

21CFRpart312.32

IND safety reporting

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.

Continued submission to the IRB

IND safety reports (if required) 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

21 CFR 56 Subpart C

IRB Functions and Operations

21 CFR 812 Subpart D

IRB Review and Approval

21 CFR Part 812 SubPart D

IRB Review and Approval

21 CFR 812.62 Subpart D

IRB approval

21 CFR 812.60 Subpart D

IRB composition, duties, and functions

21 CFR 50.50 Subpart D

IRB duties

21CFRpart50.50

IRB duties

45CFRpart46.304

IRB exclusive of prisoners as members

21CFRpart56.110

IRB expedited review

45CFRpart46.108

IRB functions

21 CFR 56.108 Subpart C

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.

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.

Unexpected adverse event or reaction

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

21 CFR 56

IRB institutional review board- also independent ethics committee(IEC) Scope IRB reviews clinical investigation is regulated by the FDA FDA as well as clinical investigations that support applications for research in marketing permits for products regulated by the FTA including foods dietary supplements the bear in nutritional content claim or health claim, infant formulas food in color additives, food additive, drugs for human use medical devices for human use biological products for human use an electronic products compliance with this part is intended to protect the rights and welfare of human subjects involved in research investigations Any clinical investigation to the FTA shall not be initiated unless the investigation has been a proved and reviewed by the IRB and remains subject to continue review ( 21 CFR 56.103)-circumstances in which IRB reviewed is required Each IRB in the united states that reviews clinical investigations to support applications for research in marketing permits for FDA must register at a site maintained by the department of health and human services HHS Each IRB must renew it's registration every three years and is excepted by the HHS Any personnel changes must be submitted to the HHS within 90 days Must report within 30 days of changing review genre such as food additives to drug trials or drug trials to devices

21 CFR 56.107 Subpart B

IRB membership

21CFRpart56.107

IRB membership

45CFRpart46.107

IRB membership

Non-Significant Device

IRB must agre with this risk assessment. Does not meet significant device categories.

Process of notification when consent waived

IRB notifies sponsor who notifies FDA

21CFRpart56 B

IRB organization and personnel

21 CFR 56.115 Subpart D

IRB records

21CFRpart56 D

IRB records

21CFRpart56.115

IRB records

21CFRpart56.106

IRB registration

21 CFR Part 56

IRB regulations

21CFR56

IRB regulations

21 CFR 56.109 Subpart C

IRB review of research

21CFRpart56.109

IRB review of research

What is the notification process of an exception to informed consent occurs?

IRB to provide in writing to sponsor than sponsor should disclose to FDA. Determinaton of investigator to use the device must be made in 5 working days of using device to IRB.

IRB Registrations

IRB under OHRP that review research involving humans must be registered Dept. of health and human services (HHS). 1. Name, address, institution, contact info of head official. 2. Contact info for who is doing registration. 3. Contact info for chairperson. 4. # of protocols, active protocols, # of IRB positions. 5. Type of products for protocols they review. OHRP approves registration- effective for 3 years.

21 CFR 812.64 Subpart D

IRB's continuing review

How can a disqualified IRB become reinstated?

IRB/institution may be reinstated upon evaluation of a written submission explaining corrective action.

21CFRpart56

IRBs

The FTA should reply with an answer within 30 calendar days however the investigation may not go on until the sponsor hears back from the FDA even if it takes longer than 30 days

If A study is put under a clinical hold under CFR 312 And they request that the FDA lift the hold,when may they begin to conduct research again?

Administrative Actions for Non-Compliance for IRBs

If FDA observes non-compliance during inspection: May 1. withhold approval of new studies. 2. No new subjects be added to ongoing studies. 3. Terminate ongoing studies when it would not endanger subjects. 4. Notify state/federal agencies when appropriate. Parent institution is responsible for IRB

Investigator and sponsor

If IRB can't approve research who do they notify?

As soon as possible notify: IRB for review and approval Sponsor for agreement Regulatory authorities (if applicable)

If a PI has to implement a change of the protocol (deviation) prior to approval, who should they notify and in what timeframe?

How must an investigator store investigational drugs which are also controlled substances?

In a securely locked, substantially constructed cabinet with limited access to prevent theft or diversion of the substance into illegal channels of distribution. 21 CRF 312.69

Investigator contacts other family and notifies IRB at continuing review

If consent not feasible and no LAR who should be contacted and by whom for participation in emergency research?

Sponsors must maintain IND study records for __________ 21 CFR 312

If study is submitted in support of an application - 2 years after an agency decision on that application If study submitted in support of an IND but not an application for marketing approval - 2 years after submission of IND

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.

Non-sig risk category

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.

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.

Pre-Market Approval

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.

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.

21 CFR 312.110 Subpart F

Import and export requirements

21 CFR 812.18 Subpart A

Import and export requirements

21 CFR 312.45 Subpart C

Inactive status

21CFRpart312.45

Inactive studies

Person (definition)

Includes any individual, partnership, corporation, association, scientific or academic establishment, government agency, or organizationa unit of a government agency and any other legal entity.

Authorization to charge is limited to the number of patients authorized to receive the drug Charging may occur for 1 year following FDA authorization. Sponsors may request to charge for additional periods

Ind expanded access charging limitations and durations

What is the IEC?

Independent Ethics Committee. 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 asurance of that protection. An independant body ( a review board, comittee, institutional, regional, national, supre-national) constituted of medical professional and non-medical members whos responsibility it is to ensure the protection of the rights, safety, and well being of human subjects invovlved in a trial and provide public assurance of protection.

IDMC (definition)

Independent data monitoring committee

21 CFR 312.310 Subpart I

Individual patients, including for emergency use

Informed consent Justice Belmont Report

Individual- fairness in subject selection (equal) Social justice- based on members of class to bear burdens and appropriateness of placing further burdens on already burdened persons

Vulnerable Subjects

Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether, justified or not of benefits associated with participation or of a retaliatory response from senior members of a hierarchical structure who refuse to participate.

21 CFR 312.31 Subpart B

Information amendments

Serious Reporting Examples (Flip to see)

Information that might materially influence the benefit risk assessment of a medicinal product or that would be sufficient to consider changes in medicinal product administration or in the overall conduct of a clinical investigation represents such examples: 1. unexpected, serious ADR, an increase in the rate of occurrence which is judged to be clinically important. 2. A significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treatment of life threatening disease. 3. A major safety finding from a newly completed clinical study (such as carcinogenicity).

21 CFR Part 50

Informed Consent Regulations

21CFR50

Informed Consent Regulations

21 CFR 50 Subpart B

Informed Consent of Human Subjects

21 CFR Part 50 SubPart B

Informed Consent of Human Subjects

21 CRF 50 Subpart B

Informed Consent of Human Subjects

21 CFR Part 50

Informed consent

21CFRpart50 B

Informed consent

21 CFR 50

Informed consent.

21 CFR 312.55 Subpart D

Informing investigators

21 CFR 812.45 Subpart C

Informing investigators

21 CFR 312.68 Subpart D

Inspection of investigator's records and reports

21 CFR 312.58 Subpart D

Inspection of sponsor's records and reports

483

Inspection report

FDA Form 483

Inspectional Observations

Form 483

Inspectional Observations

FDA Form 483

Inspectional Observations - issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts.

The FDA form 483 is used for _______

Inspectional oberservation

FDA Form 483

Inspectional observations

21 CFR 56

Institutional Review Boards

21 CFR Part 56

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.

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 45 CFR 46.103 and documents how the institution will protect the welfare and rights of research subjects based on federal regulations.

21 CFR 56

Institutional review boards

21CFRpart312.315

Intermediate size patient populations

21 CFR 312.315 Subpart I

Intermediate-size patient populations

ICH E6

Internarionl

ICH E6 also called

International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (E6)

ICH (definition)

International conference on Harmonisation

21 CFR 56.120 Subpart E

Lesser administrative actions

Accountability records should include ?

Inventory of product/drug Dispensation records Batch information/expiration dates, etc

Accountability records should include...?

Inventory of product/drug Dispensation records Batch information/expiration dates, etc

21 CFR 812

Investigational Device Exceptions

21 CFR Part 812

Investigational Device Exemption

Title 21 CFR Part 812 details

Investigational Device Exemption

What is an IDE?

Investigational Device Exemption. It 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.

21 CFR 812

Investigational Device Exemptions

21 CFR Part 812

Investigational Device Exemptions

21CFR812

Investigational Device Exemptions

21 CFR 312

Investigational New Drug Application

21 CFR 312 Subpart B

Investigational New Drug Application (IND)

21 CFR 312

Investigational new drug application

21 CFR 312B

Investigational new drug application IND

21 CFR 312 B all

Investigational new drug application IND 312.20 requirement for an IND 312.21 phases of an investigation 312.22 General principles of the IND submission 312.23 IND content and format 312.30 protocol amendment 312.32 information amendments 312.33 annual reports 312.38 withdrawl of an IND

21 CFR 812.25 Subpart B

Investigational plan

what document contains all information known to date regarding an investigational drug?

Investigator Brochure.

21 CFR 312.62 Subpart D

Investigator recordkeeping and record retention

21 CFR 312.64 Subpart D

Investigator reports

21 CFR 312

Investigator responsibilities

21 CFR Part 312

Investigator responsibilities

21CFRpart312.64

Investigator will report AEs

Record Keeping

Investigators: 2 years after marketing applications approval or 2 years after investigation is discontinued and FDA is notified. Sponsor: Should maintain all sponsor specific docs for at least 2 years after they discontinue development. IRB: 3 years after completion of research.

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.

What is the purpose of an audit?

It is independent of and separate from routine monitoring or quality control functions, should be used to evaluate trial conduct and compliance with the protocol SOP's, GCP, and the applicable regulatory requirements.

ICH Countries

Japan, US, Europe

21CFRpart56.114

Joint review possible (CIRB)

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.

FDA Form 482

Letter of Intent to Inspect

FDA 482

Letter of intent to inspect

FDA Form 483

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

21 CFR 312.6 Subpart A

Labeling of an investigational new drug

21 CFR 812.5 Subpart A

Labeling of investigational devices

What are the basic componenets of compliance? (LRGPP)

Law, regulation, guidance, policy and procedure

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

Class I (device)

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

21CFRpart312.62

Maintain adequate and accurate records

A. Selecting qualified investigators and providing them information needed to conduct investigation properly B. Ensuring proper monitoring and selecting monitors C. Ensure that investigation is conducted in accordance with generally investigational plan and protocols contain the IND D. Maintaining affective I&D with respect to investigation E. Ensuring that FDA and all investigators are promptly informed of significant new adverse effects or risks regarding the drug

Major responsibilities of sponsors under CFR 312

Ensuring investigation conducted according to form 1572, the investigational plan and applicable regulations protecting subjects under the investigators care control of drugs under investigation informed consent

Major responsibility of investigators under CFR 312

MedWatch 3500A

Mandatory reporting

Sponsor

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

Sponsor investigator

Means an individual who both initiates and conducts an investigation under who's immediate direction the investigational drug is administered or or dispensed. the term does not include any person or other than an individual their requirements applicable to a sponsor under this part include both those applicable to investigator in a sponsor

Expanded Access to Investigational Drugs Requirements

Meant to facility availability of drugs to patients with serious diagnosis or conditions and there is not alternative. Drugs with limited availability by REMS. 1. Patients have serious or immediately life threatening condition with no alternatives. 2. Benefit justifies risk of treatment use and potential risks are not unreasonable. 3. Providing the drug for use will not interfere with clinical investigations or compromise potential development. 4. Expanded access submission submitted. Goes into effect 30 days after FDA reviews.

21 CFR Part 860

Medical Device Classifications Procedures

Title 21 CFR Part 860 details

Medical Device Classifications Procedures

21 CFR Part 803

Medical Device Reporting

Title 21 CFR Part 803 details

Medical Device Reporting

3500

Medwatch / serious adverse event report

21 CFR 312.47 Subpart C

Meetings

5

Minimum number of people on an IRB

21 CFR 312 Subpart F

Miscellaneous

Class II (device)

Moderate risk, usually requires a 510k --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

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

Class II (device)

Moderate risk: usually requires a 510k 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

21 CFR 812.46 Subpart C

Monitoring investigators

ICH M series

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.

Subject Recruitment and Retention

Must be approved by IRB prior to use. No coercive wording and following subject payment guidelines.

Medical Device

Must be recognized in official national formulary or US pharmacopeia. Intended for use in the diagnosis, treatment, mitigation or prevention of disease in man or other animals

What are the IRBs responsibilities when ICF cannot be obtained in emergency situations

Must ensure procedures are in place to inform at earliest time the subject or LAR of the subjects participation in the study. IRB determinations of this must be retained for 3 yrs. Must document: Life treatening. ICF is not feasible. Research will cause direct benefit. Waiver not practical.

The Belmont Report (1979)

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

Belmont Report 1979

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

Study Start-up Activities (9)

Negotiate contract/budget;Compile regulatory docs (essential docs);Complete IRB application and Consent; IRB approval and IBC if applicable; Attended investigators meeting; In-service staff; Prepare/create source docs; Complete protocol specific training; Set up billing prices and procedures

Is informed consent required when treating/diagnosing a patient with an HUD? 21 CFR 812

No The act and the HDE regulations do not require informed consent. Because an HDE provides for marketing approval, use of the HUD does not constitute research or an investigation... However, there is nothing in the law or regulations that prohibits a state or institution from requiring prospective informed consent, when feasible. In fact, most HDE holders have developed patient labeling that incorporates information that may be used to assist a patient in making an informed decision about the use of the device. See 21 CFR 814.104(b)(4)(ii).

FDA Inspection Classification Code: NAI

No Action Indicated No objectionable conditions or practices were found during the inspection

are restudy visits required by law?

No.

Does the 1572 need to be submitted to FDA

No. Although the sponsor is required to collect 1572 from the investigator, FDA does not require the form to be submitted to the agency.

Are CV's required to be signed and dated? (Form 1572)

No. FDA regulations do not require a CV to be signed and dated. The investigator's dated signature on the 1572 is sufficient to attest to the accuracy of the CV or other statement of qualifications submitted.

What is non-compliance

Noncompliance with the protocol, SOPs, and GCP and/or applicable regulatory requirements by an investigator institution or by members of the sponsors staff should lead to prompt action by the sponsor to secure compliance.

FDA Form 482

Notice of FDA Inspection form

Form FDA 482

Notice of FDA inspection form

FDA Form 482

Notice of Inspection

Form 482

Notice of Inspection

What is the FDA Form 482?

Notice of Inspection

482

Notice of inspection

1947

Nuremberg Code

OHRP

Office For Human Research Protections. 1. Protects volunteers in research conducted supported by US Dept. of Health and Human Services 2. Usually inspects IRBs

FDA Inspection Classification Code: OAI

Official Action Indicated Regulatory and administrative actions will be recommended

Post-market Studies

Often referred to as post-marketing surveillance: Ensure that newly marketed medicines achieve the highest safety standards.

On-site vs. centralized monitoring

On site= performed at site of trial Centralized= remote eval of accummulated data by qualified prs (data managers, biostats)

Human subjects exposed to on reasonable risk of illness or injury, I and he doesn't contain sufficient information to assess safety, methods facilities and controls and packaging of drug or in adequate, investigation conducted in a manner different than described in protocol, drug is being promoted or distribute it for commercial purposes not justified, I am do you contains untrue statement of a material fact or image material info required by part, sponsor fails promptly to investigate and inform FTA of serious an unexpected adverse events, Sponsor fails to submit accurate annual report of investigation's, sponsor fails to comply with CFR 50 or CFR 56, I am D has remained in active for five years or more, sponsor fails to delay propose investigation under IND or suspend ongoing investigation that is been placed on clinical hold

On what grounds may a study under CFR 312 be terminated?

What is the MINIMAL amount of times per year the IRB must review ongoing research ?

Once a year

21 CFR 56 Subpart B

Organization and PErsonnel

Discuss the basics of study design?

Overall goals: 1. It is the structure of any scientific work. It gives direction and systematizes the research. Correlative Studies: 1.Observational 2.Cohort 3.Cross sectional

ISO 14155:2011 GCP

Overuse of investigational device. SADE reporting. IB contents. Ament internationa standard for devices. Does not apply to invitro medical devices.

who should the sponsor representative meet with?

PI, sub-PI, CRC, pharmacist, lab tech, site manager

who should meet the sponsor at the prestudy visit?

PI, sub-PI, CRC, pharmacist, lab technician, site manager.

PMA

Permanent approval

Drug development Phase 0

Pharmacokinetics and pharmacodynamics

Clinical Trial Phases

Phase 1: Healthy Volunteers. Toxicity. PK/PD Profiles. Determine Dose. Protocol design is less structured. Phase 2: short term risks. Effectiveness. Phase 3: Determine effectiveness. Confirm Phase 2.

During which phases is a treatment protocol usually made available

Phase 3 but if data is compelling, may be available during Phase 2. After all clinical trials have been completed and sponsor of trials is awaiting/pursuing marketing approval.

21 CFR 312.85 Subpart E

Phase 4 studies

21CFRpart312.85

Phase 4 studies / post marketing

21 CFR 312.21 Subpart B

Phases of an investigation

Drug development Phase III

Pivotal Studies (n = 300-3000) - goal to obtain large enough population to show statistical evidence of efficacy and safety

Four types of controls

Placebo Active-treatment Dose-comparison No-treatment

Drug development phase IV

Post marketing surveillance - goal to collect safety information in a larger population

Phase 4

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

21 CFR Part 814

Premarket Approval of Medical Devices (and Humanitarian Use Devices)

21CFR814

Premarket approval of devices and Humanitarian device exemptions.

21 CFR Part 814

Premarket approval of medical devices

Title 21 CFR Part 814 details

Premarket approval of medical devices

Define significant risk device

Presents a potential for serious risk to health, safety or welfare in either of these situations: -intended as an implant -used for supporting or sustaining human life -used for diagnosing, curing, mitigating or treating disease

Definition of Minimum Risk

Probability and magnitude of harm or discomfort anticipated in research are not greater than those encountered in daily life or with routine tests/procedures.

21 CFR 812.7 Subpart A

Prohibition of promotion and other practices

21 CFR 312.7 Subpart A

Promotion of investigational drugs

21CFRpart312.7

Promotion of investigational drugs

Beneficience

Protecting from harm Maximize benefits while minimizing harm

21 CFR 50

Protection of Human Subjects

21 CFR Part 50

Protection of Human Subjects

45CFRpart46

Protection of human subjects

Definition of Inspection

Protection of human subjects, verify Data act by regulatory authorities of official review of documents, facilities, records, any other resources. May affect decision to accept data for marketing.

45CFRpart46 C

Protections for prisoners

21 CFR 312.30 Subpart B

Protocol amendments

21CFRpart312.30

Protocol amendments

Pre-Market Approval (PMA)

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

A. Statement of the objectives and purpose of study B. Investigator information including names addresses curriculum vitae's etc. C. Criteria for patient selection exclusion and estimate of number of patients to be studied D. Description of study design including control group if any description of methods to minimize bias on the part of subjects investigators and analysts E. Method for determining doses to be administered, planned maximum dosage, and duration of individual patient exposure to drug D. Description of observations and measurements to be made to feel feel objectives of study E. Description of clinical procedures, lab tests, or other measures taken to monitor effects of drug in humans and minimize risk

Protocols for I in D studies should include

Expanded Access Study

Provides a pathway for patients to gain access to investigational drugs, biologics, and medical devices used to diagnose, monitor, or treat patients with serious diseases or conditions for which there are no comparable or satisfactory therapy options available outside of clinical trials.

21 CFR 56.122 Subpart E

Public disclosure of information regarding revocation

21 CFR 312.80 Subpart E

Purpose

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.

ICH Q series

Quality

21 CFR Part 820

Quality systems regulations

Title 21 CFR Part 820 details

Quality systems regulations

IND Study Record Keeping - sponsor must maintain adequate records showing... (3)

Receipt, shipment, and other disposition of the drug

21 CFR 312.57 Subpart D

Recordkeeping and record retention

21 CFR 56 Subpart D

Records and Reports

21 CFR Part 812 SubPart G

Records and Reports

What records must be maintained by investigators for investigational drug supplies?

Records of disposition including dates, quantities, and use by study subjects. 21CRF 312.62

Basic Elements of the ICF 6 of 8

Research involving more than minimal risk requires an explanation of compensation and explanation of medical treatment available if injury occurs

21 CFR 56.106 Subpart B

Registration

45 CFR Part 46 SubPart E

Registration of IRB

45CFRpart46 E

Registration of IRBs

21 CFR 56.123 Subpart E

Reinstatement of an IRB or an institution

21 CFR 812.27 Subpart B

Report of prior investigations

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 312.305 Subpart I

Requirements for all expanded access uses

21 CFR 312.20 Subpart B

Requirements for an IND

21CFRpart50.55

Requirements for permission by parents and assent

21 CFR 20.25 (8 requirements of consent)

Research is involved Questions - who to contact Alternatives Risks and discomforts Benefits Voluntary Participation Confidentiality of records Compensation being offered

21 CFR Part 50 D

Research w/ min risk = can occur if no more than min risk + assent & consent received. Research greater than min risk w/prospect of direct benefits = can occur if risk is justified by benefits + assent & consent received. Research greater than min risk w/ no prospect of direct benefits= can occur if minimum increase over min risk, experiences are similar to SOC theyd be receiving, likely to give general knowledge about their disorder, assent & consent

21 CFR 312 Subpart H

Reserved

21 CFR 812 Subpart F

Reserved

21 CFR 812.65 Subpart D

Reserved

21 CFR Subpart C

Reserved

What are the 3 principles of Belmon Report?

Respect for Persons Beneficience Justice:

Belmont Report Basic Ethical Principals

Respect for persons Beneficence Justice

What are the three main basic ethical principles of the Belmont Report?

Respect for persons. Beneficence. Justice.

21 CFR 812 Subpart E

Responsibilities of Investigators

21 CFR Part 812 SubPart E

Responsibilities of Investigators

21 CFR 812 Subpart C

Responsibilities of Sponsors

21 CFR Part 812 SubPart C

Responsibilities of Sponsors

21 CFR 312 Subpart D

Responsibilities of Sponsors and Investigators

21CFRpart312 D

Responsibilities of sponsors and investigators

21 CFR 312 D

Responsibilities of sponsors and investigators 312.50 General responsibilities of sponsors 312.52 transfer of obligations to a contract research organization 312.53 selecting investigators in monitors 312.54 emergency research 312.55 informing investigators 312.56 review of ongoing investigations 312.57 Record keeping and record retention 312.58 inspection of sponsors records and reports 312.59 disposition of a new supply of investigational drug 312.60 General responsibilities of investigators 312.61 Control of the investigational drug 312.62 investigator record keeping and record retention 312.64 investigator reports 312.66 assurance of IRB review 312.68 inspection of investigators records and reports 312.69 handling of controlled substances 312.70 disqualification of a clinical investigator

Explain the rules relating to financial disclosure?

Responsible for inmplementing the public and confidential financial disclusre systems to prevent conflicts of interest and to identify potential conflicts by providing review of the financial interest in both current and prospective employees.

21 CFR 56.112 Subpart C

Review by institution

21 CFR 312.56 Subpart D

Review of ongoing investigations

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.

Typical order of events for a monitoring visit

Review study status review regulatory files Review source documents verify CRF data Verify investigational product management and accountability Meet PI

Investigator's Brochure

Reviewed annually, revised as needed.

21 CFR 312.84 Subpart E

Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and severely-debilitating illnesses

Sponsor must: 1. Provide evidence that drug has potential benefit through investigation providing significant advantage over current products 2. Show that data from trial is essential in showing drug is effective or safe 3. Trial not possible without charging due to cost of drug being extraordinary to sponsor (due to large quantity, scarcity of resources, etc) Duration if charging may be for the length of clinical trial unless FDA specifies shorter time

Rules for charging for drug in a clinical trial and duration

Sponsor must: 1. Provide assurance that charging won't interfere with developing drug for market approval 2. Provide evidence of sufficient enrollment in ongoing clinical trials needed for marketing approval to assure FDA that trials will be successfully completed 3. Evidence of adequate progress in development of drug for market approval 4. Info submitted under general plan specifying drug development milestones to be completed in next year

Rules for charging for expanded access in drug trual

21 CFR 312.88 Subpart E

Safeguards for patient safey

ICH S series

Safety

Drug development Phase I

Safety (n = 20-80)

21 CFR 312.81 Subpart E

Scope

21 CFR 321.1 Subpart A

Scope

21 CFR 56.101 Subpart A

Scope

21 CFR 812.1 Subpart A

Scope

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

Select qualified investigator, provided information to conduct the study, ensure proper monitoring, ensure compliance with general investigational plan and protocols, maintain an effective IND, Ensure FDA and investigators are notified of significant new adverse events or risks.

21 CFR 312.53 Subpart D

Selecting investigators and monitors

21 CFR 812.43 Subpart C

Selecting investigators and monitors

What AE qualifies for expedited reporting? ICH E2A

Serious and Unexpected

report to IRB:

Serious, unexpected and related.

Short form stating that consent has been presented orally IRB approved written summary of what is said to subject Copies of each signed are given to subject

Short form consent documents

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.

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

payments made by the sponsor 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.

Significant payments of other sorts

21 CFR 812.66 Subpart D

Significant risk device determinations

SMO

Site management organization - Companies contracted with by the sponsor to find and manage the sites conducting the study.

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.

21 CFR 812.110 Subpart E

Specific responsibilities of investigators

1. Cover sheet 2. Table of contents 3. Intronstatement and general investigational plan 4.Investigators brochure 5. Protocols 6. Chemistry manufacturing and control information 7. Pharmacology and toxicology information 8. Previous human experience with the investigational drug

Sponsor includes all of the following in an IND application to the FDA

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

Sponsor report potential serious risks associated with investigational product to FDA and all investigators asap, but not more than 15 calendar days

1. Cost to produce drug for commercial sale

Sponsors may not claim indirect costs incurred during and IND trial- these include:

1. Cost per unit to manufacture the drug 2. Costs to acquire the drug from other manufactures 3. Ship and handle costs for the drug Sponsors must back this up with documentation and accompanied by a statement from and independent CPA

Sponsors may only recover direct costs incurred in an IND trial. These include:

BSA Calculation

Square root of (height in cm x weight in kg) / 3600

Basic Elements of the ICF 5 of 8

Statement describing the extent to which any confidentiality of records identifying subject

FDA Form 1572

Statement of Investigator

Form 1572

Statement of Investigator

FDA Form 1572

Statement of Investigator - an agreement signed by the investigator to provide certain information to the sponsor and assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic.

FDA Form 1572

Statement of the Investigator

1572

Statement of the investigator

Basic Elements of the ICF 8 of 8

Statement that participation is voluntary, refusal involves no penalty, and that subject may discontinue at any time without penalty

21CFRpart50.53

Studies with greater than minimal risk, no prospect of direct benefit, increase in knowledge

Phase III

Study Participants: 300 to 3,000 volunteers who have the disease or condition Length of Study: 1 to 4 years Purpose: Efficacy and monitoring of adverse reactions

Phase II

Study Participants: Up to several hundred people with the disease/condition. Length of Study: Several months to 2 years Purpose: Efficacy and side effects

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

Study period plus 1 year

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

Study period plus 1 year.

21CFRpart312.21

Study phases (1, 2, 3)

Site Qualification Visit

Study sponsor or rep 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, availability of appropriate equipment, sufficient staff, and adequate potential subject population to screen from.

Interim Monitoring Visits

Study sponsor or their rep (CRO) 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 regs do not. Person should be qualified by training and experience to monitor the investigation.

same as PT ID

Subject Identification Code

Phase 1 Clinical holds 21 CFR 312

Subject safety concerns

Clinical Hold (IND) what happens to current subjects

Subjects already in the study should be taken off therapy unless specified by the FDA

Emergency research waiver

Subjects are in a life-threatening situation and available treatments are unproven or unsatisfactory. Obtaining consent is on 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.

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

45 CFR 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.

The Belmont Report

Summarizes the basic principals that should underlie the conduct of biomedical and behavioral research involving human subjects.

21 CFR 812.35 Subpart B

Supplemental applications

True or False ? IRB's must register to the department of HHS prior to reviewing any Clinical investigations?

True

Any adverse event for which there is a reasonable possibility that the drug caused the adverse event meaning there is evidence to suggest a cuddle relationship between the drug in the adverse event

Suspected adverse reaction definition

SUSAR

Suspected and Unexpected Serious Adverse Reaction

21 CFR 56.113 Subpart C

Suspension or termination of IRB approval of research

Definition of Audit

Systematic inddependent exam of trial related activities and documents to determine compliance with sponsor SOPs/GCPs. Sponsor or CRO performs. Verify data integrity.

21 CFR 312.44 Subpart C

Termination

21 CFR 20 Other elements of consent

Termination by agents Pregnancy language Cost associated with protocol Withdrawal from the protocol Number of subjects total Findings that are important

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.

1976

The belmont report

Use of placebo

The benefits, risks, effectivess, etc. must be tested except: When no proven intervetion exists. Then the use of placebo, or no intervetion is acceptable. Also, if a compelling and scientific methodological reasons for intervention

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.

What information is an investigator required to divulge regarding each study subject?

The investigator may withhold subject names unless the records of particular subjects require more detailed study, or if there is a reason to believe the records do not represent the actual cases, or results. 21 CRF 312.68

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.

21CFR812

The non-significant risk category was created to avoid delay and expensive where the anticipated risk to human subjects did not justify the involves of the FDA.

What is the well being (of trial subjects)

The physical and mental integrity of the subjects participating in a clinical trial.

What is minimal risk.

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.

Minimal Risk

The probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

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 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. ( IRB may defer to the FDA to make the initial determination).

What is trial design?

The sponsor should utilize qualifed individuals (clinical, physicians, biostats, etc.) as appropriate throughout all stages of the trial process from designing the protocol and CRFs and planning the analysis to analyzing and preparing interim and final clinical trial reports.

Children: Clinical investigation involving greater than minimal risk and no prospect of direct benefit, but likely to yield general knowledge of disorder or condition

This is only permitted if the IRB finds and documents that: A: Risk of the study represents a minor increase over minimal risk B: Intervention/procedure presents experiences that are reasonably commesurate C: Intervention/procedure likely to yield generalizable knowledge about disorder or condition D: Adequate provision for assent and permission of parents

True or False: Parent institution is presumed responsible for the IRB

True - in the case of IRB noncompliance FDA will direct action against institution unless evidence determines responsibility solely on the IRB or component of institution

Children: Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit of individual subject

This is only permitted if the IRB finds and documents that: A: Risk to the subject is justified by anticipated benefit B: Relation of anticipated benefit is at least favorable compared to alternative approaches. If there is an alternative treatment with equal benefit and less risk, the child subject cannot be enrolled in the study. C: Adequate provision for assent and permission of patents to enroll the child subject.

Class III Devices

Those for which insufficient information exists to assure safety and effectiveness solely through general or special controls. 1. usually support or sustain human life 2. Are of substantial importance in preventing impairment of human health 3. Present a potential, unreasonable risk of illness or injury

Exemption for Investigation of a Device. 21 CFR 812.2 (c)

Those that are used in accordance with its labeling: Ex, does not present significant risk. Not used as a diagnostic product or procedure.

Class II Devices

Those which general controls alone are insufficient to assure safety and effectiveness and existing methods are available to provide such assurances

Within five working days

Timeframe after consent is waived to notify IRB and physicians

What is the role of the IRB?

To assure protection of the rights and well being of research subjects. Determines if proposed research is a benefit to participants, does not cause harm, and promotes good clinical practice.

21 CFR 312.52 Subpart D

Transfer of obligations to a contract research organization

Respect for persons

Treated as independent agents: those with diminished autonomy are protected Subjects enter research voluntarily and with adequate information

Respect for persosn

Treated as independent agents: those with diminished autonomy are protected Subjects enter research voluntarily and with adequate information

21 CFR 312.320 Subpart I

Treatment IND or treatment protocol

21 CFR 312.83 Subpart E

Treatment protocols

21CFRpart312.34

Treatment use of an IND

21 CFR 312.34

Treatment use of an Investigational new drug

Title/ section 21 CFR 312.34 details

Treatment use of an Investigational new drug

21 CFR Part 312.34

Treatment use of an Investigational new drug.

21 CFR 812.36 Subpart B

Treatment use of an investigational device

A Trial Delegation list should identify the training that individuals have received that qualifies them to perform delegated tacks (True/False)

True

In device studies, the field clinical engineer's activities should be described in the protocol and informed consent (if face-to-face contact with subjects) (True/False)

True

Investigators conducting studies of drugs with potentially fatal toxicity should be readily available 24 hours / day and in reasonably close proximity to study subjects (True/False)

True

Investigators should develop a plan for the oversite of the clinical trial that might include the creation of specific SOPs (True/False)

True

The ICF must be signed and dated by the subject (True/False)

True

The institution is responsible for designating the IRB

True

True

True or false- drugs intended solely for tests in vitro or in lab research animals, or placebos are exempt from cfr 312.160

the investigator is responsible for IRB compliance with the CFR

Ture

laws govern clinical research

US Code of Federal Regulations (CFR): 21FDA, 45 HHS state and local laws

Federal Food, Drug, and Cosmetic Act (FD&C Act)

US Federal Law (Enacted by congress so statutory law)

21 CFR 312.16A

Under 21 CFR 312 - investigational new drug application Labeling of an investigational drug It should say, "caution new drug limited by federal or United States law to investigational use"

21 CFR 312.7 A

Under 21 CFR 312 - investigational new drug application Promotion of investigational drugs A sponsor or investigator or any person acting on behalf of a sponsor shall not represent in April she will contacts that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug A sponsor or investigator shall not commercially distribute or test market and investigational new drug

21 CFR 312.8A

Under 21 CFR 312 - investigational new drug application general provisions Charging for investigational drugs under IND 1) A sponsor must justify the amount to be charged in accordance with this paragraph- provide evidence that the drug has a potential clinical benefit would provide a significant advantage over available products to treat disease or a condition 2) A sponsor must obtain prior written authorization from FDA to charge for investigational drug 3) FDA will withdraw authorization to charge if it determines that charging is interfering with the development of a drug for marketing approval or that the criteria for the authorization are no longer being that 4) demonstrate that the clinical trial cannot be conducted without charging because the cost of the drug is extraordinary to the sponsor the cost may be extraordinary due to manufacturing complexity of scarcity of a natural resource ( due to the size of the trial or duration of the trial) Unless FDA specifies a shorter period of charging me continue for the length of the clinical trial Charging for expanded access to investigational drug or treatment use

21 CFR 312.1A

Under 21 CFR 312 - investigational new drug application general provisions Waivers- sponsor waivers Investigational new drug application to FDA Sponsor my request FDA to wave applicable requirement under this part waiver request maybe Smith either in an IND or an information amendment to an IND.

21 CFR 312B.21

Under 21 CFR 312B IND Phases of an investigation An IND maybe submitted for one or more phases of an investigation the clinical investigation of the previously and has a drug is generally divided into three phases although in general the phases are conducted sequentially they may overlap 1) phase 1- closely monitored and maybe conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans the side effects associated with the increasing dose and if possible to gain early evidence of effectiveness ---sufficient information about the drugs pharmacokinetics and Pharma logical effects. Should be obtained to permit the design of a well-controlled scientifically valid phase 2 study ---around 20 to 80 subjects 2)phase 2- conducted to evaluate the effectiveness of the drug for a particular indication or indications and patience with the disease or condition under the study. To determine the common short term side effects and risks associated with the drug. ---around no more than couple hundred subjects 3)phase 3- Studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug in their intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit risk relationships in adequate basis for physician labeling ---several hundred to several thousand subjects After his primary objectives in reviewing and I and D are in all these is of the investigation to assure the safety and rights of subjects and in phase 2 and three to help assure the quality of the scientific a valuation of drugs is adequate to permit and evaluation of the drugs efficacy and safety

21 CFR 312B.20

Under 21 CFR 312B IND Requirement for an IND A sponsor shall submit an IND to FTA if the sponsor intends to conduct a clinical investigation with an investigational new drug with human subjects A sponsor shall submit a separate IND for any clinical investigation involving an exception from informed consent Such a clinical investigation any trial is not permitted to proceed without the prior written authorization from the FDA FDA shop provide a written determination 30 days after FDA receives the IND or earlier

21 CFR 50.25B explain

Under 21 CFR 50B Basic elements 1) A statement that the study involves research the explanation of the purpose of the research and expected duration of the subjects participation description of the procedures to be followed and identification of any procedures which are experimental 2) description of any reasonably foreseeable risk's or discomfort to the subject 3) A description of any benefits to the subject or two others which may reasonably be expected from the research 4) A note of confidentiality 5) an exclamation as to whether any medical treatments are available if injury occurs 6) I disclosure of appropriate alternative procedures or courses of treatment of any that might be advantageous to the subject 7) Who to contact and who to contact in emergency 8) statement that participation is voluntary Others 1) I statements explain procedures involving rest to other subjects such embryo or fetus if the subject may become pregnant 2) anticipated circumstances under which the subject participation it may be terminated by the messy eater without regard to subjects consent 3) additional cost to the subject from participating in the trial 4) consequences of a subjects decision to withdraw from the research and procedures for orderly termination of participation by the subject 6) approximate number of subjects enrolled and study

21 CFR 50.27B explain

Under 21 CFR 50B Documentation of informed consent 1) must be approved by IRB 2) must be written consentsigned and dated by the subject or subjects legally authorized representative a copy shall be given to the person signing the form Exceptions 1) A written consent document that embodies the elements of the informed consent may be read to the subject or the subjects legally authorized representative but the investigator shall give either adequate opportunity to read it before and it is signed Short form written 2) A short form of written consent document sitting at the elements of the informed consent have been presented orally to the subject or subjects legally authorized representative there must be a witness to the oral presentation also the IRB shall prove a written summary of what is to be said to the subject or representative only the short form it's self is to be signed by the subject or represent However the witness shall sign both the short form and a copy of the summary and the person actually obtaining the consent shall find a copy of the summary a copy of the summary shall be given to the subjects in addition to the copy of the short form

Short form written

Under 21 CFR 50B Short form written 21 CFR 50.27 Oral consent 2) A short form of written consent document sitting at the elements of the informed consent have been presented orally to the subject or subjects legally authorized representative there must be a witness to the oral presentation also the IRB shall prove a written summary of what is to be said to the subject or representative only the short form it's self is to be signed by the subject or represent However the witness shall sign both the short form and a copy of the summary and the person actually obtaining the consent shall find a copy of the summary a copy of the summary shall be given to the subjects in addition to the copy of the short form

21 CFR 50.23B exceptions

Under 21 CFR 50B informed consent 1) The human subject is confronted by a life-threatening situation requiring the use of a test article or drug (5 working days after a after use of the drug this decision needs to be reviewed and evaluated in writing by physician who is not participating in the clinical trial- needs to be submitted to the IRB within five working days after the use of the test article 2) informed consent cannot be obtained from subject because of an inability to communicate with or obtain legal effect of consent from the subject 3) Time is not sufficient to obtain consent from the subjects legal representative 4) there is available no alternative method of a prude or generally recognized therapy that provides an equal or greater likelihood I'm saving the life of the subjects (Same for device)

21 CFR 50.55D

Under 21 CFR 50D Requirements for permission by parents or guardians and or assent by children The IRB must determine the adequate provisions are made for soliciting the scent of the children one of the judgment of the IRB the children are capable of providing assent Take in account to the ages maturity and psychological state of the children involved This judgment may be made for all the children to be involved in the clinical investigation under a protocol for for each child as the IRB deems appropriate The permission of each child's parent and guardian is granted both parents must give them permission unless one parent is deceased unknown incompetent or not reasonably available or when only one parent has a legal responsibility of the child Permission by parents or guardians must be documented in accordance of GCP When Ira B determines that the center is acquired it must also determine whether or how assent must be documented Execeptions of assent 1) capability of some or all children is so limited that they cannot reasonably be consulted 2) well being outweighs the risk 3) The clinical investigation involves no more the minimal risk

21 CFR 50.51D

Under 21 CFR 50D Clinical investigation is not involving greater than minimal risk in children 1) no greater than minimal risk for children is present and may involve children as subjects only if the IRB find No greater than minimal risk to children is presented Adequate provisions are made for soliciting the scent of the children and the permission of their parents or guardians

21 CFR 50.52D

Under 21 CFR 50D Clinical investigation the molding greater than minimal risk by presenting the prospect of direct benefit to individual subjects---May involve children as subjects only if IRB finds 1) The risk is justified by anticipated benefit to the subjects 2) relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternatives 3)adequate provisions are made for this listing the scent of the children in the permission of their parents

21 CFR 50.50D

Under 21 CFR 50D IRB duties Each IRB must review clinical investigations involving children as subjects covered by this sub party in approve only those clinical investigations that satisfy the criteria

21 CFR 54.4

Under 21 CFR 54 An applicant must submit a list of all clinical investigators who conducted covered clinical studies to determine whether applicants meet FDA marketing requirements Identifying those critical investigators who are full time or part time employees of the sponsor of each covered study they may also disclose concerning financial interest of a clinical investigator who is not full time or part time employee of the sponsor If they are unable to do so the applicant shall certify that despite the applicants due diligence to obtain the information required in this section shall certify that despite the applicants attempts son include the reason They either need a certification described in the section or a disclosure statement described in this paragraph 1) certification application covered I'll submit for all investigators to whom the certification applies form 345 for the form shall be dated and signed by the chief financial officer or responsible corporate official or representative 2) disclosure statement if an investigator does not submit certification the applicant shall submit a completed form 3455 disclosing completely and accurately the following Any financial arrangements and trade between the sponsor of the study in clinical investigator involves where the value could influence the outcome of the study Any significant payments of other sorts from the sponsor of the study such as a grant or fund compensation consultation or honorarium Any proprietary interest in the drug; any significant equity interest in the sponsor holding the trial; any steps taken to minimize the potential for bias The investigator shall promptly update this information of any relevant changes occur in the course of the investigation or for one year following completion of the study to the FDA

21 CFR 56.104

Under 21 CFR 56 IRB Exemptions from the IRB requirement 1)Any investigation before July 27, 1981 2)Emergency use of a test article provided that such an emergency use is reported to the IRB within five working days 3) taste in food quality evaluations in consumer except some studies if without additives are consumed

21 CFR 56B

Under 21 CFR 56-IRB IRB membership 21 CFR 56.107 Must have at least five members with varying backgrounds If an IRB regularly reviews research that involves vulnerable category of subjects such as children prisoners pregnant women or handicapped or mentally disabled persons consideration shall be given to the inclusion of one or more officials were knowledgeable about inexperienced in working with those objects At least One member should be an expert in scientific area At least one member is not affiliated with the institution or who is not part of the mediate family of the person who is affiliated with institution No members can have a conflict of interest No IRB may consist entirely of members of one profession one person can not be scientific IRB may invite individuals of competence in special areas True View complex issues

21 CFR 56.110C

Under 21 CFR 56C -IRB functions and operations Expedited review procedures for certain kinds of research involving no more the minimal Risk and for minor or changes in approved research 1) some or all of the research appearing on the listby reviewers to involve no more the minimal risk 2) minor changes in previously approved research during the period of one year or less for which approval is authorized

An adverse event that is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed and is not consistent with the risk information described in the general investigational plan or elsewhere in the current application

Unexpected adverse event definition

FD&C Location

United States Code (USC), which has all general and permanent US laws beginning at 21 USC 301

CFR also called

United States Code of Federal Regulations

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.

Phase 4

Used to delineate additional information about the drug's risks, benefits, and optimal use

Phase 1 Clinical Trials

Usually 20-80 subjects. Meant to assess initial safety and efficacy usually single center

Phase 2 Clinical Trials

Usually no more than several hundred subjects multi-centered

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.

FDA Inspection Classification Code: VAI

Voluntary Action Indicated Objectionable conditions or practices were found, but the agency is not prepared to take or recommend any administrative regulatory actions

MedWatch 3500

Voluntary reporting

21 CFR 56.105 Subpart A

Waiver of IRB requirement

21 CFR 312.10 Subpart A

Waivers

21 CFR 812.10 Subpart A

Waivers

21 CFR 50.56 Subpart D

Wards

21CFRpart50.56

Wards of state

Any increase in drug dosage, significant changes in the design of a protocol such as addition or dropping of a control group, the addition of a new test or procedure

What are some examples of a need it protocol amendment to the FDA in and I and D study?

Subjects may not be given the investigational drug, during ongoing studies no new subjects maybe recruit it to the study and placed on the drug, patient already in the study should be taken off therapy involving the drug unless specifically allowed by FDA in the interest of patient safety

What are the restrictions put on too and I in D study when it is under a clinical hold?

A. Brief description of drugs substance including structural formula if know B. Summary of pharmacological and talks a logical effects of drugs in animals and if known humans C. Summary of pharmacokinetics and biological disposition of drug and animals and if noon humans D. Summary of info relating to safety and effectiveness in human E. Descriptions a possible risks and side effects

What should the sponsor include in an investigator is brochure?

A. A brief introductory statement with name of drug pharmacological class structure and formula for dosage B. Summary of previous human experience with drug C. Brief description of overall plan for investigating the drug product ever the following year

What should the sponsor include in the introductory statement of an I in D application

Any records showing receipt shipment or other disposition of the drug, any records showing financial interests of investigators they should be retained for two years after a marketing application is approved for the drug or until two years after shipment and delivery of the drug is discontinued

What types of records should a sponsor retain and for how long?

New protocols, changes in a protocol, new investigators added to the study,

What types of things are protocol amendments submit it to four?

Investigator

When consent is not obtained and and investigational device is used, who must report the characteristics of the device to the subjects physician within 5 working days?

After IRB approval, and 30 days after FDA receives the IND unless FDA notifies the sponsor that the investigation just described are subject to a clinical hold Or On earlier notification by FDA that the investigation may begin

When does an IND go into effect?

30 days after FDA receives the IND or unless the FDA notifies earlier that the drug maybe shipped

When is a sponsor allowed to ship an investigational new drug to investigators named in the I in D?

It's been submitted to FDA for its review and has been approved by the IRB

When may protocol Changes go into affect under CF are 312?

ASAP but no later than 7 calendar days after finding out

When must a sponsor notify FDA of unexpected fatal or life-threatening suspected adverse reaction?

CAPA

a process to identify root cause of issues or problems and actions to resolve them

PI

Who is responsibile for the investigational product at the trial site?

The sponsor using form 3500A within 15 calendar days after learning the info

Who must submit IND safety reports, why, and when?

Belmont Report: Justice

Who ought to receive the benefits of research and bear its burdens? "fairness in distribution" or "what is deserved". Equals ought to be treated equally. 1. To each an equal share. 2. To each according to individual need. 3. to each according to individual effort. 4. to each according to societal contribution. 5. to each according to merit.

Investigator

Who provides the IRB with a copy of the investigator brochure?

Short form written consent doc- subject, and witness Copy of summary- signed by witness and consent authorized

Who signs what in the short form consent process?

Sponsor Submits a protocol amendment describing any change in a phase 1 protocol that affects the safety of subjects or phase 2 or three protocol that significantly affects the safety the scope or the scientific quality of the study

Who submits protocol changes to the FDA and for what should protocol amendment be submitted?

IRB

Who's responsibility is it to ensure that procedures are in place, to inform subjects or family members of investigational details as soon as possible in emergency research?

21 CFR 312.38 Subpart B

Withdrawal of an IND

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

Withdrawal of an IND--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

With ICF exemptions how long do the investigator and physician have to submit documentation to the IRB?

Within 5 working days after the use of the test article

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

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.

FDA Regulations: legally binding?

YES (it's administrative law)

Can a clinical investigator submit an IDE?

Yes. They can sponsor their own study. They are considered a sponsor-investigator and must comply with all responsibilities of both sponsor and investigator.

An AE is a suspected adverse reaction only if there is evidence suggesting...

a causal relationship between the drug and AE

Assent

a child's affirmation agreement to participate in a clinical investigation

Med device: Non-Significant Risk (NSR)

a device that does not meet SR requirement.

Human subject 45 CFR 46

a living individual about whom an investigator conducting research obtains: data or identifiable private information

Sponsor

a person/entity who initiates a clinical investigation

3454

absence of financial interest

A____________ can be any unfavorable and unintended sign) including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

adverse event

purpose of a termination visit

all data collected and verified final accounting and disposition of the investigational product final reconciliation of study supplies study files are complete and correct.

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 before proceeding with the trial.

IRB General Definition

an independent body constituted of medical, scientific, and non-scientific members whose responsibility it is to ensure the protection of the rights, safety, and well being of human subjects. Renewing approving and providing CR and protocol amendments.

Investigator

an individual who actually conducts a clinical investigation

Sponsor-Investigator

an individual who both initiates and actually conducts a clinical investigation

when does the IND get updated?

annually, and as changes occur.

Clinical Investigation

any experiment that involves a test article and one or more human subjects and that either is subject to requirement for prior submission to the FDA, results are intended to be submitted to the FDA as part of an application for research or marketing permit

Biologics Licensing

application for approval from FDA is a PLA, for biologics is a BLA. 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.

What if the FDA shows up?

ask for ID and 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

IRB must retained study records for 45 CFR 46

at least 3 years after completion of research

How many members must sit on an IRB

at least 5 with varying backgrounds, including persons of knowledge in acceptability of research, include persons knowledgeable in acceptability of research in terms of institutional commitments, regulations, applicable law and standards of conduct and practice.

Compassionate Use

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.

Suspected adverse reaction 21 CFR 312

causal relationship between drug and adverse event (reasonable possibility that it is related)

FDA may withdraw authorization for IND charging if

charging is interfering is interfering with drug development

SIV purpose

clarify the applicable regulations, and requirements of the protocols and carefully review the actual process of implementing the protocol at the site.

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

comparator

Phase IV

conducted after FDA has approved the drug. Such as Fast-tracked drugs. (evaluates age and ethic groups, safety, pharmacoeconomic data, marketing launch).

Belmont report

created on April 18, 1979 -describes ethical principles and guidelines for protection of human subjects

A ________is a printed, optical or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject

crf

Example of NSR

crutches, braces (cannot penetrate skin, ect, do not require IDE (investigational device exemption)

What date should an investigator write when he failed to sign the consent form on the date of consent?

date of investigators signature

812 "immediately life threatening" definition

death likely within months or premature death without early treatment

When is the monitoring visit typically conducted?

depending on SOPs

Definition of research Belmont Report

designates an activity designed to test a hypothesis, permit conclusions to be drawn

Nuremberg Code

developed 1947 in response to Nuremberg war crimes

Devices exempt from 812

devices in commercial distribution prior to 1976 non-invasive diagnostic devices devices for veterinary use device undergoing consumer testing

is permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial

direct access

3455

disclosure.

21 CFR 50.27 Subpart B

documentation of informed consent

control group design

eliminates bias

Minimal risk

encountered in daily lives or usually standard treatment

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!

Phase 1

first time on humans, short term, usually healthy (unless cancer, HIV ect), establish safety and tolerance of compound in humans. Info collected - pharmacodynamics, pharmacokinetics, bioavailability, bioequivalence, dose proportionality. (Safety, vital signs, plasma and serum concentrations, sid effects)

Which form is used to certifiy absence of financial interest?

form 3454

Class II

general control+special controls (x-ray machines, monitors)

Medical device class III

general controls + premarket approval (HIV diagnostic tests, pacemaker, silicone gel-filled breast implants, and drug eluting stents. Usually require premarket approval application (PMA)

Medical device class II

general controls + special controls e.g. physiologic monitors, x-ray machine, infusion pumps. May required 501(k) clearance

Medical device class I

general controls e.g. bandages, glove, tongue depressor

Class III

general controls+ premarket approval (pacemaker, diagnostic test, silicone gel breast implant)

What is 21CFR50.20 Subpart B?

general requirements for informed consent

CAPA

identify root cause or problem and how to solve them

What are requirements for waived consent?

if no more than minimal risk and involves no procedures for which written consent is normally required-- IRB may require investigator to provide written statement of research to subjects

Reporting Timeframe for Fatal or Life threatening ICH E2A

immediately but no later than 7 days

If no subjects are entered into clinical study for a period of 2 years or more under IND or if all investigators under IND remain on clinical hold for 1 year or more, the IND may be placed on _________ by the FDA

inactive status

Definition of Practice Belmont Report

interventions that are designed solely to enhance well-being of an individual patient or client that have a reasonable expectation of success

SIV order of events

introduction, detailed review study and objectives, review investigator obligations, review sponsor obligations, review regulatory documents, tour facility, investigational product inventory, training as needed, Q/A

a pre-study visit:

introduction, overview of study and objectives, discuss investigator obligations, discuss sponsor obligations, tour facility, Q/A

What areas of the trial should a monitor be familiar with?

investigational product, protocol, IC form and any other written information to be provided to subjects, sponsor's SOPS, GCP, and applicable regulatory requirements

Inspection of Clinical Trial Site

investigators who conduct FDA regulated clinical are required to permit FDA investigators to access copy and verify any trial related records or reports

cross over design

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

A written consent document that embodies the elements...

may be read to the patient. Investigator must give adequate opportunity for patient/subject to read.

Sponsor

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

assent

means a child's affirmative agreement to participate in a clinical investigation. consent from 1 or both parents or LAR is required.

Monitoring vs Auditing

monitoring= protect subjects, data accurate, conduct of trial in compliance with GCP, etc. auditing= EVALUATE trial conduct and compliance with protocols, SOPs, GCP and applicable regs.

double bllinded

neither the subjects nor the experimenters know which subjects are in the test and control groups

Any unexpected, serious adverse experience associated with drug use or any finding from animal studies suggesting significant risk for human subjects must be reported _______

no later than 15 calendar days

If a sponsor's investigation of AE not initially reportable but later found to be reportable must be reported _______

no later than 15 days after the determination is made

Unexpected fatal or life-threatening adverse reactions must be reported _______

no later than 7 calendar days

typical publication policy

no publication can be submitted without written permission from the sponsor

Investigational devices

no significant risks do not require an IDE - if an IDE if filed investigator signs off an investigators agreement for device studies , not a 1572. - Send to IRB, then sponsor sends IDE for FDA. - For sig risk, goes to IRB, then full IDE for FDA.

single blinded

only the participant does not know whether they are part of the treatment or control group,

Institution (Definition)

person other than an individual who engages in the conduct of research on subjects or in the delivery of medical services to individuals as a primary activity or providing residential or custodial care to humans. Examples: hospitals, retirement home, confinement facility, academic establishment, device manufactury "facility".

Medical device studies do not have phases, but they are usually done in two steps:

pilot and pivotal

randomized double blilnded

placebo-controlled trial of a medical treatment, some of the participants are given the treatment, others are given fake treatment (placebo), and neither the researchers nor the participants know which is which until the study ends

510K

pre-market approval (PMA) of new drug application for devices

Informed Consent Beneficence Belmont Report

protect against risk of harm to subjects and that we be concerned about the loss of substantial benefits that might be gained from research

21 CFR 50 part D

protection of childern

The main concept of 21 CFR 50 is

protection of human subjects

what documents need IRB approval?

protocol/amendments, con set form and any revision(s), subject recruitment materials and any information/study materials distributed to study subjects.

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.

Final report

required by law at the end of a study

Pre-Market Approval (PMA)

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

Informed consent Respect for Persons Belmont Report

requires that subjects be given opportunity to choose what shall and shall not happen to them ICF elements: information, comprehension, and voluntariness

Investigational new drug for which an IND is in effect is exempt from...

the premarketing approval requirements and may be shipped lawfully for the purpose of conducting a Clinical Investigation

Belmont Report (1979)

respect for persons, beneficence, justice

CRO Responsibilities

responsibilities transferred from sponsor MUST BE IN WRITING.

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.

significant risk device

s a study of a device that presents a potential for serious risk to the health, safety, or welfare of a subject and (1) is intended as an implant; or (2) is used in supporting or sustaining human life; or (3) is of substantial importance in diagnosing, curing, mitigating

Sponsor must report any suspected adverse event that is both...

serious and unexpected

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.

ICF

should be signed and dated 2 copies one for the subject or LAR another for the person obtaining the consent

THE ICH specifices that the subject must receive a ________ copy

signed and dated

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.

Although CROs are held to same standards as sponsors when responsibilities are transferred, who is ultimately responsible for the quality and integrity of the trial data?

sponsor

Minimal Risk

the probability and magnitude of harm or discomfort anticipated are not greater in and of themselves than the probability of harm ordinarily encountered

Final reports for significant devices

sponsor to notify FDA within 30 days of completion and final report within 6 months

Exceptions to informed consent

subject is unable to consent (unable to communicate) life-threatening condition insufficient time to obtain consent no available alternative therapy

Investigator IND

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

Form 1571

submitted to FDA - IND becomes effective 30 days after receipt by FDA, barring any requests for additional information. Approved if no requests for more info.

declaration Helsinki (1964)

the World Medical Association established recommendations guiding medical doctors in biomedical research involving human participants.

Permission

the agreement of parent or guardian for participation of her or her child or ward in a clinical investigation. Must be obtained and contain elements of informed consent.

When children who are wards of the state are approved to be included in clinical investigations the IRB must require

the appointment of an advocate for each child who is a ward - the advocate will serve in addition to individual acting on behalf of child - one person may serve as advocate for more than one child - advocate must have background and experience to act in the best interest of the child - advocate must not be associated in any way with the clinical investigation, investigators, or guardian organization

What is 21 CFR 50.23 Subpart B?

the exception to the general requirements

Minimal risk

the likelihood of harm is no greater than that encountered in daily life or during routine PE

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

the start of the legal proceedings process for disqualification of investigators who are repeatedly or deliberately non-complaint to regulations and/or had committed fraud.

The CFR and ICH E6 both require that there is documentation of consent and that...

the subject receives a copy of the consent form

Informed consent shall be documented by

the use of a written consent form approved by an IRB and signed and dated by the subject or representative at the time of consent. A copy shall be given to the subject.

An approved Investigational Device Exemption (IDE) permits a device that would be required

to comply with performance standard or have premarket approval to be shipped lawfully for conducting investigations

Purpose of a monitoring visit

to ensure protocol and regulatory compliance as well as to verify data integrity.

Phase IIb

to evaluate efficacy and safety

Phase III

treat anticipated population, hundreds or thousands of patients. Uses a selected dose in sample. (dosing interval, drug-disease interactions, drug-drug interactions, risk benefit information).

IRBs must have written minutes for each meeting

true

termination visits are required by law

true

Monitoring visits are required by law

true. 21CFR requires sponsors to monitor clinical investigations. Monitoring is required by ICH guidelines and further specified in sponsor SOPs and FDA monitoring guidelines.

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.

Eligibility Criteria

used to define the specific subject population the sponor wants in the study. Requires review of medical record, very specific (inclusion/exclusion). Sponsor may grant waivers for certain criteria - must ask.

If a sponsor or investigator no withdraws from responsibility to retain records and has someone else do it, notice of transfer to FDA should be done when

within 10 working days

Final reports are due by investigator when?

within 3 months of completion of study