ACRP CP EXAM AND STUDY GUIDE 2024, Exams of Nursing

Download ACRP CP EXAM AND STUDY GUIDE 2024 and more Exams Nursing in PDF only on Docsity! 1 | P a g e ACRP CP EXAM AND STUDY GUIDE 2024 WITH ACTUAL CORRECT QUESTIONS AND VERIFIED DETAILED ANSWERS |FREQUENTLY TESTED QUESTIONS AND SOLUTIONS |NEWEST|LATEST 2024 |ALREADY GRADED A+| GUARANTEED PASS . Which signatures are required by ICH Guidelines to be on the Informed Consent Form (ICF)? a. The investigator b. The person who conducted the informed consent discussion c. The investigator and the subject d. The subject b, d Whose responsibility is it to safeguard the rights and safety of subjects in clinical trials? (Select all that apply) a. The investigator b. The sponsor c. The IRB/IEC d. The subjects' general practitioner(GP) a, b, c . Which hospital personnel are normally directly involved in a clinical trial? (Select all that apply) a. Research nurses b. The sponsor c. Pharmacists d. Hospital orderlies a, c Who does the investigator need to inform if he/she deviates from the protocol? (Select all that apply) a. The sponsor b. The regulatory authorities 2 | P a g e c. The office staff d. The IRB/IEC a, b, d Who should have access to the trial files? (Select all that apply) a. The subject b. The monitor c. The investigator d. The pharmacist b, c An Adverse Event (AE) that is severe in intensity: a. Is always classified as serious b. Is never classified as serious c. May not meet the definition of serious d. Should be submitted to the sponsor within 24 hours c Which of the following is always true? a. Adverse Drug Reactions (ADRs) are evidence that the drug is working b. An Adverse Drug Reaction (ADR) is an Adverse Event (AE) c. An Adverse Event (AE) is an Adverse Drug Reaction (ADR) d. Adverse Events (AEs) are less frequently observed in placebo arms. b Which of the following tasks is the investigator responsible for? (Select all that apply) a. Treating the subject if an Adverse Event (AE) occurs in the case the investigator is a qualified physician or dentist b. Make reasonable efforts to ascertain the reasons for a subject's premature withdrawal from the trial c. Encouraging subjects to report all Adverse Events (AEs) d. Upon permission of the subject, inform primary physician of subject's participation in the trial a, b, c, d Why is it a good idea to develop standard procedures? (Select all that apply) a. To assign responsibility b. To promote compliance c. To ensure that the trial is run consistently d. To practice logical thinking skills a, b, c What topics are discussed during the pre-trial visit? (Select all that apply) a. Laboratory requirements 5 | P a g e her to bring the medication back to the clinic as soon as possible or at her next visit. c. Record nothing in the source document or in the product accountability log. d. Record no missed doses in the source document and in the investigational product accountability log. b If the investigator becomes ill during the trial, what will happen to the study? a. The monitor will take over the running of the study until the investigator returns. b. A "second-in-command" (appointed before the start of the study) will take over the running of the study until the investigator returns. c. The study will be put on hold until the investigator is sufficiently well to return to work. d. This study will be postponed for one month (or a period prearranged with the sponsor). After this period, if the investigator is still ill, a fellow member of the team will be appointed investigator. b The subject arrives for the informed consent interview, but the investigator has no more informed consent forms. What should the investigator do? (Select all that apply) a. Write the details on a blank piece of paper b. Ask the subject to come back c. Have already made sure that there were enough forms before the interview d. Photocopy another subject's form and use correction fluid to remove the details b, c What action should be taken if the protocol is altered during the trial? (Select all that apply) a. The trial must begin again. b. The subject should be asked to re-consent if alterations to the protocol could affect their willingness to participate. c. The sponsor must dismiss the investigator. d. The IRB/IEC should be informed and approve the changes if the trial is to continue. b, d A site has been notified it will be inspected. What is the best way to ensure that the site is adequately prepared? a. Complete any incomplete forms with any relevant information the investigator can remember. b. Comply with ICH-GCP guidelines and protocol requirements throughout the study. c. Ensure that everything is tidy. d. Cover up any shortcomings where the investigator thinks inspectors will reveal serious findings. A site is being renovated and no longer has adequate storage space to hold all of the past studies it has conducted. Some studies are older than 20 years. Some Investigational Products (IPs) are now marketed. How can the site determine which files it still needs to store? a. Contact the sponsor for each trial to ask for a letter outlining instructions for disposition of records. b. Dispose of studies who products are now marketed in the U.S. for at least 2 years. 6 | P a g e c. Contact the sponsor for the files the site no longer can store and ask them to store the records. d. Dispose of any studies older than 20 years since patent has expired. a A non-English speaking subject has responded to a recruitment ad to participate in a trial for treatment of her diabetes. She arrives at the site with her daughter who is fluent in English. The informed consent forms are only available in English. What actions are compliant with GCP? a. Find a member of the clinic staff who speaks the same language as the subject to serve as the interpreter. b. Contact the IRB/IEC and ask for an exemption to screen subject. c. Call the sponsor to request a translation of the informed consent. d. Ask the subject's daughter to serve as interpreter and read the consent form to the subject. c The investigator at a big research center asked the monitor to complete the drug accountability forms as the site staff was not able to complete this on time before the Quality Control (QC) visit of the monitor. How should the monitor respond best? a. The monitor should not respond and ask advice from their manager on how to act. b. The monitor should refuse kindly and ask the site staff to complete the drug accountability forms. c. The monitor should do as the investigator asks because the investigator is the leader of the trial. d. The monitor should suggest to collaborate with the site staff and complete the drug accountability forms together at the occasion of the site visit. b An investigator is willing to lead the conduct of a clinical trial if the sponsor allows deviations from the protocol to accommodate the trial subjects. How should the sponsor react to this request? a. The sponsor should refuse this request as no protocol changes are ever allowed. b. The sponsor should state that each request would need to be considered for a possible amendment prior to allowing any deviations. c. The sponsor should ask the local regulatory bodies for advice. d. The sponsor should allow this as the investigator is responsible for trial conduct. b . During a routine monitoring visit the monitor finds out the Informed Consent Form (ICF) of one of the subjects enrolled in the trial was NOT personally dated by the subject. What is the BEST corrective action to be taken by the monitor? a. The monitor should leave as is and make a note of it in the monitoring visit report. b. The monitor should ask the site staff to inform the IRB/IEC of the error. c. The monitor should ask the site staff to discuss the issue with the subject and document the discussion in the source documents. d. The monitor should ask the site staff to take action and have the subject date personally and provide an explanation of the change on the original ICF. d 7 | P a g e A Clinical Research Coordinator (CRC) adjusted the dose of the Investigational Product (IP) for subject as the subject was suffering from Adverse Events (AEs) like headaches and vomiting. When is a CRC allowed to do this task? a. Only when the CRC is a qualified physician b. Only under the supervision of another site staff member who is named on the signature and delegation log c. Never d. Always; patient safety comes first a A monitor is making corrections on the Case Report Form (CRF) during a monitoring visit and asks the site staff (as identified on the signature and delegation log) to sign and date these corrections. This is an accepted way of working because: a. Anybody can complete the CRF b. The sponsor is ultimately responsible for the quality of the trial data and the investigator only needs to document the corrections. c. It does not matter who makes the corrections on the CRF (sponsor representatives or ite staff identified on the signature and delegation log) as long as they are made when necessary, endorsed by the investigator, and documented. d. The monitor is best suited to make those changes because he/she is considered the experts on the protocol. c In general, unused investigational drugs: a. Can be kept for the next study b. Can be destroyed by the investigator or pharmacy c. Can be re-dispensed by the pharmacy d. Must be returned to the sponsor d 92. How long is the follow up period for subjects after Adverse Events (AEs)? a. One year b. It is specified in the protocol c. Two years d. Six months b 93. Which of the following statements would be unacceptable in a consent form? a. In the event of any injury related to this research, you will be given medical treatment. b. I waive any possibility of compensation for injuries that I may receive as a result of participation in this research. c. Your participation in this research is voluntary. If you choose not to participate but change your mind later, your decision will not affect your relationship with your doctor. 10 | P a g e What is the minimum number of members on an IRB/IEC? a. 3 b. 5 c. 7 d. 8 b 5. Who is responsible for providing the trial protocol? a. The sponsor b. The investigator c. The IRB/IEC d. The Institution a What does 'DSMB' stand for? a. Data Record Monitoring Board b. Drug Statistics Measurement Bureau c. Drug Safety Monitoring Board d. Data and Safety Monitoring Board d 7. In any trial, what should be the main concern of the physician? a. The welfare of the subjects b. Ensuring that the allotted quota of subjects enrolled c. The esteem that will be gained from a successful trial outcome d. The scientific outcome of the trial a 8. The World Medical Association (WMA) ethical principles for medical research involving human subjects is called: a. The International Research Act b. The Belmont Report c. The National Research Act d. The Declaration of Helsinki d 9. The process by which a subject voluntarily confirms his or her willingness to participate in a clinical trial is known as: a. Intent to treat b. Legally authorized agreement 11 | P a g e c. Informed consent of trial subjects d. IRB/IEC approval c 10. One of the primary purposes of a Phase I study is to: a. Demonstrate long term safety and efficacy b. Determine he metabolic and pharmacologic action of the drug in humans c. Demonstrate efficacy within the established safe dose range d. Gather information on additional indications for the drug b 11. What is the purpose of the 'Data and Safety Monitoring Board (DSMB)'? a. To approve the trial protocol b. To ensure that the monitor is performing his/her duties correctly c. To assess the progress of a clinical trial, the safety data, and the critical efficacy endpoints d. To ensure the accuracy of data and to carry out data analysis c 12. What does the IRB/IEC evaluate? (select all that apply) a. The subject-selection procedure b. The rights, safety, and well-being of the subjects participating in the trial c. The scientific tenability of the trial d. The contract between the sponsor and investigator a, b, c 13. Which of the following documents is the investigator obliged to comply with during the trial? (select all that apply) a. The sponsor's desire to present the investigational product in the best possible light b. All applicable laws and regulations c. ICH-GCP d. The trial protocol b, c, d 14. What is the purpose of the initiation visit? (Select all that apply) a. To carry out source documentation verification b. To review standard procedures c. To review the blank Case Report Forms (CRFs) d. To review the protocol b, c, d 15. Who is ultimately responsible for Source Data Verification (SDV)? a. The coordinator b. The subject 12 | P a g e c. The monitor d. The investigator c 16. Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject. a. True b. False a 17. The Declaration of Helsinki was developed by: a. The Nuremberg tribunal b. The World Medical Association c. The government of Finland d. The American Medical Association b 18. This phase determines therapeutic benefit and is usually done in a larger, specific population. a. Phase 1 b. Phase 2 c. Phase 3 d. Phase 4 c 19. This phase begins after drug approval and explores therapeutic use: a. Phase 1 b. Phase 2 c. Phase 3 d. Phase 4 d 20. This is the most typical study. Investigates human pharmacology. It is the initial administration or an investigational new drug into humans. It is most commonly done in healthy subjects. a. Phase 1 b. Phase 2 c. Phase 3 d. Phase 4 a 21. Providing a unified standard for Europe US, and Japan to facilitate the acceptance of clinical trials is the... a. Mission statement of the ICH b. Mission statement of the Declaration of Helsinki 15 | P a g e c. An autopsy report, if available d. The name and address of the subject's general practitioner (GP) a, c 32. What documentation should be supplied to the sponsor before the study? (Select all that apply) a. The CVs of all investigators and other study personnel who are significantly involved in trial related duties b. The signed contract between sponsor and investigator c. The completed subject informed consent forms d. The completed Case Report Form (CRF) a, b 33. Who must sign the Informed Consent Form (ICF)? (Select all that apply) a. The subject with the subject's legal representative (as applicable) b. The monitor c. A member of the IRB/IEC d. The person who conducted the informed consent interview a, d 34. Which of the following documents are required by the IRB/IEC before approval? (Select all that apply) a. Telephone script for patient recruitment b. Clinical Trial Budget c. Subject information leaflet d. Study protocol a, c, d 35. What details need to be documented in the subject notes when an Adverse Event (AE) occurs? (Select all that apply) a. What the subject thinks caused the event b. No documentation is necessary c. The severity of the event d. When the event occurred c, d 36. Who is responsible for the appropriate monitoring of clinical trials? a. The Sponsor b. The Principal Investigator c. The Contract Research d. The IRB/IEC a 16 | P a g e 37. During the trial, who is responsible for communicating with the IRB/IEC? a. The pharmacist b. The sponsor c. The monitor d. The investigator d 38. Which of the following individuals could be members of an IRB/IEC? (Select all that apply) a. The sponsor b. Lay people c. Trial Subjects d. Medical professionals b, d 39. In what format should approval be received from the IRB/IEC? a. Electronic b. Verbal c. Personal d. Written d 40. How can an Adverse Drug Reaction (ADR) be defined? a. As an investigational drug that requires a second drug to be taken in order for the first one to be effective b. As a noxious and unintended response to the investigational drug c. As a positive response to the investigational drug d. As an investigational drug that prevents any other drug from being effective b 41. Which of the following would be most appropriate for Adverse Event (AE) reporting? a. Telling subjects to only report Serious Adverse Events (SAEs) b. Documenting and reporting all Adverse Events (AEs). However trivial they may appear to be c. Only documenting Adverse Events (AEs) if more than one subject reports the event d. Only informing subjects about the Serious Adverse Events (SAEs) that are likely to occur b 42. Which of the following criteria is described in ICH-GCP as necessary for classifying an Adverse Event (AE) as an Adverse Drug Reaction (ADR)? a. That a causal relationship is at least a reasonable possibility b. That a causal relationship is a definite possibility c. That a causal relationship is a strong possibility d. That a causal relationship is a very strong possibility a 17 | P a g e 43. What information needs to be included in the subject's medical records? (Select all that apply) a. Medical history b. Occurrence of AE's c. Randomization number d. Name of the monitor a, b, c 44. Which groups of potential subjects are mentioned in ICH-GCP as being 'vulnerable subjects'? (Select all that apply) a. Junior members of the medical profession b. People with heart conditions c. Employees of the pharmaceutical industry d. Members of the armed forces a, c, d 45. Who conducts clinical research Quality Control (QC) activities? a. Investigator b. Inspector c. Monitor d. Site staff c 46. According to the Declaration of Helsinki, physicians may use an unproven intervention. a. True b. False a 47. What is the minimum amount of time after formal discontinuation of the clinical development of an investigational product that essential documents should be retained according to ICH-GCP? a. 16 years after the last marketing application approval in an ICH-GCP region b. 4 years after the last marketing application approval in an ICH-GCP region c. 2 years after the last marketing application approval in an ICH-GCP region d. 8 years after the last marketing application approval in an ICH-GCP region c 48. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and it cannot be carried out in a non-vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or interventions that result from the research. a. True b. False a 49. A candidate presents him/herself for a monitor position. What qualifications should the potential monitor be able to provide proof of to be considered for the position? a. Have the clinical knowledge needed to monitor a trial 20 | P a g e Acceptable Representative (LAR) c. When the study has minimal risk d. When the study has more than minimal risk a 60. What will be reviewed during an audit? (Select all that apply) a. Procedures for reporting Serious Adverse Events (SAEs) b. Informed consent procedures c. The accounts of the hospital/research unit d. Adherence to protocol a, b, d 61. In which of the following instances is it necessary to contact the IRB/IEC? a. When a subject is found to be noncompliant with the trial medication b. When a Serious, Unexpected Adverse Drug Reaction (SADRs) occurs c. Each time a new subject is enrolled d. If the investigator does not complete enrollment b What individual serves as the primary liaison between the sponsor and the investigator? monitor Who is responsible for verifying that the investigator follows the approved protocol and all approved amendments? monitor Who must be notified if a trial is suspended or terminated prematurely? the sponsor should promptly inform the investigator/institutions and the regulatory authorities of the termination or suspension and the reasons for the termination or suspension Who must the monitor inform of CRF entry errors, omissions, or illegibly? investigator factoral design Used for the specific purpose of examining interaction of A and B; 2 or more treatments are evaluated simultaneously through the use of varying combinations of the treatments 1. A alone 2. B alone 21 | P a g e 3. both A & B (useful in determining joint effects of A & B) 4. neither A or B *another important use of the design is to establish the dose-response characteristics of the simultaneous use of treatments C & D What are the purposes of multi center trials? 1. an accepted way of evaluating a new medication more efficiently; may present as the only practical means of accruing sufficient subjects to satisfy the trial objective within a reasonable time-frame 2. to provide a better bias for the subsequent generalization of its findings phase I (human pharmacology) SAFETY; starts with the initial administration of an investigational new drug into humans; small # of study subjects 20-80 aspects of phase 1 trials - to determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected - characterization of a drug's absorption, distribution, metabolism, and excretion continues throughout the development plan -pharmacodynamic studies and studies relating drug blood levels to response (PK/PD studies) may be conducted healthy volunteer subjects or in patients with the target disease phase II (therapeutic exploratory) EFFICACY; the primary objective is to explore therapeutic efficacy in patients; studies are typically conducted in a group of patients who are selected by relatively narrow criteria, leading to a relatively homogenous population and are closely monitored; early studies often utilize dose escalation designs; several 100 subjects goal - determine the dose(s) and regimen for phase III trials - include evaluation of potential study endpoints, therapeutic regimens, and target populations - determine short term side effects and risks associated with the drug phase III (therapeutic confirmatory) LONG-TERM SAFETY/SURVIVAL; primary objective is to demonstrate, or confirm therapeutic benefit; designed to confirm the preliminary evidence accumulated in phase II that a drug is safe and effective for use in the intended indication and recipient population; they complete the information needed to support adequate instructions for use of the drug (official product information); several 100 - 1000's of subjects studies may further explore the dose-response relationship, or explore the drug's use in wider populations, in different stages of disease, or in combination with another drug 22 | P a g e *end of phase III is when NDA is sent to the FDA for approval phase IV (therapeutic use) POST MARKET; begins after drug approval; are all studies (other than routine surveillance) performed after drug approval and related to the approved indication; address FDA requirements for additional information not in NDA commonly conducted studies include additional drug-drug interaction, dose-response or safety studies, and studies designed to support use under the approved indication, e.g. mortality/morbidity studies, epidemiological studies adverse event any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment e.g. abnormal laboratory finding, symptom, or disease adverse drug reaction all noxious and unintended responses to a medicinal product related to any dose phrase "responses to a medicinal products," means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility unexpected adverse drug reaction an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. IB for an unapproved investigational medicinal product) - expedited reporting is required for additional occurrences of the reaction serious adverse event (experience) or reaction any untoward medicinal occurrence that at any dose: - results in death - is life-threatening (pt. was a risk of death at the time of the event) - requires inpatient hospitalization or prolongation of existing hospitalization - results in persistent or significant disability/incapacity, or - is a congenital anomaly/birth defect What documents or circumstances are used to determine whether an adverse event/reaction is expected? 1. IB 2. an event more specific or more severe than described in the IB would be considered "unexpected" 25 | P a g e - complications of analysis and interpretation arising from the loss of subjects - difficulties in assigning AEs which occur in later tx periods to the appropriate tx group sequential designs are used to facilitate the conduct of interim analysis; it is more practicable to assess grouped subject outcomes at periodic intervals during the trial than on a continuous basis as data from each subject become available design is used in large, long-term trials of mortality or major non-fatal endpoints; safety reasons the exact sample size in a group sequential trial cannot be fixed in advance because it depends upon the play of chance in combination with the chosen stopping guideline and the true treatment difference T/F: The GCP guidelines describe the minimum information that should be included in the IB? true placebo concurrent control Placebo is a form of inert substance, or an intervention designed to simulate medical therapy, without specificity for the condition being treated. The placebo must share the same appearance, frequency, and formulation as the active drug. Placebo control helps to discriminate outcomes due to intervention (new product) from outcomes due to other factors. no-treatment concurrent control No intervention will be administered in control arm in this design. Study end points must be objective in this design. The downsides are potential for observer bias and difficulty in blinding in this design dose-comparison concurrent control Different doses or regimens of same treatment are used as active arm and control arm in this design. The purpose is to establish a relationship between dose and efficacy/safety of the intervention. active-treatment concurrent control This design involves comparison of a new drug to a standard drug or compare combination of new and standard therapies versus standard therapy alone. This design can be used to demonstrate equivalence, non-inferiority, and superiority. This design is most ethical whenever approved drugs are available for the disease under study. The Declaration of Helsinki mandates the use of standard treatment as controls An AE that was not evident during baseline is considered to be: a. a pre-existing condition b. an untoward medical event c. an SAE d. unexpected an untoward medical event 26 | P a g e sponsor-investigator An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (it does not include a corporation or agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator What is the role of the independent data monitoring committee (IDMC)? An IDMC may be established by the sponsor to assess at intervals the progress of a clinical trial, safety data, and critical efficacy variables; recommends to the sponsor whether to continue, modify, or terminate a trial the IDMC should have written operating procedures and maintain written records of all its meetings When is it required to have an impartial witness present during the ICF process? If a subject is unable to read or if a legally acceptable representative is unable to read, and impartial witness should be present during the entire ICF discussion A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the ICF process; it would not include the spouse single-blind only the subject is blinded but the Investigator is aware double-blind when the subject and the Investigator and sponsor staff who are involved in the tx or clinical evaluation of the subjects are unaware of the tx assignments What is an objective parameter? an objective symptom can be measured or observed and it not dependent on, or influenced by, the subject's feelings or opinions; e.g. vaginal bleeding is observed What FDA document must all investigators sign prior to participating in a drug clinical trial? FDA form 1572 - a legally binding document designed to inform clinical investigators of their research obligations and secure the investigator's commitment to follow pertinent FDA regulations What is the purpose of a 1572 form? 1) to provide the sponsor with information about the investigator's qualifications and the clinical site that will enable the sponsor to establish and document that the investigator is qualified and the site is an appropriate location at which to conduct the clinical investigation, and 2) to inform the investigator of his/her obligations and obtain the investigator's commitment to follow pertinent FDA regulations. 27 | P a g e What is the Code of Federal Regulations (CFRs)? The U.S. Department of Health and Human Services (HHS) issues and enforces rules pertaining to the protection of human subjects in research. All regulations issued by federal agencies under the statutory authority established by Congress are published in the Code of Federal Regulations (CFR). What are the 8 elements of informed consent? 1. statement that the study involves research, an explanation of the purposes of research and expected duration of participation, description of procedures and identification of experimental procedures 2. description of foreseeable risks or discomforts 3. description of any benefits to subject or others 4. disclosure of alternative procedures or course of tx 5. describe extent of confidentiality records identifying the subject (FDA inspection, regulatory authorities, etc) 6. explanation of compensation or medical tx available if injury occurs 7. who to contact for answers to pertinent questions about research and subjects rights and who to contact in the event of research related injury 8. statement that participation is voluntary and participation can be discontinued without penalty Where would you look to find official government information regarding GCP? US CFR T/F: the IRB should be invited to attend a site initiation meeting? false T/F: the ICH guideline binds the regulatory agencies in Japan, the U.S., and Europe to particular actions Does not prohibit alternative approaches that satisfy requirements of applicable statutes, regulations or both T/F: an audit certificate indicates that the auditors approve of a site's activities false; it provides confirmation that an audit has taken place What are the 3 different forms of a case report form (CRF)? 1. electronic 2. optical 3. printed T/F: a clinical protocol may serve as the basis for a contract between two parties true What rights does direct access give a member of a regulatory authority, sponsor, monitor, or auditor? permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial 30 | P a g e The monitor is responsible for verifying investigator's qualifications and resources and for ensuring that these remain adequate throughout the study. true T/F. The monitor is responsible for verifying that the investigator and the investigator's trial staff are adequately informed about the trial. true Who bears the responsibility for ensuring that communication among investigators in a multi-center trial is facilitated? sponsor T/F. All new information should be communicated through a revised IB. More important new information may be shared prior to the IB revision Who is responsible for ensuring that the IRB/IEC has the most current IB? Investigator/Institution The sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator T/F. The investigator / institution must maintain a copy of the agreement between the sponsor and CRO. Sponsor maintains this Who must maintain certificate(s) of analysis of investigational product(s) shipped? sponsor Who must maintain copies of monitoring visit reports? sponsor Who maintains the signed informed consent forms? Investigator/institution Who maintains the list of qualified people assigned significant trial-related duties? Investigator/institution and sponsor T/F. The monitor is responsible for ensuring that individuals assisting with the trial are adequately informed of the protocol, investigational product, and the duties of the assistants. false; the investigator Who is accountable for investigational products(s) at the trial site(s)? Monitor and investigator 31 | P a g e What is the minimum time frame in which the investigator / institution must submit written trial progress reports to the IRB/IEC? At least annually To whom must adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluation be reported? Investigator/institution, regulatory authorities Who has authority to prematurely suspend or terminate a trial? Sponsor, investigator, or IRB/IEC Regardless of who terminates or suspends a trial, who must provide a detailed written explanation of the termination or suspension? sponsor short form written consent A short form written consent document stating that the elements of informed consent required by 50.25 have been presented orally to the subject or the subject's legally authorized representative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subject or the representative. Only the short form itself is to be signed by the subject or the representative. However, the witness shall sign both the short form and a copy of the summary, and the person actually obtaining the consent shall sign a copy of the summary. A copy of the summary shall be given to the subject or the representative in addition to a copy of the short form. What details need to be documented in the subject source documentation when an AE occurs? 1. the severity of the event 2. when the event occurred 3. setting in which the event occurred What is the difference between severe and serious? Severe describes the intensity of a specific event. Serious describes an event in which the patient was at risk of death Who is responsible for designing the clinical trial protocol? sponsor Who is ultimately responsible for Source Data Verification or SDV? monitor You are in the role of Study Manager for the sponsor. One of your monitors reports significant noncompliance at a site. Which of the following options would be the first course of action for you to implement? 32 | P a g e root cause analysis What are the 3 special populations mentioned in ICH E8? 1. pregnant women 2. nursing women 3. children According to ICH E8, which of the following are response variables that are chosen to assess the drug's effects? study endpoints T/F: the intention of ICH E8 is to describe internationally accepted principles and practices in the conduct of both individual clinical trials and overall development strategy for new medicinal products true Per ICH E8, methods used to evaluate patient usage of the test drug should be what? specified in the protocol and actual usage documented T/F: the DSMB is a separate entity from an IRB/IEC? true What is the purpose of the DSMB? to assess the progress of a clinical trial, the safety data, and the critical efficacy endpoints DSMBs have the power to recommend which of the following? - that the sponsor should continue the trial - that the sponsor should modify the trial - the the sponsor should stop the trial Which variable in a study should be used to determine the sample size? primary variable When writing an early phase clinical study plan, which of the following do you pay attention to, if you wish to maximize the chance of observing specific clinical effects of interest? the target population Which ICH guidance pertains to the pediatric population? ICH E11 T/F: due to low blood volumes, researchers should not do pharmacokinetic studies in the pediatric population false 35 | P a g e dichotomization or other categorization of continuous or ordinal variable may sometimes be desirable; categorization are most useful when they have clear clinical relevance; because categorization normally implies a loss of information, a consequence will be a loss of power in the analysis Quality of the trial type monitoring for the purpose of overseeing the quality of the trial, the checks involved in trial monitoring may include whether the protocol is being followed, the acceptability of data being accrued, the success of planned accrual targets, the appropriateness of the design assumptions, success in keeping patients in trials, etc. does not require access to information on comparative tx effects, nor unblinding of data and therefore has no impact on type 1 error; monitoring for this purpose is the responsibility of the sponsor or CRO interim analysis monitoring involves the accruing of comparative tx results; requires unblinded (i.e. key breaking) access to tx group assignment (actual tx assignment or identification of group assignment) and comparative tx group summary information. protocol must contain statistical plan for the interim analysis to prevent certain types of bias interim analysis any analysis intended to compare treatment arms with respect to efficacy or safety at any time prior to the formal completion of a trial; should be a completely confidential process all interim analyses should be carefully planned in advanced and described in the protocol; a protocol amendment describing the interim analysis should be completed prior to unblinded access to tx comparison data (in special circumstances) Reasons to stop a trial early (using group sequential design) 1. superiority of the tx under study is clearly established 2. demonstration of a relevant tx difference has become unlikely 3. unacceptable AEs What is the composition of the IDMC? is a separate entity from an IRB or IEC; its composition should include clinical trial scientists knowledgeable in the appropriate disciplines including statistics can have sponsor representatives on the IDMC What two principles guide decisions made in an analysis set? 1. minimize bias 2. avoid inflation of type I error full analysis set 36 | P a g e the analysis set which is as complete as possible and as close as possible to the intention-to-treat ideal (includes all randomized subjects) of including all randomized subjects per protocol set A subset of the subjects in the full analysis set who are more compliant with the protocol. This data would be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements, and absence of major protocol deviations. Bayesian approach Approaches to data analysis that provide a posterior probability distribution for some parameter (e.g. treatment effect), derived from the observed data and a prior probability distribution for the parameter. The posterior distribution is then used as the basis for statistical inference. blind review The checking and assessment of data during the period of time between trial completion (the last observation on the last subject) and the breaking of the blind, for the purpose of finalising the planned analysis. double dummy A technique for retaining the blind when administering supplies in a clinical trial, when the two treatments cannot be made identical. Supplies are prepared for Treatment A (active and indistinguishable placebo) and for Treatment B (active and indistinguishable placebo). Subjects then take two sets of treatment; either A (active) and B (placebo), or A (placebo) and B (active). equivalence trial A trial with the primary objective of showing that the response to two or more treatments differs by an amount which is clinically unimportant. This is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence margin of clinically acceptable differences. Non-inferiority trial A trial with the primary objective of showing that the response to the investigational product is not clinically inferior to a comparative agent (active or placebo control). What is the most important factor when making the decision to proceed with a pediatric development program for a medicinal product? the presence of a serious or life-threatening disease for which the medicinal product represents a potentially important advance in therapy Belmont Report (1979) ethical principles and guidelines for the protection of human subjects of research. 37 | P a g e respect for persons individuals should be treated as autonomous agents and persons with diminished autonomy are entitled to protection An autonomous person A person capable of deliberation about personal goals and of acting under the direction of such deliberation Beneficence Do not harm and maximize possible benefits and minimize possible harms Justice 1) to each person an equal share 2) to each person according to individual need 3) to each person according to individual effort 4) to each person according to societal contributions 5) to each person according to merit Justice · The selection of research subjects needs to be scrutinized in order to determine whether some classes are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied. Justice · Whenever research supported by public funds leads to the development of therapeutic devices and procedures, justice demands both that these not provide advantages only to those who can afford them and that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research. Three elements of the consent process information, comprehension, voluntariness What is an example of how the principle of beneficence can be applied to a study employing human subjects Determining the study has a maximization of benefits and a minimization of risks What are the three principles discussed in the Belmont Report? Respect for persons, beneficence, justice The Belmont Report's principle of respect for persons incorporates at least 2 ethical convictions: first, that individuals should be treated as autonomous agents, and second, that: Persons with diminished autonomy are entitled to protection Nuremberg Code (1947) 40 | P a g e 1) Application for initial review 2) Application for continuing review: IRB must re-review greater than minimal risk not less than once per year 3) Amendments or modifications 4) Reports of unanticipated problems US Department of Health and Human Services Responsible for 45 CFR 46 National Institutes of Health (NIH) Includes funding agencies that provide federal funding for biomedical research U.S. Food and Drug Administration (FDA) Oversees the use of all drugs, devices, biologics, etc. including their use in research with human subjects International Council for Harmonisation (ICH) offers GP guidelines A subject in a clinical research trial experiences a serious, unanticipated adverse drug experience. How should the investigator proceed, with respect to the IRB, after the discovery of the adverse event occurrence? Report the adverse drug experience in a timely manner, in keeping with the IRB's policies and procedures, using the forms or the mechanism provided by the IRB How long is an investigator required to keep consent documents, IRB correspondence, and research records? A minimum of three years after completion of the study According to federal regulations, which of the following best describes when expedited review of a new, proposed study may be used by the IRB? The study involves no more than minimal risk and meets one of the allowable categories of expedited review specified in federal regulations Amendments involving changes to IRB approved protocols do NOT need prior IRB approval if: The changes must be immediately implemented for the health and well-being of the subjects IRB continuing review of a greater than minimal risk approved protocol that is currently enrolling subjects must: occur at least annually Informed consent 41 | P a g e The process that begins with the recruitment and screening of a subject and the signing of the consent document and continues throughout the subject's involvement in the research and beyond study termination Informed consent is mandated by the US Department of HHS at 45 CFR 46 and the US FDA at 21 CFR 50. These regulations were developed to: 1) protect human subjects 2) Ensure that potential study subjects clearly understand the benefits and risks associated with their participation in a study 3) Provide the potential study subjects with all information needed to reach a decision on whether or not to participate in a research study Broad consent Prospective consent for unspecified future research Legally Authorized Representative(LAR) Individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research. If there is no applicable law addressing this issue, LAR means an individual recognized by institutional policy as acceptable for providing consent in the non-research context on behalf of the prospective subjects to the subject's participation in the procedure(s) involved in the research The emphasis of the discussion of informed consent is: on subject comprehension and presenting information that a "reasonable person" would want to have in order to make an informed decision to participate, and an opportunity to discuss the information According to 46/116(b), legally appropriate informed consent will include the following elements: 1) a statement that the study involves research, an explanation of the research's purpose and the expected duration of the subject's participation, a description of the procedures to be follow, and identification of an procedures that are experimental 2) A description of any reasonably foreseeable risks or discomforts to the subject 3) A description of any benefits to the subjects or to others that may reasonably be expected from the research 4) A disclosure of appropriate alternative procedures or courses of treatment if any, that might be advantageous to the subject 5) · A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained 6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained. 7) An explanation of whom to contact for answers to pertinent questions about the research and research subject's rights, and whom to contact in the event of a research-related injury to the subject. 8) A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. 9) One of the following statements about any research that involves the collection of identifiable private 42 | P a g e information or identifiable biospecimens: A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or In addition, if relevant to the research, legally effective informed consent will also include the following elements: 1) Statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable 2) Anticipated 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 that may result from participation in the research 4) The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject 5) A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject · For research that is subject to HHS regulation at 45 CFR 46 (Protection of Human Subjects), the consent form must also include (if appropriate): 1) A statements that the subjects biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit 2) A statement regarding whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions; and 3) For research involving biospecimens, whether the research will (if known) or might include whole genome sequencing (that is, sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen) The FDA does require the following statements in the informed consent form: 1) Statement that the subjects' records may possibly be inspected by the FDA 2) Statement that the clinical trial will be listed in a registry. HHS regulations at 45 CFR 46.116 allow an IRB to waive or alter for informed consent under the following circumstances: 1) Government projects 2) General waivers and alterations 3) Screening, recruiting, or determining eligibility FDA at 21 CFR 50.23 and 50.24 provides exceptions to the requirement for informed consent under the following circumstances: 1) In situations where requirements for exception from informed consent are met for emergency research 2) In life threatening conditions involving an individual subject where requirements for an exception from informed consent are met and include documentation of all of the following: The researcher, with the concurrence of another physician, believes the situation necessitates the use of 45 | P a g e According to OHRP, it considers unanticipated problems, in general, to include any incident, experience, or outcome that meets ALL OF THE FOLLOWING criteria: 1) Unexpected given the research procedures that are described in the research plan-related documents, such as the IRB-approved research plan and informed consent documents and the characteristics of the subject population being studied; 2) Related or possibly related to participation in the research; and 3) Suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized 21 CFR 312.50 (Investigational New Drug Application 2014) requires sponsors to ensure that FDA and all participating investigators are promptly informed of: significant new adverse effects or risks with respect to the drug OHRP defines adverse event as: any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign, symptom, or disease, temporally associated with the subject's participation in the research, whether or not considered related to the subject's participation in the research One of the criteria necessary to qualify as an unanticipated problem is whether the event is related or possibly related to participation in the research. In addition, it must be unanticipated and involve risk to subjects or others. Only adverse events that are also unanticipated problems need to be reported to the IRB Unanticipated adverse device effects Unanticipated problems in device research 21 CFR 812 Any serious AE on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application, or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. For device studies, both the research and sponsor have specific reporting responsibilities: 1) In 21 CFR 812. 150(a)(1), the researcher is required to submit reports of unanticipated adverse device effects to the IRB and the sponsor "as soon as possible, but in no later than 10 working days after the investigator first learns of the effect" 2) In 21 CFR 812.150(b)(1), the sponsor is required to report unanticipated adverse device effects to the FDA and " to all reviewing IRB's and participating investigators within 10 working days after the sponsor first receives notice of the effect" A Data Safety Monitoring Board report for an investigator-initiated investigational drug study indicates a significantly higher than anticipated rate of an expected AE. This event required revision of the informed consent form to disclose the higher rate. A change in the eligibility criteria of the protocol to reduce the risk was implemented. Current subjects would be reconsented. 46 | P a g e This is an unanticipated problem A second study drug is given on Day 7 to counteract the toxicity of Drug 1. Subject #4-706 is given Drug 1 on Day 1. Due to a snowstorm, Subject 4-706 is delayed for several days before returning to the site for Drug 2. Missing the administration of Drug 2 on Day 7 placed the subject at risk of significant toxicity. This event required the subject be notified of the increased risk and required close monitoring of the subject by phone. This is an unanticipated problem that does not include an adverse event A subject received the wrong study drug resulting in severe nausea and vomiting, and a visit to the emergency room for treatment. The subject notified the study coordinator the day after the emergency room visit. The study coordinator reviewed the subject's study records and discovered the error. The coordinator notified the subject of the study drug error, which caused the nausea and vomiting. The investigator notified the IRB and the IRB approved a revision of the standard pharmacy procedure for administering investigational drugs. This is an unanticipated problem, which resulted in an adverse event Housekeeping employees of the medical center were recruited for a federally funded study of blood pressure, blood count levels, infectious disease history, and job stress. The interviews and blood tests were conducted in a private location not affiliated with the study center. Follow-up interviews were conducted in the same location. The study coordinator stopped at the cafeteria on her way back to the study office after the second study visit for the last three study subjects and lost the three file folders. Records of one subject indicated he had a history of a STD and another had recently been treated for TB. The subjects were notified of the loss. Following this event, the IRB approved a protocol change requiring that all records be transmitted electronically to the study office using the medical center's secure network. This is an unanticipated problem and not an adverse event An investigational biologic administered to the first two subjects in a Phase II clinical trial was not appropriately screened for two viral contaminants, HIV and Hep B, due to human error in the screening process. Follow-up testing indicated that the subjects and their partners were not infected. The subjects and others were notified of the increased risk. This is an unanticipated problem requiring notification to the IRB and FDA An unanticipated problem must include these three criteria: 1) unexpected 2) related 3) greater risk of harm Vulnerable subjects persons who have difficulty providing voluntary, informed consent arising from limitations in decision- making capacity or situational circumstances or because they are especially at risk for exploitation 47 | P a g e Historically, those who are vulnerable have been subjected to one or more of these four common types of abuses in human research: 1) Physical control: physical forced to participate in research. This presents a lack of voluntariness. 2) Coercion: The use of a credible threat of harm or force to control another person. This also presents a lack of voluntariness. 3) Undue influence: The misuse of a position of confidence or power to lead or influence 4) Manipulation: Examples include lying about information, withholding information, or exaggerating information. The NBAC looks at characteristics individuals might have that would prevent them from being able to provide voluntary informed consent. The traits may be thought of as falling into six broad areas: cognitive or communicative, institutional, deferential, medical, economic, and social. Deferential vulnerability similar to institutional vulnerability but the authority over the prospective subject is due to informal power relationships rather than formal hierarchies HHS 45 CFR 46.111(b) (Protection of Human Subjects 2018) provides the following list of examples of vulnerable subjects: 1) Children 2) Prisoners 3) Individuals with impaired decision-making capacity 4) Economically or educationally disadvantaged persons Subjects with a serious illness may be at risk for exploitation because they may be desperate for a possible cure. This is an example of: Medical vulnerability Identify the following groups that are protected in the federal regulations (45 CFR 46) in Subparts B, C, and D with additional protections: Pregnant women, prisoners, children According to the authors, there are four common abuses that historically are described as giving rise to vulnerability. Which response below contains the correct four? Physical control, coercion, under influence, and manipulation A subject participates in a drug study because treatment is available at no or reduced cost, and he could not otherwise afford it. This is an example of: Economic vulnerability Which is an example of a situation where deferential vulnerability might be a factor? A physician recruiting patients to be subjects 50 | P a g e Non-significant Risk (NSR) Devices NSR devices are studied without FDA oversight if the sponsor complies with certain FDA requirements such as monitoring, record keeping, and properly labeling the investigational device. The IRB must agree that the study meets the criteria for NSR. The clinical trial of an NSR device requires IRB approval, informed consent, and proper study monitoring and it must meet all other regulatory compliance requirements. However, an NSR device study does not require approval by the FDA and only must follow the abbreviated requirements at 21 CFR 812.2(b). Examples of NSR devices include: Conventional hospital catheters Dental filling materials Menstrual pads or tampons TENS devices Emergency use the use of an investigational drug or device with a human subject in a life-threatening situation, or in which no standard acceptable treatment is available and there is not sufficient time to obtain IRB approval If an individual subject does not meet the criteria for an existing research plan, or an approved research plan does not exist, the usual procedure is for the physician to: contact the manufacturer and determine if the drug can be made available for an "emergency use" under the company's IND If there is no IND, the FDA per 21 CFR 312.36 may authorize the manufacturer to allow the drug to be used in advance of an IND submission In addition, if the company agrees to provide the product, the physician can contact FDA, explain the situation, and obtain an emergency IND to permit the drug's shipment If there is no IDE, the physician may use the device and notify FDA of it use after the fact. The physician should obtain both an independent assessment from another physician and informed consent from the subject, before emergency use of the device occurs For emergency use of devices, concurrence of the IRB chair is required before the use takes place IRB review and approval is required in all circumstances if the researcher: wishes to use the data for research purposes Subsequent use of the investigational product at the organization should have prospective IRB review and approval. If the IRB was not notified before the investigational drug or device was used in an emergency situation: the IRB should be notified per organizational policy or within 5 working days. The FDA and sponsor should be notified as necessary. Investigator initiated trial (IIT) 51 | P a g e Researchers who design and conduct their own studies assume responsibility of the researcher and the sponsor Responsibilities of the sponsor include: 1) Selecting clinical researchers qualified by training and experience 2) Informing and qualifying researchers by obtaining their commitment to supervise the study, follow the research plan, and obtain consent 3) Monitoring the study's conduct by auditing documentation and conducting site visits 4) Completing regulatory filing related to the IND or IDE, adverse events, amendments or revisions, progress reports, withdrawal of IRB approval, and final reports 5) Controlling the distribution, tracking, ad dispensation of the regulated products · Researcher Responsibilities: ultimately, investigators are responsible for the conduct of the investigation, as well as: 1) Ensuring IRB approval for the study is obtained before any subjects are enrolled 2) Ensuring that informed consent is obtained in accordance with FDA regulations 3) Ensuring that the investigation is conduced according to the investigational plan and applicable regulations 4) Administering the drug or using the device only in subjects under the researcher's supervision or under the supervision of a recognized sub-researcher 5) Maintaining adequate records of the dispensation of the drug or device 6) Returning unused materials at the end of trial 7) Preparing and maintaining adequate case histories and signed informed consent documents 8) Maintaining correspondence with the IRB and the sponsor to make sure that both have reviewed research plan amendments, recruiting materials, and Investigator's Brochures 9) Retaining records in accordance with regulations 10) Provide progress, safety, final, and financial disclosure reports 11) Notifying the sponsor if IRB approval is withdrawn 12) Complying with International Council for Harmonisation (ICH) guidelines, if applicable · The FDA's Bioresearch Monitoring Program conducts ______ ______ and _____ ______ _____ inspections of IRBs, clinical researchers, and sponsors for cause & not for cause 21 CFR 11 (Electronic Records; Electronic Signatures) Part 11 Intended to enable the use of electronic documents in the regulatory process for drugs and devices For electronic systems to comply with Part 11, a number of requirements must be met, including: 1) Computer systems utilizing electronic records and signatures must ensure accuracy, reliability, and consistent performance. SOPs, audits, testing, and training are required. 2) Computer systems must use and maintain secure, computer-generated, time-stamped audit trails independently recording the date and time of entries and actions that create, modify, or delete electronic records 3) Computer systems must use system checks ensuring that only those individuals authorized to use the 52 | P a g e system are allowed access to the system, alter records, and perform operations 4) Procedures must be established to ensure that records are retained for a duration of time, in an appropriate format, and to meet FDA requirements at a minimum. A sponsor proposes research to evaluate reengineering a commercially available pacemaker. It is hoped that the new pacemaker will pose fewer risks to individuals when compared to the current commercially available products. How should this device be classified? Significant risk device An adult with ADHD presents to a physician. To date, no behavioral or drug interventions have proven useful. The physician has just read several reports about a drug that is approved and marketed for another indication, but has shown benefits for ADHD. The physician wants to prescribe this drug, in the labeled marketed dose, for the individual patient. Which of the following would be the most appropriate course of action? Treat the patient with the drug based on physician's best medical judgement An investigator proposes to study a marketed product sold to treat high blood pressure in individuals over age 12 using a liquid formulation for children under age 12. The drug sponsor hopes that the information from the research can be used to change the labeling for use of the drug in younger children. Which of the following is the investigator's most appropriate action? Submit the research protocol to the IRB for review and submit an IND application the FDA before conduction research The FDAs regulations related to electronic records and electronic signatures (21 CFR Part 11) are intended to: a. Allow the use of electronic documents and signatures in the regulatory process for drugs and devices An academic medical center is selecting a new database system for clinical research. The system needs to be "Part 11 compliant" in order to allow: The medical center to replace the use of paper records with electronic records for its research The International Committee of medical Journal Editors recommends that authorship be based on these criteria 1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work 2) Drafting the work or revising it critically for important intellectual content 3) Final approval of the version to be published 4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Iit is the collective responsibility of the research team to determine who qualifies as an author. Ideally, authorship should be discussed when a project begins and while it is ongoing, including when someone joins or leaves the research team. 55 | P a g e Tech transfer" facilities research collaborations that can make financial profit for institutions and researchers by bringing new findings to market. · Researchers collaborating with industry may be asked to sign a _____ -__________ ___________, promising not to publish results or methods without the sponsor's authorization and agreeing to a period of time in which the sponsor can assess the value of new findings. non-disclosure agreement Working with community partners with different experiences and perspectives brings both benefits and challenges to academic research: 1) Some communities have developed their own research review committees, and insist on reviewing both research proposals that plan to involve their members and the final reports from completed projects 2) Communities may seem themselves as the owners of data collected about them, and may seek to control access to research material and the presentation of findings, especially those that may be negative or perceived as stigmatizing 3) Community members who contribute to data collection may expect to be listed as authors of any resulting report 4) Including community members as researchers on a project may subject them to federal or institutional requirements for formal training and oversight in the protection of human subjects, disclosure of conflict of interest, and research integrity. The content, level of detail, and source of such training may vary significantly from community to community International research collaboration researchers or sponsors from one country conducting or funding work in another Transnational and global research growing important of supranational governmental organizations, such as the European Union, in funding research and setting research policy, and of research on problems that cross national boundaries, such as climate change or infectious disease Factors that can impact international collaborations include: 1) The use of animals in research is subject to little oversight in some countries but is highly regulated in others. 2) Although the Declaration of Helsinki provides widely recognized international ethical guidelines for biomedical research, national regulations on research with human subjects vary worldwide as do cultural interpretations of vulnerability and protection 3) International collaborations may be affected by national export controls that limit or prohibit sharing research data, materials, or training with citizens of countries seen to pose risks to national security. 4) Language barriers may persist even among collaborators who use English in their professional work. In addition to disciplinary jargon, there may be concepts in one culture for which other languages have no word or multiple words with important nuances 56 | P a g e Although research collaboration itself is not regulated, general research regulations and policies address various aspects of collaboration. These include: 1) Sharing of data and materials 2) Financial management 3) The role of committees for the protection of human subjects and animal welfare 4) Financial conflicts of interest The ownership and sharing of data generated in federally-sponsored research is regulated by the _________ _________ granting agency _____ _________________ typically govern collaborative research funded by US federal agencies wherever the research takes place. US Regulations A _______________ of understanding may be written broadly to document an open-ended relationship or may detail expectations and commitments on a time-limited project memorandum A memorandum usually spells out the goals of the collaboration, the contexts and time period in which the research will occur, the people bound by the document, ownership of intellectual property, responsibilities of authorship, trainees' roles and supervision, and who bears certain financial costs. Collaborations funded by a grant or contract may involve __________________ among the parties that define payment schedules, intellectual property rights and access to data, and the scope of work for each researcher or research team. subcontracts Such subcontracts are usually developed by institutional officials with concern for legal commitments and financial liability. One of the most important steps in establishing a collaboration is to determine who is _____________ for the various components of the project and create a leadership plan that describes processes for making important decisions accountable Equally important, however, is a shared commitment to values and practices that support the honesty, reliability, and integrity of the research as a whole. What is the most appropriate process for research collaborators to use in determining which journal they should submit their work to? The research team should discuss the issue early on and while the project is ongoing What is the main function of a Technology Transfer Office with respect to collaborative research? 57 | P a g e It helps collaborative researchers to commercialize their work A research collaboration can be enhanced by: Discussing intellectual property issues while the collaboration is forming In any collaboration, data ownership is typically determined by: The type and source of funds used to support the project Which of the following statements is true regarding the regulations that govern research? US funded research collaborations are often governed by US regulations no matter where the research takes place Reliability usually defined in terms of replication, or whether one obtains the same result on repeated measures of the same phenomenon. In other words, it refers to consistency of outcome if the conditions of things being studied have not themselves changed. Validity refers to the more complex notion of whether operationalized concepts-using the measurement definitions, devices, and methods of the research plan- actually measure what they purport to measure. Methodological Issues Those associated with ensuring that a research study is well-deigned with respect to statistical analysis Methodologic issues include choices about: o Population and sample selection o Group assignment o Data collection o Data analysis o Data presentation A collection plan should govern the acquisition of data. Issues to consider include: o Which data should be collected o By what means should that data be collected in order to ensure reliability and validity o How much data should be collected- for example, how many subjects or events are required for adequate statistical power? o Which collection methods will be used and how will those methods reduce the likelihood of error or bias? o Who will undertake each data-related task? o How will training on the necessary methods and equipment be provided to each research team member? o Who will supervise the work and how will the quality and integrity of the study data be ensured? 60 | P a g e peer review · The most important function of peer review is to serve as a form of __________ _____________. Yet there is some evidence that peer review has a rather limited impact on the quality of publications and might block highly innovative, but unorthodox, work from being published and from receiving grant funding. quality control · Peer reviews can be characterized as open, single-blind, or double-blind o Open review: refers to the reviewer knowing the author's identity and the author knowing the reviewer's identity o Single-blind review: refers to the reviewer know the author's identity but the reviewer's identity is confidential and not revealed to the author o Double-blind review: refers to neither the author nor the reviewer knowing each other's identity. Single blind review tends to be more common than double-blind review in many scientific and engineering fields Peer review of manuscripts submitted to professional journals is widespread. Journal editors usually select two or more reviewers, who are supposed to be experts on the paper's subject matter. Reviewers typically pass judgement on the: o Appropriateness of the subject as it relates to the journal's focus o Originality and significance of the findings o Validity of the methodology used o Strength of the results and conclusions o Quality of the writing Different US agencies and organizations use different metrics to evaluate grant proposals. In general, a grant proposal submitted to federal agencies will be judged on: o Scholarly significance o Methodology o Qualifications of the researchers o Preliminary data supporting the proposal o Appropriateness of the budget requested o Potential societal impact of the proposal Which of the following statements is true regarding the responsibilities of a reviewer? A reviewer's conflict of interest should be disclosed to the journal editor or grant agency The main reason that grant proposal reviewers with a conflict of interest should remove themselves from the review process is because: Their removal lessens the chance that bias will affect the review process The main reason that the Royal Society of London developed the modern form of peer review was to: Control the quality of published papers 61 | P a g e Which of the following is the most appropriate step to take if authors believe that their manuscript was reviewed unfairly? The author can contact the editor with their concerns A reviewer's main responsibility is to: Behave professionally Which of the following is most likely to constitute an act of plagiarism? Copying someone else's text word-for-word without using quotation marks and adding a citation at the end of the material Paraphrasing another author's paragraph by substituting one or two words in each sentence and then adding one citation to the author at the end of the paragraph: . May constitute plagiarism because the original material has not been sufficiently modified to constitute a proper paraphrase An idea is most likely to represent "common knowledge" if: It can be safely assumed that the readers and the author are both thoroughly familiar with the idea and its source 1) Which one of the following statements most accurately describes how plagiarism has been defined in this module? Plagiarism applies not only to ideas that are found in print but also those that are communicated verbally. · The US Office of Science and Technology Policy (OSTP) proposed a research _________________ policy, which was subsequently adopted by ten federal agencies. The Federal Research Misconduct Policy defines research misconduct as fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results. misconduct To be considered research misconduct, the behavior must have been performed "intentionally, knowingly, or _______________" recklessly detrimental research practices Questionable research practices: behaviors that closely border on research misconduct but do not fall under its strict definition Noncompliance conducting research in a manner that disregards or violates federal regulations or organizational policies. Noncompliance often involves the failure to adhere to appropriate research practices when working with human or animal subjects. 62 | P a g e Organizations that receive federal funding must have policies and procedures in place to handle allegations of research misconduct. A typical organizational policy will outline: o Definitions of research misconduct o Procedures for reporting and investigating research misconduct o Rights and obligations for all parties involved in the research misconduct process o Provisions for protecting whistleblowers, individuals handling the misconduct process, and persons accused of research misconduct. The Federal Research Misconduct Policy describes the main phases that usually take place at the organization in response to an allegation of research misconduct. They are: o Inquiry: The assessment of whether the allegation has substance and if an investigation is warranted o Investigation: The formal development of a factual record, followed by the examination of that record, which can lead to the dismissal of the case, a recommendation for a finding of research misconduct, or other appropriate remedies. o Adjudication: During which recommendations are reviewed and appropriate corrective actions determined. The federal ORI provides guidelines to assist organizations with conducting inquiries and investigations for research funded by the US Department of ___________ and ___________ ____________. An organization many choose to apply federal standards to all potential research misconduct or choose to have similar or different standards. Health and Human Services If a finding of research misconduct is verified, the organization must then review the recommendations through the ______________process to determine an appropriate course of corrective actions. The actions typically range from a warning, further training, additional supervision, or sanctions to retraction of a work product or dismissal from one's job. adjudication If the misconduct is connected to a federally-funded project, the organization must report the investigation's results and the corrective action plan to the relevant federal agency. In addition, the federal government may require the organization to return the grant funds. Which of the following is most likely to be considered plagiarism? Using materials from a source without proper citation According to the US Federal Research Misconduct Policy, falsification involves: Manipulating research materials, equipment, or processes, or changing or omitting data According to US Federal Research Misconduct Policy, which of the following is considered to be research misconduct? Plagiarism Which of the following is the most effective strategy for preventing research misconduct? 65 | P a g e It is the _________'s responsibility to determine whether any of an investigator's SFIs could directly and significantly affect the research, or is in an entity whose financial interest could be affected by the research if it is determined that either of these conditions is present, an FCOI exists institutions If the institution makes an FCOI determination, prior to the expenditure of any research funds, it must develop and implement a management plan to reduce or eliminate the FCOI, and ensure, to the extent possible, that the research will be free from bias. Common management plan elements include: o Public disclosure of the COI in publications and presentations o Disclosure to human subjects participating in the research o Informing other research team members o Appointment of an independent third party to monitor the research o Changing personnel or personnel roles in the research The investigator must confirm agreement with the institution's management plan, and the institution must monitor the investigator's ongoing compliance with the management plan on an annual basis during the period of the research reward. Therefore, it is the responsibility of the ______________ to verify compliance by retaining documents such as notices to journal editors or conference audiences, consent forms from human subject research, or notice to research personnel. investigator Within how many days of acquiring or discovering a significant financial interest is the investigator required to submit an update disclosure to the institution? 30 days According to the US Public Health Service, the definition of the term "investigator": Includes anyone involved in the conduct or reporting or research Which of the following is true regarding the US PHS and its approach to the disclosure of SFI? Any equity interest in a non-publicly traded company must be disclosed At a minimum, how often are investigators funded by the US NIH required to receive conflict of interest training? 4 years Which of the following most accurately describes when investigators pursuing US PHS funding are required to disclose their SFI to their institution? No later than the time of applying for funding In the course of bringing an idea to fruition, investigators may receive compensation for the following: o Their advice and consultation o The rights to their inventions o Speaking in educational forums 66 | P a g e In the case of PHS-funded research, institutions must ensure, however, that these financial interests do not create unacceptable risks to research objectivity. If an institution identifies a FCOI, it must develop and implement a management plan to mitigate bias due to the conflict Under the regulations (42 CFR 50, Subpart F), institutions must take on additional responsibilities with respect to COIs in PHS-funded research. As such, institutions must: o Maintain up-to-date, written, enforced policy on financial conflicts of interest that complies with this subpart, and make such policy available via a publicly accessible Web site. o Designate an institutional official(s) to solicit and review disclosures of significant financial interests from each investigator who is planning to participate in, or is participating in, the PHS-funded research o Provide guidelines consistent with this subpart for the designated institutional official(s) to determine whether an Investigator's significant financial interest is related to PHS-funded research and, if so related, whether the significant financial interest is a financial conflict of interest o Take such actions as necessary to manage financial conflicts of interest...Management of an identified financial conflict of interest requires development and implementation of a management plan and, if necessary, a retrospective review and a mitigation report. PHS-funded investigators must disclose SFIs related to their institutional responsibilities and reimbursed or sponsored travel to their institutions. That is, the institution must review the disclosed information and determine whether the interests: o Relate to an investigator's PHS-supported research o Could have a direct and significant effect on the design, conduct, or reporting of the research (an FCOI) § Institutions must submit reports prior to the expenditure of funds and when competitive and non- competitive renewals are granted for ongoing projects. They must report newly disclosed FCOIs for PHS- funded research within ____ days of becoming aware of the new interest. They must also report annual updates at the time of submission of the annual progress report. 60 Institutions must report the following information to the PHS awarding component: o The grant/contract # o The name of the project director, PI, or contact person o The name of the investigator with the FCOI o The name of the entity with which the investigator has the FCOI o The nature of the FCOI o The value of the FCOI in specific ranges o A description of how the SFI relates to the PHS-funded research and the basis for the institution's determination that the SFI conflicts with the research The institution must update the funding agency on the status of the FCOI and any changes to the management plan annually. In accordance with the regulations, an institution's management plan must describe the: 67 | P a g e o Role and principal duties of the conflicted Investigator in the research project o Conditions of the management plan o How the management plan is designed to safeguard objectivity in the research project o Confirmation of the Investigator's agreement to the management plan o How the management plan will be monitored to ensure Investigator compliance o Other information as needed In accordance with the US FDA regulations (21 CFR 54), financial disclosures must be submitted to and retained by the sponsor of the research. The sponsor is the individual or entity that holds the IND or IDE for FDA-regulated research. If researchers hold the IND or IDE, the______________-____________ is responsible for collecting and maintaining financial disclosures and related management plans. sponsor-investigator The revised PHS regulations require institutions to make certain info about the FCOIs of senior/key personnel publicly available, which they can do in one of two ways: 1) on a public website or 2) in response to a written request within 5 business days. The information to be publicly disclosed is a subset of the info reported to the NIH. It includes the conflicted investigator's name, title, and role; the name of any entities in which the investigator has an SRI; the nature of the SFI; and the annual dollar value in specific ranges. If a researcher does not disclose an SFI in a timely manner, or if for any reason the institution did not previously review it, the institution must, within ____ days from that point, determine whether the SFI relates to PHS-funded research and if it is an FCOI. If it is a FCOI, the institution must implement, at least on an interm basis, a management plan 60 When a researcher fails to disclose a FCOI in a timely manner or comply with a management plan, or were the institution fails to manage a FCOI, the institution must, within _____ days, compete a retrospective review of research to determine whether there was bias in the design, conduct, or reporting of the research conducted during the period of noncompliance. If an institution identifies bias, it must develop a mitigation report that outlines a plan of action to eliminate or mitigate the effect of the bias. The institution must report the results of that determination and the mitigation report to the PHS. 120 The revised HHS regulations have specific requirements for collaborative PHS-funded research between awardee institutions and their subrecipients. Financial interest must be monitored and dealt with at the awardee institutions to assure the PHS of the appropriate identification and elimination or management of the FCOI. The collaborating institutions can accomplish this through an agreement that specifies which institution's COI policy will apply to the research project. 70 | P a g e Essential Documents defined by ICH E6 Section 1.23 as the documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced Informed Consent Form the document that includes the information needed for potential subjects to have sufficient information to provide informed consent to participate in a clinical trial. The FDA regulations and ICH E6 describe the information that must be included in the consent form Institutional Review Board (IRB) defined by FDA regulation at 21 CFR 56.102 as any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights and welfare of the human subjects Independent Ethics Committee (IEC) defined by ICH E6 Section 1.27 as an independent body, constituted of medical professionals and non- medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favorable opinion on the trial protocol, the suitability of the investigator(s), facilities, and the methods and materials to be used in obtaining and documenting informed consent of trial subjects Investigator's brochure (IB) a compilation of the clinical and nonclinical data on the investigational product and serves as a resource for investigators, IRBs/Independent Ethics Committees (IECs) during the conduct of a clinical trial Source Document The initial documentation of data in a clinical study and includes recorded observations, laboratory reports, medical records, etc. Validation of computer systems defined by ICH E6 Section 1.65 as a process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system. The approach to validation should be based on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results Study feasibility factors that influence if the investigator can conduct a specific clinical trial including the investigator's expertise and interest, perceived ability to meet recruitment goals, and whether sufficient support staff and other resources are available 71 | P a g e ICH E6 Section 4.1 notes a number of investigator obligations: o The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirements, and should provide evidence of such qualifications through up-to-date CV and/pr other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies) o The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current IB, in the product information and in other information sources provided by the sponsor o The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements o The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies) o The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties · The sponsor organization will generally assess the site first by means of a _______________ site visit. At this assessment visit, the sponsor representative will review the study requirements and answer any questions that the investigator or staff might have about the execution of the study prestudy o The representative will also assess the suitability of including the investigator in the study, according to the qualifications outlined in 21 CFR 312.53(a), Selecting Investigators and Monitors The sponsor will determine if the investigator has adequate resources as outlined in ICH E6 Section 4.2: o A potential for recruiting the required number of eligible subjects within the agreed recruitment period o Sufficient time to properly conduct and complete the trial within the agreed trial period o Adequate staff and facilities to conduct the trial properly and safely for the foreseen duration o That all persons assisting with the trial are adequately informed on the protocol, the investigational product, and their trial-related duties and functions ICH Section 4.3 describes the investigator's responsibilities with respect to medical care of subjects. According to the guidance, investigators should make certain that adequate medical care is provided to the subjects for AEs, and abnormal laboratory values that are related to the trial. If the investigator becomes aware that medical care is needed, the investigator should inform the subject. A qualified physician should be responsible as either an investigator or sub-I for all trial related medical decisions. According to ICH E6 Section 4.3.3, if the subject agrees, the investigator should inform the subject's primary physician about the subject's participation in the trial. ICH E6 Section 4.3.4 also notes that although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reasons, while fully respecting the subject's rights 72 | P a g e Generally, the sponsor will enter into a clinical trial _____________ (CTA) with the investigator. This agreement is a contract that defines both the terms of study conduct and the financial agreements. There are also several other documents that must be completed before the investigator can begin to participate in the trial agreement By signing the Form ______ _________, the investigator enters into a legally binding contract with the FDA. FDA 1572 The sponsor is the conduit for transmitting this information to the FDA. By signing Form FDA 1572, the investigator assumes full responsibility for the study, attests that he/she has read the IB, and agrees to conduct the study according to the protocol and FDA regulations. The investigator agrees specifically to: 1) Personally conduct or supervise the study in accordance with the protocol and GCP guidelines 2) Protect the health and welfare of research subjects in accordance with 21 CFR 50 (Protection of Human Subjects), by informing subjects that the product is investigational, ensuring that study procedures are explained adequately and performed appropriately, and by promptly identifying and reporting safety information, among other responsibilities. 3) Report to the sponsor AEs that occur 4) Ensure that all personnel assisting in the conduct of the trial understand their obligations and commitments 5) Maintain adequate and accurate records, and make these records available for inspection 6) Ensure that an IRB that complies with the requirements in 21 CFR 56 provides initial and ongoing review and approval of the investigation 7) Comply with the requirements in 21 CFR 312 (Investigational New Drug Application) There are 2 instances when it is necessary for an investigator to complete and sign a new 1572: 1) When an investigator is participating in a new protocol that has been added to the IND 2) When a new investigator is added to the study o The investigator is also required to provide evidence that he or she is qualified to properly conduct the trial through submission of an up to date ____ CV FDFs Disclosures are required for covered clinical studies which are clinical trials of drugs or devices from which the data will be submitted to the FDA to support a marketing application or relied upon by the FDA to establish effectiveness For purposes of ________, the term investigator includes anyone who is directly involved in the treatment or evaluation of research subjects. The term also includes the spouse and each dependent child of the investigator 75 | P a g e terminated and the FDA is notified. The investigator is required to make the records available to the monitor, auditors, the IRB/IEC, the FDA, and other regulatory authorities 2 The ______________ is responsible for ensuring the accuracy completeness, legibility, and timeliness of the data in the CRFs and in all required reports. The data reported on the CRF and source document should be explained. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. If the investigator or research staff needs to make changes to a CRF, the sponsor's requirements for making such changes should be followed. Changes to source data should be traceable, should not obscure the original entry and should be explained if necessary According the ICH E6 Section 4.9.3, such changes should be dated, initialed, and explained. The changes should not obscure or cover up the original entry investigator Investigators are responsible for conducting the trial as outlined in the protocol and cannot deviate from the protocol unless the __________ is necessary to eliminate an immediate hazard to one or more subjects. Investigators document the acceptance to follow the protocol in a protocol signature page or contract deviation Any deviation should be explained in writing. If an investigator plans to deviate from the protocol for a purpose other than to eliminate an immediate hazard, the investigator must obtain prior approval from the _____________ and the IRB/IEC. If a deviation was needed to eliminate a hazard, the deviation must be documented and rationale submitted to the sponsor, IRB/IEC, and regulatory authorities. sponsor In some instances, an investigator inadvertently deviates from the protocol. When such _______________ deviations are discovered, the investigator should explain the deviation in writing. In addition, the investigator should take appropriate corrective actions and will follow the steps necessary to ensure that similar deviations do not occur in the future. unplanned If the investigator deviates from the protocol without IRB/IEC approval to eliminate an immediate hazard to subjects, the ____________ should report the deviation as soon as possible to the sponsor and the IRB/IEC to determine its reporting requirements as some sites may have different reporting policies. investigator Throughout the study, investigators are required to report _______ promptly to the sponsor organization. The sponsor provides guidance to the investigator to ensure that appropriate information is collected. SAEs 76 | P a g e Investigators also must provide periodic updates to the IRB/IEC in accordance with its policies. This typically occurs at least ______ per year but may be required more often by the individual IRB/IEC once Investigators are required to report promptly to the IRB all ______________ problems involving risks to human subjects or others including AEs that should be considered unanticipated problems, Investigators should check with the reviewing IRB/IEC to determine its reporting requirements as some sites may have different reporting policies. unanticipated Once the study has been terminated, the investigator is required to notify the IRB/IEC and provide a ___________ report The sponsor representative will ensure that the site and subject study records are complete. The investigator then must maintain all study records as noted above. The investigator may also have to provide the sponsor with any required reports. summary According to ICH, if the study is terminated prematurely or suspected for any reason, the investigator/institution should promptly inform the trial ____________, should assure appropriate therapy and follow-up for the subjects, and, where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies) subjects Investigators agreeing to participate in pharmaceutical company sponsored clinical investigations have commitments to the sponsor, IRB/IEC, subjects, and FDA o The Sponsor 1) Recruit subjects within the agreed timeframe 2) Perform study procedures according to the protocol 3) Complete and submit required regulatory documents (Form FDA 1572, FDFs, etc.) 4) Notify the sponsor of any facility changes or changes that call for a revised Form FDA 1572 5) Maintain study site records 6) Maintain subject source documents and study records 7) Notify sponsor of serious AEs o The IRB/IEC 1) Submit study documents for initial and ongoing approval 2) Notify IRB/IEC of SAEs 3) Notify IRB/IEC of unanticipated problems involving risks to subjects or others 4) Provide periodic updates (as required by IRB/IEC) 5) Provide notice of study completion/termination and summary of the study o Research Subjects 77 | P a g e 1) Ensure that informed consent is obtained before starting study procedures 2) Ensure that study procedures are explained adequately and performed appropriately 3) Ensure that the rights and welfare of study subjects are protected 4) Ensure the medical safety of the subject to the extent possible o FDA 1) Allow inspections of the facilities and records 2) Retain study records 3) Comply with GCP standards Form FDA 1572, Statement of Investigator, is legally binding between the investigator and the: FDA In completing Form FDA 1572, Statement of Investigator, the investigator agrees to Conduct or supervise the investigation personally Identify which party is responsible for reporting directly to the FDA the investigator's financial interests with the sponsor: The sponsor The investigator must report adverse events to the: Sponsor Which of the following is an investigator's commitment to the sponsor? Submit a new Form FDA 1572 to the sponsor as needed The informed consent process includes: 1) Recruiting subjects, including advertising for research subjects and discussions that occur during the screening process 2) Providing specific information about the study in a way that is understandable to potential subjects while giving them adequate time to consider participation 3) Answering the potential subjects' questions 4) Obtaining the voluntary agreement of subjects to take part in the study 5) Verifying the subjects' continued consent to participate as the study progresses Informed consent is regulated by the US FDA regulations at 21 CFR 50 and US Department of Health and Human Services (HHS) at 45 CFR 46. These regulations differ slightly, as the HHS regulations were revised in 2017 and include some additional requirements as well as an alternative process (broad consent). ______ _____ also has requirements for informed consent in clinical trials. ICH E6 HHS regulations at 45 CFR 46 require that information be presented to the subject in an understandable way that facilitates ______________________ 80 | P a g e When a clinical trial includes subjects who can only be enrolled in the trial with the consent of the subject's ________, the subject should be informed about the trial to the extent compatible with the subject's understanding and, if capable, the subject should assent, or agree, by signing and personally dating the written informed consent. (ICH E6 Section 4.8.12) LAR the FDA regulations require the IRB/IEC to ensure that assent from children is obtained, unless the requirement for assent is waived. Per these regulations at 21 CFR 50.55 c (Protection of human subjects), the IRB/IEC can waive the requirement for assent if it determines: 1) The children are incapable of understanding the research; 2) There is a prospect of direct benefit to the children that is not available outside of the research; or 3) If the requirements for a waiver of consent are met In limited circumstances, the FDA at 21 CFR 56/109 c (IRBs) allows for an investigator to obtain consent ___________ without obtaining a signature on the consent form. The IRB must approve this consent process which is referred to as a "waiver of documentation of consent". The IRB can approve this type of waiver only when study participation presents minimal risk to the subject and the research involves no procedures requiring consent outside the context of participation in a research study. Even though the requirement for a signature on the consent form is waived, the subject must be given all of the information required by the regulations. The IRB may require the investigator to provide the subject with written materials about the research verbally 21 CFR 50.23 and 50.24 (Protection oh Human Subjects) provide exceptions to the requirement for informed consent under the following circumstances: 1) In research situations where requirements for exception from informed consent are met for emergency research 2) In treatment situations where an individual has a life-threatening condition and the following requirements are met and documented: · The investigator, with the concurrence of another physician not directly involved in the care of the patient, believes the situation necessitates the use of a test article · The subject and/or LAR is unable to communicate consent · There is insufficient time to obtain consent · No alternative exists that will provide an equal or better chance of saving the subject's life · The IRB/IEC is informed of the use of the investigational product without informed consent within 5 working days of the event ICH E6 requires the ______________ to describe the process for conducting research in emergency situations without first obtaining consent and requires IRB/IEC approval of the process. The subject or legal representative should be informed as soon as possible and consent, as appropriate 81 | P a g e protocol On 24 July 2017, the FDA issued guidance that they will not object if an IRB approves a waiver or alteration of consent for a no more than minimal risk clinical investigation if the IRB determines that: 1) The clinical investigation involves no more than minimal risk as defined in 21 CFR 50.3 or 56.102 2) The waiver or alteration will not adversely affect the rights and welfare of the subjects; 3) The research could not practicably be carried out without the waiver or alteration; and 4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation The FDA and HHS issued joint guidance for IRBs, investigators, and sponsors on the use of electronic systems to obtain informed consent. The guidance focuses on the procedures to be followed when using eIC. This guidance also makes it clear that the responsibility for obtaining the subject's consent ultimately lies with the __________________, and cannot be delegated to an electronic system. investigator Which of the following statements in a consent form is an example of exculpatory language? I waive any possibility of compensation for injuries that I may receive as a result of participation in this research An investigator is confronted with a life-threatening situation that necessitates using a test article in a human subject who is unable to provide informed consent and there is no time to obtain consent for the individual's legal representative. Under the FDA regulations, which of the following describes the best course of action for the investigator: The investigator and another physician not part of the study agree that the situation necessitates the use of the test article and the IRB will be notified later Under which circumstance does the FDA allow verbal consent prior to the participation in a research study? The study is minimal risk A 46 year old man is currently enrolled in a Phase III study of a drug for sever diabetic neuropathy. While the study is ongoing, a new drug becomes commercially available that may have equal or greater benefit to the subject. The investigator should do which of the following? Discuss the pros and cons of both the investigational drug and the commercially available drug and then allow the subject to decide whether to withdraw from the research to take the new drug In the US, Europe, Japan, and other countries, the ________ ______ guideline has been adopted to aid in compliance with regulatory requirements of the multitude of government regulatory agencies. ICH E6 While most sponsors are entities within the device/pharmaceutical industry, individual investigators also can seek FDA approval to study an investigational drug or device. These individuals are known as 82 | P a g e ____________-________________ and they must follow requirements for both investigators and research sponsors. sponsor-investigators Controlled the subjects are split into at least 2 groups: those receiving the experimental agent and those receiving a standard treatment for the condition, no treatment, or a placebo. If subjects are assigned randomly into these groups, the study is a randomized controlled trial. Good Clinical Practice (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. Investigator the individual who actually conducts the trial Pharmacodynamics the effects of the agent while in the body Pharmacokinetics describes how the agent moves through and is excreted from the body Sponsor the individual or company that takes responsibility for and initiates a clinical trial · The FDA regulations at 21 CFR 312.126(a) (Applications for FDA Approval) indicates that, the purpose of conducting ____________ _______________ of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of disease, placebo effect, or biased observation clinical investigations To provide the FDA with the requested evidence, a sponsor seeks to show the safety and efficacy of a new drug by: 1) Defining routes of administration and dosing frequencies 2) Testing drug formulations 3) Exploring combination and adjuvant therapies 4) Assessing the pharmacokinetics and pharmacogenomics of the agent 5) Evaluating the effect of the drug or device on the subject's QOL According to the US Food, Drug, and Cosmetic Act, it is illegal to give an experimental article to a human being. Before conducting human clinical trials with an experimental drug, sponsors must file an ___ ___________ (Form FDA ________) with the FDA IND application (Form FDA 1571) 85 | P a g e The ICH E6 guidelines similarly allow for the use of electronic records. ICH E6 Section 5.5.3 requires that when using electronic trial data handling or remote electronic trial data systems, the sponsor should: o Ensure and document that the electronic data processing system conforms to the sponsor's established requirements for completeness, accuracy, reliability, and consistent intended performance o Maintain SOPs for using these systems. The SOPs should cover system set-up, installation, and use, as well as describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning and decommissioning. o Ensure systems are designed to permit data changes without deletion of entered data o Maintain secure user access to data o Maintain list of individuals authorized to make changes o Maintain adequate backup of the data o Safeguard the blinding o Ensure the integrity of the data, especially when making changes to computerized systems such as software upgrades or migration of data o ICH E6 also defines what a certified copy of the original record is. In order for a record to be a certified copy, the paper or electronic copy of the original record must have been verified or generated through a validated process to produce an exact copy of the original. When a copy is used to replace an original document in a trial, it should fulfill the requirements for certified copy Per 42 CFR 11, applicable clinical trials must be registered and have results submitted to the __________________________ databank. Applicable clinical trials include clinical trials of FDA-regulated drug, biological, and device products and pediatric post-market surveillance studies of devices required by the FDA under the FD&C Act. The NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information also requires registration for all clinical trials funded wholly or partly by the NIH ClinicalTrials.gov The sponsor is usually the responsible party for the purposes of submitting information about the clinical trial, unless the sponsor designates a qualified PI as the responsible party. According to 42 CFR 11, the responsible party would need to: 1) Register the trial on ClinicalTrials.gov 2) Submit summary results and AE information about the trial to ClinicalTrials.gov 3) Ensure the information about the registered trial was accurately submitted to ClinicalTrials.gov The US Department of HHS regulations at 45 CFR 46, Subpart A, commonly referred to as the ___________ ___________, requires one consent form per clinical trial to be posted to a publicly available federal website for clinical trials conducted or supported by a federal department or agency Common Rule Development of most new drugs, from discovery to marketing approval, usually takes: 9 years 86 | P a g e Adults with more than a 12 month history of migraines were assigned randomly in a double-blinded study to receive treatment with experimental drug X (10 or 20 mg/day) or placebo. The primary effect measure was the reduction in severity of the migraine attacks. Enrollment was 1200 subjects. Which of the following best describes the clinical phase of this study? Phase III Long-term toxicology of an experimental drug in animals most likely refers to which part of drug development? Preclinical Pharmacokinetics and pharmacodynamics of a new formulation of an investigational drug most likely refers to which clinical phase of a study in humans? Phase I For a Phase I new drug study in humans, what is the primary source of the data included in the initial IB? Preclinical data The goal of the _______ is to standardize technical guidelines and requirements for drug marketing registrations, so that applications for marketing to various regulatory agencies around the world can occur without redundant testing. ICH _____ _____ has become the international standard for the design, conduct, monitoring, and reporting of clinical research of investigational drugs. ICH E6 Compliance with _____ standards enhances protection of study subjects and the integrity of the data collected during a trial GCP · In 2016, the ICH revised the E6 guideline to reflect the current research landscape, reflecting increases in globalization, study complexity, and technological capabilities. The revised guidelines are entitled "Integrated Addendum to ICH E6: Guidelines for GCP E6" After the ICH E6 was finalized, several countries adopted it as law. In the US however, the FDA adopted the ICH E6 only as guidance. Therefore, ICH guidelines do not have the force of law in the US and are not regulations. Therefore, in the US, compliance with ICH E6 is voluntary, but as with any published FDA guidance, compliance is considered part of GCP. For sponsors, the advantage of complying with the ICH guideline is that the FDA and equivalent government agencies in other countries consider studies conducted in accordance with ICF E6 to meet the regulatory requirements of the drug approval processes for all of these countries. 87 | P a g e Increasingly, sponsors want investigators to meet the ICH E6 requirements. However, certain requirements of the ICH E6 are not included in FDA or US Department of HHS regulations. Therefore, investigators need to be aware of the differences between ICH E6 guideline, FDA regulations, and HHS regulations so that they can fully comply with the ICH requirements when requested by ____________ sponsors The advantage of complying with the ICH E6 guideline is that the ______ and equivalent government agencies in other countries will consider studies conducted in accordance with the ICH guideline to meet the regulatory requirements of the drug approval processes for all of these countries. FDA ICH guidelines cover 4 main categories and a letter of reference codes each category: Quality topics: Those relating to chemical and pharmaceutical quality assurance Safety topics: Those relating to in vitro and in vivo preclinical research Efficacy topics: Those relating to research in human subjects Multidisciplinary topics: Topics that do not fit uniquely into one of the categories above The ICH E6 topic falls under the ____________ category in the ICH guidelines and pertains specifically to the conduct of clinical research to support marketing applications for drugs. ICH E6 provides a unified standard for designing, conducting, recording, and reporting research involving human subjects efficacy The 2 important goals of ICH E6 are to assure that: 1) The rights, well-being, and confidentiality of trial subjects are protected 2) Trial data are credible · The ICH E6 guidelines is organized in sections. Each section is briefly described: o Introduction o Section 1: Glossary o Section 2: Principles of ICH GCP 1) Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s) 2) Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. 3) The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society 90 | P a g e investigator to be responsible for trial-related medical decisions. The FDA does not explicitly require this. 3) ICH E6 Section 4.9.0 requires that the investigator maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site's trial subjects. Source data should be attributable, legible, contemporaneous, original, accurate, and compete. Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary. ICH E6 includes conditions about essential documents in the clinical trial master file, including that: 1) Sponsor and investigator should maintain a record of the location(s) of their respective essential documents, including source documents. The storage system should provide for document identification, search and retrieval 2) Individual trials may require additional documents not mentioned in the essential document list. The sponsor and/or investigator should include these as part of the TMF 3) The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during and after the trial 4) When a copy is used to replace an original document, it should fulfill the requirements for certified copies. 5) The sponsor should not have exclusive control of Case Report Form (CRF) data 6) The sponsor should ensure that the investigator has control of and continuous access to CRF data reported to sponsor The sponsor is responsible for monitoring the study, per both ICH E6 and FDA regulations. ICH E6 has more detailed sponsor monitoring requirement. ICH E6 Section 5.18.3 states that the sponsor should: 1) Develop a systematic, prioritized risk-based approach to monitoring 2) The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, only centralized monitoring. Centralized monitoring, also referred to as remote monitoring, is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons 3) Document the rationale for the chosen monitoring strategy ICH E6 Section 5.18.6 requires ____________ to submit written reports to the sponsor after each trial- site visit or trial-related communication. The sponsor is also required to document monitoring results ICH E6 Section 5.18.7 also requires sponsors to develop a monitoring plan tailored to the specific human subject protection and data integrity risks of the trial 91 | P a g e The FDA regulations at 21 CFR 312.50 only states that the sponsor is responsible for ensuring proper monitoring of the investigation monitors Signature by person conducting the consent discussion 1) ICH E6 Section 4.8.8 states that prior to a subjects participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's LAR and by the person who conducted the informed consent discussion 2) The FDA regulations at 21 CFR 50.27 (a) only require the signature of the subject and the date the subject signed the consent form 3) To assure compliance with the ICH requirement, the consent form should include a signature line labeled "person conducting informed consent discussion". This line should not be labeled Investigator's Signature ICH E6 Section 4.8.11 requires that the subject or the legally acceptable LAR receive a copy of the signed and dated written informed consent form 1) The FDA regulations allows a copy of a signed or unsigned form 2) To be compliant with ICH E6 guidelines, the investigator should include a statement in the consent form that the subject will receive a signed and dated copy of the consent form. Persons obtaining consent must then ensure that this procedure is followed Elements of Consent 1) Alternative treatments: ICH E6 Section 4.8.10 requires an explanation of the alternative procedures or courses of treatment that may be available to the subject, and their important potential benefits and risks. Most sponsors, investigators, and IRBs have not included the benefits and risks of alternative treatments in consent forms. This is an area where many sponsors and IRBs decide to limit their compliance with ICH. However, the investigator should explain the risks and benefits of alternative treatments to subjects when the information is necessary for the subject's full understanding and exercise of autonomy 2) The FDA regulations at 21 CFR 50.25 state that the consent form must include a statement that the study involves research, and explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental. 3) ICH E6 Section 4.8.10 states that in addition to the required FDA elements, the informed consent should include: "The trial treatments and the probability for random assignment to each treatment. This difference can be addressed by including a description of each arm of the study in the consent form, and including a statement about the likelihood of receiving each of the arms. 92 | P a g e The ICH E6 guideline provides a list of documents that the IRB should review, under US regulations, IRBs routinely review most of the materials listed. Compliance with ICH requires reviewing all the listed materials 1) Trial protocol/amendments 2) Written ICF and consent form updates that the investigator proposes for use in the trial 3) Subject recruitment procedures 4) Written information to be provided to subjects 5) IB 6) Available safety information 7) Information about payments and compensation available to subjects 8) The investigator's current CV and/or other documentation evidencing qualifications 9) Any other documents that the IRB/IEC may require to fulfill its responsibilities ICH E6 section 3.4 and 21 CFR 56.115 both state that the IRB/IEC should retain all relevant records for ___ years after completion of the trial 3 ICH E6 Section 3.3.7 states that the IRB/IEC should specify that no deviation from, or changes of, the protocol should be initiated without prior IRB/IEC written approval. ICH E6 adds that investigators should document and explain any deviations from the approved protocol 1) ICH E6 Sections 8.2.7, 8.3.2, and 8.3.3 require documented approval/favorable opinion of the protocol and any amendments 2) FDA regulations require review of changes in research However, review of deviations is not explicitly required. Investigators should clarify with sponsors and their IRB how the review of deviations will be satisfied. A primary purpose of the ICH is to: Minimize the need for redundant research The ICH GCP guidelines: Set standards for the design, conduct, monitoring and reporting of clinical research ICH E6 describes standards that apply to: Investigators, sponsors, and IRBs In the US, following the ICH E6 guideline is: Voluntary for FDA-regulated drug studies What is the status of ICH in US It is a FDA guidance 95 | P a g e their opinion. Some reviewing divisions will agree to provide an opinion and others will require a full IND/IDE submission before making a determination If an IND/IDE is required, the FDA will review the submission and send questions or other issues for investigator response and clarification as necessary. However, if the FDA has not responded within 30 days of IND submission, agency approval is assumed and the investigation can proceed. In all of the situations listed above (No IND submission, request from FDA to review if IND is needed) _______/_______review and approval is still required for the study, and sponsor-investigators must comply with all responsibilities of investigators IRB/IEC Whenever a trial involves a new drug that has not been approved by the FDA the sponsor-investigator must submit the following information to the FDA to obtain an IND: o Cover letter o Form FDA 1571 (Investigational New Drug Application) o Form FDA 1572 (Statement of Investigator) o Introductory statement and general investigational plan o IB o Protocol(s) o Chemistry, manufacturing, and controls information o Pharmacology and toxicity information o Previous human experience with drug o Additional information o Relevant information In some instances, the manufacturer of an IND might already have an active IND for the drug being studied by a sponsor-investigator, In these instances, the manufacturer may agree to provide a letter of cross-reference that enables the sponsor-investigator to reference the following technical information from the manufacturer's IND into the sponsor-investigator IND: o Chemistry, manufacturing, and controls information o Pharmacology and toxicology information o Previous human experience with the drug This cross- referencing between INDs prevents the unnecessary submission of duplicate information to the FDA and lessens the burden on the sponsor-investigator. However, if the drug product or process is different from that on the drug information being cross-referenced from the manufacturer's IND, a CMC section detailing those different processes must be included in the sponsor-investigator IND Form FDA 1571 is a contractual agreement between the sponsor and FDA. By signing the 1571, the sponsor-investigator agrees to the following: o Not to begin clinical investigations until 30 days after FDA's receipt of the IND, unless the investigator receives earlier notification from the FDA o Not to begin or continue investigations covered by the IND of those studies are placed on clinical hold 96 | P a g e o That an IRB/IEC that complies with 21 CFR 56 will be responsible for initial and continuing review and approval of each of the studies in the proposed clinical investigations o To conduct the investigation in accordance with all other applicable regulatory requirements The content for an IND for studies of marketed products is the same as the content for studies of new drugs, with the following exception: a copy of the approved labeling can be provided in lieu of the __________________ ________________ Investigator's Brochure Responsibilities of sponsor-investigators include: o Implement a system to manage quality throughout the design, conduct, recording, evaluation, reporting, and archiving of clinical trials o Implement research as approved o Report all changes to the IND to FDA including Protocol changes Technical changes to CMC or preclinical section Annual reports AEs requiring expedited reporting o Monitor conduct and progress of clinical trials including documentation of monitoring plan and monitoring results o Maintain records or receipt, shipment, and other disposition of the drug if the drug is considered investigational o Review and evaluate information relevant to safety of the drug o Provide oversight to subcontractors (for example, CROs) o Follow-up of non-compliance through root cause analysis and corrective and preventative actions o Maintain record of location of essential documents for clinical trial Once an IND is submitted and becomes effective, a sponsor-investigator who is an IND holder is required to submit the following reports/updates to the FDA o Protocol amendments New sponsor protocol A change in an existing protocol when the entire sponsor protocol is not revised Identifying and adding a new investigator to a study o Information amendments: must be submitted when new toxicology, chemistry or other technical information is available. The IND holder must also report study discontinuation to the FDA as an 97 | P a g e information amendment. o Adverse events and IND safety reports: Investigators must immediately report SAEs to the sponsor- investigator and must report all other AEs as required by the protocol Sponsor investigators must notify regulatory authorities and all participating investigators in writing of events that are both unexpected and serious, and are associated with the use of drugs as soon as possible, but not later than 15 calendar days after the sponsor-investigator determines that information received must be reported. In the US, these reports from the sponsor-investigator are called IND safety reports. Adverse reactions that are unexpected, fatal, or life threatening must be reported no later than 7 calendar days after the sponsor-investigator receives the information. o Annual reports: submit annual reports to the FDA within 60 days of the anniversary date that the IND went into effect o Final reports: shortly after completion of the investigator's participation in the investigation Financial disclosure reports: financial information that comply with the certification requirements described in 21 CFR 54 o An IDE submission includes: 1) Cover letter to the FDA 2) Cross-reference letter from device supplier 3) Table of contents 4) Report of prior investigations 5) Investigational plan 6) Manufacturing information 7) Investigational information 8) IRB information 9) Sales information 10) Device labeling 11) Informed consent materials 12) Any other relevant information that FDA requests for review of the IDE application 13) Information previously submitted to FDA in accordance with 21 CFR 812 may be incorporated as reference Risk categories for Device 1) Significant risk (SR) device investigations: all significant risk device studies must be performed under an IDE, unless exempt under 21 CFR 812.2 3) Nonsignificant Risk (NSR) Device investigations: do not need to be performed under an IDE. IRB approval, informed consent, and appropriate monitoring of the study are required for most NSR studies The sponsor-investigator is responsible for making the initial risk determination for devices and presenting it to the IRB. The FDA is available to help sponsor-investigators and IRBs in making the risk determination