ACRP-CP

· 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"

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

Investigator responsibilities differ between ICH E6 and FDA regulations

1) 21 CFR 312.52 is more explicit in requiring the investigator to provide a signed statement (Form FDA 1572)to the FDA. ICH does not require a signed statement from the investigator to a regulatory authority. 2) ICH E6 Section 43 addresses the medical care of trial subjects and requires a qualified physician 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.

The exemption criteria at 21 CFR 812.2 (Investigational Device Exemptions) are the following:

1) A device other than a transitional device, in commercial distribution immediately before 28 May 1976, when used or investigated in accordance with the indications in labeling in effect at that time 2) A device, other than a transitional device, introduced into commercial distribution on or after 28 May 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before 28 May 1976, and that is used or investigated in accordance with the indications in the labeling FDA reviewed under Subpart E of 21 CFR 807 in determining substantial equivalence 3) A diagnostic device if the sponsor complies with applicable requirements in 21 CFR 809.10 and if the testing: o Is non-invasive o Does not require an invasive sampling procedure that presents significant risk o Does not by design or intention introduce energy into a subject; and o Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure 4) A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk 5) A device intended solely for veterinary use 6) A device shipped solely for research on or with laboratory animals and labeled in accordance with 21 CFR 812.5 7) A custom device as defined in 21 CFR 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution

· 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)

An author's responsibilities include confirming that:

1) All relevant work is cited, both confirming and contradictory, in order to provide the reader with a full understanding of how the work relates to the existing literature within the field, and to recognize and acknowledge the work of others in the field 2) All data are accurately and clearly presented 3) Key underlying assumptions are clearly stated 4) The work is described in sufficient detail so that in principle it can be replicated 5) Potentially hazardous aspects of the research are clearly identified 6) Conflicts of interest that may, consciously or unconsciously, bias the interpretation of the research findings have been disclosed to editors and readers

Upon receipt of an IDE application, the FDA will send a notice indicating the date the submission was received. For SR studies, the FDA has 30 days to respond to an IDE submission. Upon review, the FDA can either:

1) Allow the proposed clinical study to begin 2) Require modifications or more information before granting approval for the study to begin

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.

In order to qualify for an abbreviated IDE (21 CFR 812.2(b)) the study must fall under one of the following categories (unless the FDA has notified the sponsor that approval of an application is required

1) An investigation of a device other than a significant risk device, if the device is not a banned device and the sponsor: o Labels the device in accordance with 21 CFR 812.5 o Obtains IRB/IEC approval of the investigation after presenting the reviewing IRB/IEC with a brief explanation of why the device is not a significant risk device, and maintains such approval o Ensures that each investigator participating in an investigation of the device obtains from each subject under the investigator's care, informed consent under part 21 CFR 50 and documents it, unless documentation is waived by an IRB/IEC under 21 CFR 56.109 o Complies with the requirements of 21 CFR 812.46 with respect to monitoring investigations o Maintains the records required under 21 CFR 812.140(b)(4) and (5) and makes the reports required under 21 CFR 812.150(b)(1) through (3) and (5) through (10) o Ensures that participating investigators maintain the records required by 21 CFR 812.140(a) 2) An investigation of a device other than one subject to paragraph (e) of this section, if the investigation was begun on or before 16 July 1980, and to be completed, and is completed, on or before 19 January 1981

The Common Rule (45 CFR 46, Subpart A) found at 46.108(a)(4): An IRB shall establish and follow written procedures for ensuring prompt reporting to the IRB; appropriate institutional officials; the department or agency head; and the Office for Human Research Protections, HHS, or any successor office, or the equivalent office within the appropriate Federal department or agency of:

1) Any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and 2) Any suspension or termination of IRB approval.

Types of IRB submissions

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

National Research Act (1974)

1) Authorized the creation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which was charged with developing an ethical code and guidelines for researchers 2) Required the establishment of IRBs at organizations receiving PHS support for human subject's research

Investigator responsibilities regarding COIs include:

1) Becoming familiar with the revised regulations and the institution's COI policies 2) Complete COI training at the required intervals, at least once every 4 years 3) Disclose SFIs to the institution annually and within thirty days of discovering or acquiring a new SFI 4) Comply with any management plan issued by the institution and retain documentation that demonstrates compliance

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

According to 21 CFR 54, the following information must be reported by investigators to the company that submits the new drug application (NDA):

1) Compensation made to the investigator in which the value of compensation could be affected by study outcome 2) A proprietary interest in the tested product, including, but not limited to, a patent, trademark, copyright or licensing agreement 3) Any equity interest in the sponsor of a covered study 4) Any equity interest in a publicly held company that exceeds $50,000 in value

21 CFR 11, often referred to as Part 11, was intended to enable the use of electronic documents in the regulatory process for drugs and devices. Part 11 specifies processes that must be in place to ensure that electronic documents and signatures are equivalent to paper documents and handwritten signatures. For 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 or entries and actions that create, modify, or delete electronic records 3) Computer systems must use system checks to ensure that only those individuals authorized to use the 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 that minimally they meet FDA requirements

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 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.

When obtaining consent from subjects for participation in clinical trials, the investigator must ensure that the following requirements are satisfied:

1) Consent must be legally effective 2) The language used to obtain consent must be understandable to the subject or the subject's LAR 3) Consent must be obtained under circumstances that allow the subject sufficient time to decide whether or not to participate 4) Consent must be obtained without undue influence or coercion

Contents of an IDE Application

1) Contact information for the sponsor 2) Report of prior investigations 3) Summary of the complete investigational plan 4) Description of methods, facilities, and controls used to manufacture, process, pack, store, and install (if appropriate) the device 5) Sample investigator agreement 6) Certification that all participating investigators have signed the agreement 7) Contact information for all IRB/IECs 8) Certification of the actions taken by each IRB/IEC regarding the study 9) Contact information for the institutions; if different from that for the IRB/IEC 10) If the device will be sold, the amount to be charged and explanation of why sale does not constitute commercialization of device 11) Claim for categorial exclusion or environmental assessment ·12) Copies of all labeling for the device 13) Copies of all forms and information to be given to subjects when obtaining informed consent 14) Any other relevant information FDA request for review of the application

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

Once an IDE is submitted and approved, the reports outlined below are required to be submitted to the FDA

1) Current investigator list: in 6 month intervals starting with the date of approval 2) Annual progress reports 3) Final report 4) Withdrawal of IRB approval 5) Recalls and device disposition 6) Reports of device use without consent 7) Financial disclosure reports if the data will be submitted to the FDA to support a marketing application or relied upon by the FDA to establish effectiveness

After careful review of the IND application, the FDA will allow human studies to proceed if it determines that the risk of exposure to the drug is reasonable. This determination is based upon:

1) Data from prior animal or human testing 2) Methods of manufacturing 3) Plans for testing and reporting significant toxicities 4) A well-developed clinical research plan that minimizes risks to the subjects

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

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

· 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 ethics of genetic and genomic research have received a great deal of attention due to several factors:

1) Genetic testing can reveal a strong predisposition to future disease, making the information psychologically powerful and raising concerns about stigma or discrimination 2) Related individuals share many of the same gene sequences in their DNA, meaning that genetic information about one individual provides information about other individuals who may or may not have consented to genetic testing 3) Genetic testing can reveal characteristics of recent and distant ancestry that may conflict with peoples' family history, with their social history, or with their religious beliefs 4) Historically, genetic concepts and information have sometimes been misused to affect social and political ends

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

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

The ICH E6 guidelines generally require more from the sponsor than the FDA does

1) ICH E6 Section 5.0 states that the sponsor should implement a system to manage quality throughout all stages of the trial process, and the quality management system should use a risk-based approach. This is a significant change for trial monitoring, which goes beyond routine periodic record auditing. The new ICH E6 integrated addendum requires sponsors to implement systems to manage quality throughout all stages of the trial process. The system should use a risk-based approach including identification of study risks to determine which may safely be omitted from continual monitoring. 2) ICH E6 Section 5.2.2 and 21 CFR 312.52 allow the sponsor to delegate responsibilities to a CRO, but ICH also requires that the sponsor ensure oversight even if duties are subcontracted to a CRO. FDA regulations states that if all obligations are transferred, a general statement that all obligations have been transferred is acceptable. ICH makes no such mention. 3) ICH E6 Section 5.5 and FDA regulations agree that the sponsor is responsible for the trial management, data handling, and record keeping. However, ICH E6 Section 5.5.3 also requires the sponsor to ensure that the electronic trial data handling and/or remote electronic trial data systems conform to the sponsor's established requirements for completeness, accuracy, reliability, and are validated and that sponsors maintain SOPs for these systems. 4)ICH E6 Section 5.20.1 requires the sponsor to take prompt action to secure compliance when noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirements is discovered. ICH E6 further requires the sponsor to perform a root cause analysis and implement an appropriate corrective and preventative action depending on the significance of the noncompliance. Also, ICH E6 Section 5.20.2 states that if the sponsor identifies continuing and/or serious noncompliance, the sponsor should end the investigator's/institution's participation in the clinical trial and notify regulatory authorities.

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.

ICH E6 allows broader access to research records and to otherwise confidential medical records that is required by FDA regulations. If investigators are required to comply with ICH, they must clearly disclose this information to subjects during the informed consent process.

1) ICH Section 4.8.10 states that the informed consent should indicate that the monitors, the auditors, the IRB/IEC, and the regulatory authorities will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject's LAR is authorizing such access 2) ICH Section 5.15.2 states that the sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection 3) The FDA regulations at 21 CFR 50.25(a)(5) state only that in seeking informed consent, the following information shall be provided to each subject...A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the FDA may inspect the records

There are two types of IDEs:

1) IDES for trials involving SR devices- the trials must be reviewed and approved by both the institution's IRB/IEC and by the FDA, and the sponsor of the trials must comply with all IDE requirements 2) Abbreviated IDEs for trials involving NSR devices- the trials require approval only by the IRB/IEC before enrollment can begin, and the sponsor of the trials must comply with abbreviated IDE requirements. Prior FDA review is not required

Regulatory documents reviewed during FDA inspections:

1) IRB/IEC membership list/roster 2) IRB/IEC correspondence 3) Investigator's brochure 4) Investigator CV 5) Protocol 6) Protocol amendments 7) Form FDA 1572 8) Informed Consent form (all approved versions, blank) 9) Signed ICF 10) Correspondence (to/from sponsor, laboratories, etc.) 11) Investigational product records 12) Site signature list 13) Monitoring log 14) CRFs (blank) 15) CRFs (completed) 16) Source documents (medical records, laboratory reports) 17) Laboratory certification 18) Laboratory normal value ranges 19) Site delegation of authority list/log

The 2011 regulations apply to all PHS-funded research available through a grant or cooperative agreement, including biomedical, behavioral, and social science research. The regulations intend to promote objectivity in research by establishing standards that provide a reasonable expectation that the design, conduct, and reporting of federally funded research will be free from bias resulting from investigator's FCOIs More specifically, the revised regulations:

1) Implement required training for investigators 2) Expand the scope and definition of SFIs that investigators must disclose, with, for example, lower thresholds for some types of SFIs 3) Intensify the responsibilities of institutions for review, management, and oversight of investigators' SFIs and FCOIs 4) Increase compliance oversight obligations for institutions and the government

Responsibilities of the sponsor-investigator for devices include:

1) Implement research as approved 2) Select qualified investigators 3) Ensure proper monitoring of the study 4) Inform the IRB and FDA of any significant information

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"

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

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 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

· Significant Risk (SR) Devices: As noted in the regulations (21 CFR 812.3), a SR device is one that:

1) Is intended to be implanted into a human 2) Is used in supporting or sustaining human life 3) Is of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise prevents impairment of human health; or 4) Otherwise presents serious risk to health, safety, and welfare of a subject

The Medical Device Amendments of 1976 and the Safe Medical Devices Act of 1990 provide the regulatory framework for medical device development, testing, approval, and marketing

1) Manufacturers who wish to market a new medical device may need to submit a premarket notification to the FDA 2) If the device is not exempt for the premarket approval, the FDA at 21 CFR 807.81 (a)(1) (Establishment Registration 2014) determines whether the device is substantially equivalent to similar devices marketed before the 1976 amendment. Those devices are often referred to as 510(k) devices and require a summary to be submitted to the FDA to determine substantial equivalence (21 CFR 807.92) 3) If the new medical device is not substantially equivalent, the company may need to demonstrate safety and efficacy in a premarket approval application, which could include clinical trials. 4) The FDA regulations at 21 CFR 812 specify how to conduct clinical trials related to investigational devices.

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)

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.

ICH E6 provides detailed information regarding the following:

1) Principles of ICH GCP 2) IRB/IEC 3) Investigator 4) Sponsor 5) Clinical trial protocol and protocol amendments 6) IB 7) Essential documents for the conduct of a clinical trial

When an investigator agrees to conduct a clinical trial of a device, the agreement is documented through a signed written investigator agreement. Agreements should include specific responsibilities of investigators such as those listed below:

1) Protecting the rights, safety, and welfare of research subjects 2) Obtaining informed consent from each subject 3) Controlling the distribution of the device being investigated 4) Maintain proper research records and making them available as required 5) Reporting research progress, safety information, final results, financial disclosures 6) Ensuring IRB/IEC review of study information for initial and continuing approval of the study 7) Supervising the use of the investigational device (SR devices only)

The regulations require that the consent process be understandable. Guidelines for improving understanding include:

1) Providing consent in a language that is understandable to the subject or his/her representative; 2) Providing non-English speaking subjects a translated informed consent document; 3) Having a translator available to assist in the consent discussion, including communicating the subject's questions and the answers to those questions; and 4) Giving the individual subject sufficient time to think about the research before consenting to research study participation

According to ICH E6 Section 4.6.3, product accountability includes the items listed below

1) Records of receipt of the product at the site (shipping records) 2) Managing the inventory and the storage of the product 3) Supplying of the product to the subjects (dispensing logs) 4) Explaining the correct usage of the product to subjects 5) Monitoring usage by subjects according to the protocol (pill counts) to ensure subject understanding and compliance 6) Return or destruction of the product at the end of the trial

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

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

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

Form FDA 1572 requirements:

1) Researchers participating in drug and biologic studies subject to the IND regulations must sign Form FDA 1572 2) Form FDA 1572 outlines the commitments that must be made by the researcher(s) regarding the conduct of the study 3) Form FDA 1572 must list education, training, and experience of researcher that qualify the researcher to conduct the study 4) Form FDA 1572 must list the research sites (names and addresses) and clinical laboratories to be used in the study 5) Form FDA 1572 must list sub-investigators 6) Form FDA 1572 must list the IRB of record for that study site 7) Form FDA 1572 must include protocol information

The IND process is a very dynamic interaction between the sponsor and the FDA during the clinical development phase of investigational drugs. The sponsor must maintain a current IND application by amending the IND with a new Form FDA 1571 and provide FDA with the following information:

1) Safety updates 2) Copies of new protocols 3) Form FDA 1572 (Statement of Investigator) the document that notifies FDA of relevant changes in investigators conducting clinical trials under the IND 4) Annual progress reports

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

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

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

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

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

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

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.

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

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

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

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

· As noted in the regulations at 312.2(b) the clinical investigation of a marketed drug does not require an IND if all of the following conditions are met:

1) The data will not be used to support a new indication, new labeling, or significant change in advertising 2) The research does not involve change to the route of administration or dosage level, subject population usage, or other factors that significantly increases the drug product's risks of harm (or decreases the acceptability of the risks) 3) The research is conducted in compliance with requirements for promotion and sale at 21 CFR 312.7

Categories for expedited review:

1) The research does not involve more than minimal risk 2) The entire research project must be consistent with one or more of the federally defined categories (IND/IDE note required)

Clinical trials are monitored to ensure that:

1) The rights and well-bring of human subjects are protected 2) The reported trial data are accurate, complete, and verifiable from source documents 3) The conduct of the trial is in compliance with the currently approved protocol and amendment(s), with GCP, with the sponsor requirements and with applicable regulations including 21 CFR 312, 812, 50, and 56

One of the responsibilities for sponsors of clinical investigations involving new drugs and medical devices under 21 CFR 312.56 AND 812.46 and ICH E6 is to monitor the progress of a clinical investigation. According to ICH E6, the purpose of trial monitoring are to verify that:

1) The rights and well-bring of human subjects are protected 2) The reported trial data is accurate, complete and verifiable from source documents 3) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirements o Sponsor-investigators must develop monitoring plans based on the human subject protection and data integrity risks of the clinical trial.

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

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

Republication might be allowed if:

1) The work is being translated into another language 2) The work is being published in an anthology or similar collection 3) The material is rewritten and targeted to a different audience 4) The authors are transparent with each respective published about the duplication and have addressed relevant copyright issues

For use of a significant risk device in research, the sponsor must submit an IDE application to the FDA per 21 CFR 812.20.

1) There is no specific form for this purpose, but the regulations list elements required in the application. 2) The trial cannot begin until the FDA grants an IDE and the IRB grants approval for the study.

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

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

Nuremberg Code (1947)

1) a requirements for voluntary consent 2) the research must have scientific merit 3) The benefits of the research must outweigh the risks 4) Subjects have the ability to terminate participation in the research at any time

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 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 distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility: or A statement that the subject's information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies.

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.

Additional protection for these individuals in research

1) pregnant women, human fetuses, and neonates 2) children 3) prisoners

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

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

An unanticipated problem must include these three criteria:

1) unexpected 2) related 3) greater risk of harm

Investigators are required to report UADEs to the sponsor and the reviewing IRB/IEC within ______ working days after becoming aware of the event. According to the regulations, the sponsor evaluates the UADE report, and then is responsible for reporting the event to the FDA

10

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

Essential documents should be retained for at least _____ years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product, unless required for a longer period by a regulatory requirement or an agreement with the sponsor

2

The investigator must maintain study records for at least ______ years after the drug has been granted marketing approval in the US for the indication tested in the study or, if no application will be filed or if the application is not approved for the indication, for at least 2 years after the investigation is 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 FDA has indicated that it is acceptable to conduct the consent discussion by phone and satisfy the requirement for a signed consent document by having the signed and dated consent form returned by fax. The IRB/IEC should prospectively approve a consent process conducted in this manner. The investigator must ensure that the subject's signature fulfills the electronic signature requirements of ___ CFR __

21 CFR 11 (Part 11)

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

The sponsor must submit an IND Safety Report to the FDA if an adverse event is 1) serious, 2) unexpected, and:

3) there is reasonable possibility that the drug caused the event

Each investigator must update the disclosure at least annually during the period covered by the grant, or within ____ days of identifying or acquiring a new SFI

30

If the FDA has not responded to the application within ____ days, approval is assumed and the study can begin

30

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

Investigators must complete training prior to engaging in PHS-funded research and re-train every ______ years. Institutions may require training under other circumstances, such as an investigator's failure to properly disclose SFIs or noncompliance with a management plan

4

At a minimum, how often are investigators funded by the US NIH required to receive conflict of interest training?

4 years

The IRB must be notified within a maximum of _____ days if a test article was used in an emergency situation for one individual are associated with an IRB-approved research study that involves research in emergencies

5

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

§ 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

Development of most new drugs, from discovery to marketing approval, usually takes:

9 years

Which of the following statements best exemplifies that importance of mentoring?

A mechanism to transmit values and standards of professional conduct

Which of the following is most likely to create a poor relationship between a mentor and a trainee?

A mentor is a person who recruits trainees merely for the mentor's own career advancement

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

An autonomous person

A person capable of deliberation about personal goals and of acting under the direction of such deliberation

Which is an example of a situation where deferential vulnerability might be a factor?

A physician recruiting patients to be subjects

Which of the following statements most accurately describes a mitigation report?

A report to the US PHS of efforts that will be taken by the institution to deal with any bias that was found in research conducted while there was an unreported FCOI

Which of the following is most likely to be considered a conflict of commitment?

A researcher cancels laboratory meetings in order to perform consulting work

IRB (Institutional Review Board)

A review committee established to help protect the rights and welfare of human research subjects

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

According to ICH E6, an inspection is defined as:

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

According to ICH E6, an "audit" is defined as:

A systematic and independent examination of trial-related activities and documents

An investigator conducting a study of a medical device under an IDE is required to complete and sign which of the following?

An investigator's agreement

Unexpected AE or unexpected suspected adverse reaction:

AE or suspected adverse reaction not listed in the IB, the protocol or consent form or elsewhere in the current IND application, or is not listed at the specificity or severity that has been observed. Unexpected, as used in this definition, also refers to AEs or suspected adverse reactions that are mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation

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

Preclinical studies: 3-6 years

Allows investigators to evaluate the drug using tissue cultures and animal models. The drug's activity is also established in animal models. The outcome of these tests allows the sponsor to determine whether the drug appears to be safe and show promise of effectiveness, thereby warranting additional study

45 CFR 46

Also known as the Common Rule, this legislation established the role of institutional review boards (IRBs) for research on human rights.

Conflict of interest (COI)

Any circumstance where the personal, professional, financial, or other private interests of a person or institution compromise or have the potential to compromise the exercise of professional judgement or obligations or may be perceived as doing so

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

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.

Federal regulations stipulate that an IRB can:

Approve research, require modifications, disapprove research, conduct continuing reviews, verify no material changes occurred since previous review, observe, suspend/terminate approval

The packaging of investigational drugs should ideally:

Be designed to help with subject compliance

IND submission: 30 days

Before conducting human clinical trials with an experimental drug, the sponsor must file an IND application (Form FDA 1571) with the FDA. The IND application includes all known information about the investigational product, such as the results of the preclinical trials. The FDA has 30 days to review this information to determine the relative safety of the article before allowing it to be tested in humans. If the FDA has concerns or questions about the drug or the study plan, the FDA contacts the sponsor and puts a clinical hold on the trial, preventing the sponsor from proceeding with the research. However, if the 30 day review period passes without notification from the FDA, the sponsor may proceed with the research as described in the IND application. Investigators are wise to verify with the sponsor or the FDA that no clinical hold has been placed on the IND before enrolling subjects in the trial

A reviewer's main responsibility is to:

Behave professionally

A double-blinded trial for a new indication is conducted under an IND comparing two marketed drugs, at twice the approved prescribed doses. On Day 2, subject 603 had difficult breathing. Although it was life-threatening initially, subject 603 was treated and discharged directly from the ED after complete recovery. On day 5, subject 20 had a headache, which led to hospitalization and required blood pressure lowering medication. These episodes cannot be explained on the basis of the pharmacological property of either drug or the subjects' medical histories. The investigator would submit an SAE report for:

Both of the subjects

Which of the following is true regarding data analysis?

Data analysis methods should usually be specified in advance before a study begins

Which of the following is true regarding the reporting of research results?

Clear specification of the methods and procedures used is essential

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

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

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

Case report form

A sponsor may transfer responsibilities and tasks to a ________, but the ultimate responsibility for the quality and integrity of the data always resides with the sponsor. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, even those subcontracted to another party by the sponsor-s contracted CRO

CRO

____________ is used by the National Cancer Institute to grade AEs

CTCAE

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

Expedited review

Can be used for established categories and minor changes in previously approved research, and for limited IRB review of select exemption categories

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 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

Life-threatening or disabling AE

Complicated by acute, life-threatening metabolic or cardiovascular complications (such as circulatory failure, hemorrhage, sepsis); life-threatening physiological consequences; or need for intensive care or emergent invasive procedure

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

Conduct or supervise the investigation personally

What are the three main goals of data lifecycle management (DLM)?

Confidentiality, availability, and integrity

Which of the following is a responsibility of each author?

Confirming that data have been accurately presented in the paper

The main reason that the Royal Society of London developed the modern form of peer review was to:

Control the quality of published papers

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

For device investigations conducted in the US, the investigator/sponsor must state whether the investigation complies with _________ regulations 21 CFR 50, 56, and 812

FDA

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

FDA

ICH E2A Clinical Safety Data Management

Definitions and Standards for Expedited Reporting This document describes the requirements for assessing safety in clinical research and focuses on the responsibilities of the sponsor for reporting AEs.

Which of the following as an example of how the Principle of Beneficence can be applied to a study employing human subjects?

Determining that the study has maximized benefits and minimized risks

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

The US PHS requires institutions to:

Disclose their investigators' new FCOIs to the PHS awarding component within 60 days of discovering them

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

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

A research collaboration can be enhanced by:

Discussing intellectual property issues while the collaboration is forming

Beneficence

Do not harm and maximize possible benefits and minimize possible harms

WHO Guidelines (1996) Standards and Operational Guidance for Ethics Review of Health-related Research with Human Participants"

Documents designed to serve as international guidelines for the review and conduct of research involving human subjects

When conducting research that involves collecting biological specimens for genetic testing, which of the following issues are the most important for the IRB to consider?

Effects of findings on other family memebers

Which of the following is an important component of drug accountability?

Drug shipping and disposition records

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 of the following most accurately describes good mentoring practice?

Encouraging trainees to receive mentoring from a collection of individuals

The overall goal of monitoring, audits, and inspection activities is to:

Ensure the protection of human research subjects and data integrity

Accurate reporting of adverse events is most important for:

Ensuring subject safety

Institutions are required by the US PHS to do which of the following:

Evaluate whether a significant financial interest is related to an investigator's research and constitutes a financial conflict of interest.

Which of the following is required at a prestudy site visit?

Evaluation of the site's capacity to conduct the study

Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgement, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Examples include allergic bronchospasm requiring intensive treatment , blood dyscrasias or convulsions that do not result in hospitalization, or the development of drug dependency or drug abuse

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

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

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.

21 CFR 52

FDA COI regulations requiring the sponsor of a clinical trial to provide certain financial interest information about the clinical trial investigators when submitting a marketing application for drug, biological product, or device.

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

FDFs

The sponsor cannot ship an investigational product to the site until the investigator has signed and submitted __________ __________ ___________or an investigator agreement for device to the sponsor

Form FDA 1572

If necessary, the sponsor representative will supply the form for reporting financial interests to the FDA

Form FDA 3455- Disclosure: Financial interests and arrangements of clinical investigators · Form FDA 3454- Certification: Financial interests and arrangements of clinical investigators

Conveyed committee review

Full committee review. Standard type of review described in the federal regulations. Must be used for the initial review of all studies that are not eligible for expedited review or exemption

Compliance with _____ standards enhances protection of study subjects and the integrity of the data collected during a trial

GCP

For investigations conducted outside the US, the investigator/sponsor must state whether the investigation complied with ________ and provide supporting information

GCP

ICH E6 requires that the sponsor obtain from the investigator/institution a statement from the IRB/IEC that it is organized and operates according to _______ and the applicable laws and regulations. Sponsors may approach IRBs directly to obtain this statement, but some sponsors request that the investigator obtain the statement from the IRB and then forward it to the sponsor

GCP

On 21 February 2018, the FDA updated its regulations for clinical investigations. Effective 21 February 2019, data submitted to support an FDA application or submission must contain a statement about whether the study was conducted in accordance with _________ or FDA regulations

GCP

It is the sponsor-investigator's responsibility to comply with ________ when conducting a study.

GCP Failure to comply with GCP standards may ultimately result in the inability to continue conducting clinical trials.

A 46 year-old man is currently enrolled in a Phase 2 study of a drug for severe diabetic neuropathy. While the study is on-going, a new drug becomes commercially available that may have equal or greater benefit to the subject. The investigator should do which of the following?

Give the subject comprehensive information about the new drug, including its side effects. Discuss the pros and cons of both the investigational drug and the commercially available drug and then allow the subject to decide whether to withdraw from the research to take the new drug.

Which of the following is the most effective strategy for preventing research misconduct?

Good mentoring

ICH E6

Guideline for Good Clinical Practice

Which of the following is the primary criterion for authorship?

Having made a significant intellectual contribution to the work

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

Identify which type of discrimination the Genetic Information Non-Discrimination Act protects individuals from:

Health insurance and employment discrimination

A general requirement for the informed consent form is that it may not include any exculpatory language. Exculpatory language is that which waives or appears to waive any of the subject's legal rights or releases or appears to release those conducting the research from liability for negligence. 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

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

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

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

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

_____ _____ has become the international standard for the design, conduct, monitoring, and reporting of clinical research of investigational drugs.

ICH E6

In terms of explaining the probability of assignment to trial arms in consent forms, which is true?

ICH notes that it should be included, but does not specify how the information should be presented

The ______ application includes all known information about the investigational product, such as the results of preclinical trials. The FDA reviews these results to determine the relative safety of the article before allowing it to be tested in humans.

IND

US regulations require sponsors to monitor the conduct of clinical trials performed under an ________ application or IDE

IND

The FDA issued helpful guidance on the use of approved drugs in clinical trials for cancer entitled:

IND Exemptions for Studies of Lawfully Marketed Drug or Biological products for the Treatment of Cancer

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)

When the sponsor-investigator holds the IND for an investigational drug he or she is responsible for annual reporting of which of the following to FDA?

IND report

21 CFR 56

IRB

Regulations require:

IRB review and approval for research involving human subjects if it is conducted, supported, or regulated by US federal departments and agencies

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

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.

Which of the following should take place during periodic site visits?

Identification of protocol violations

The new ICH E6(R2) integrated addendum requires sponsors to implement systems to manage quality throughout all stages of the trial process. The system should use a risk-based approach including which of the following?

Identification of study risks to determine which may safely be omitted from continual monitoring

Investigators may also seek an opinion from the FDA as to whether an IND/IDE is needed. To obtain such an opinion, investigators should contact the reviewing division for the drug's/device's therapeutic indication and ask them to review and issue an opinion as to whether an IND/IDE is required for the study based on the protocol. The investigator will receive a response from the division indicating 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.

FDA regulation allow, in special circumstances, individual patients to access investigational devices before FDA approval and not as part of a clinical trial. For example, the regulations at 21 CFR 812 allow for approval of an IDE for an investigational device for "treatment use" in situations where the patient has a "life-threatening disease or condition for which there is no comparable or satisfactory alternative device or therapy available"

If such situations occur, investigators should contact their sponsor or device manufacturer for additional information and guidance

The clinical investigator should respond to the Form FDA 483 in writing within 15 business days.

If the FDA does not receive a written response within 15 business days, it may not consider the response when determining the adequacy of corrective actions. If observations are considered absent corrective actions, it is more likely that the FDA will take more definitive steps to achieve compliance such as issuing a Warning Letter

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.

If the awardee institution's policy applies, the agreement needs to specify a deadline for the subrecipient to submit disclosures of their researchers' SFIs to the awardee institution, so it can review the SFIs for FCOI and take necessary action within the timeframe specified by the regulation.

SAEs must be reported immediately. The term "immediately" is not defined in the regulation, but the industry standard is to report the event within 24 hours.

If the event does not meet the definition of serious but reporting is required by the protocol, the investigator must report the events according to the timetable specified in the protocol. For reported deaths, the investigator should supply the sponsor and IRB/IEC with any additional requested information

Which of the following is true regarding authors who seek to publish the same content in multiple papers?

If the same content is used in multiple papers, it is essential that this information be properly disclosed to journal editors and other relevant entities

Post marketing: Ongoing

In many cases, clinical trials of a compound will continue after a marketing application has been approved. There are several reasons for conducting post approval, or Phase IV, clinical trials. Some of the trials are conducted voluntarily by drug companies for various reasons such as collecting long-term safety and efficacy data or comparing the drug with other drugs on the market. Other Phase IV trials are required by regulatory authorities such as the FDA.

· The FDA regulations require investigators to report "unanticipated problems" to the reviewing IRB/IEC. An unanticipated problem is an event that is unexpected, serious, and has implications for the conduct of the study.

In most instances, a single AE would not be reportable as an unanticipated problem. Instead, investigators would usually report an analysis of aggregated AE data indicating an unanticipated risk. Investigators should refer to the policies of the IRB/IEC providing oversight of a clinical trial to determine how the IRB/IEC has incorporated this guidance into its policies and its reporting requirements of unanticipated problems.

Cumulative Effects

In some instances, an AE occurs only after a certain absolute dose level has been reached, whether it takes many single doses to reach this level or just prolonged administration. These tend to be specific types of events, such as cardiac toxicity with some classes of anticancer drugs, and should be monitored as indicated by the protocol

IDE Applications

In the US, clinical trials of investigational devices to satisfy a PMA cannot begin without an IDE unless the trial meets the exemption criteria or qualifies for an abbreviated IDE. An IDE may also be required for clinical trials studying substantial modification to, or new intended uses for, devices already on the market. The sponsor is required to submit an IDE application to the FDA for approval before beginning a clinical study

Where is information on storage requirements for the investigational product usually found?

In the study protocol

According to the US Public Health Service, the definition of the term "investigator":

Includes anyone involved in the conduct or reporting or research

National Institutes of Health (NIH)

Includes funding agencies that provide federal funding for biomedical 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

Which of the following statements is true regarding the International Committee of Medical Journal Editors guidelines?

Individuals who do not meet the criteria for authorship but who have made a noteworthy contribution are normally listed in the acknowledgements section

Which of the following best describes the principle of Respect for Persons as described in the Belmont Report?

Information, comprehension, voluntariness

21 CFR 50

Informed Consent

What is included in the Nuremberg Code?

Informed consent

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

21 CFR 312

Investigational Drugs and Biologics

21 CFR 812

Investigational Medical Devices

Who has ultimate responsibility for an investigational product?

Investigator

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

The __________________ __________________ and the background section of the protocol delineate known effects of the investigational agent, anticipated side effects derived from preclinical studies, and what is know about similar drugs. Current literature and package inserts of FDA approved drugs also provide information about the known effects of a particular drug

Investigator's Brochure (IB)

Delegation of authority

Investigators may delegate responsibilities to appropriately qualified persons. This must be documented in writing, usually with a delegation of authority log that contains the names of study staff members and the responsibilities assigned to them, with their signature and date as well as the PI's initials and date. The investigator is still ultimately responsible for the conduct of the study, and is responsible for supervising and/or training any individual to whom he/she delegates tasks

Which of the following statements is true regarding the reporting of outside interests and the management of conflicts?

Investigators must disclose their significant financial interests related to their institutional responsibilities and not just those related to a particular project

ICH E6 describes standards that apply to:

Investigators, sponsors, and IRBs

The National Commission (1975-1978

Issued a series of reports on vulnerable populations (such as fetuses, children, prisoners, and the "mentally infirm") psychosurgery, IRBs, and other topics that included recommendations for regulating human subjects' research. These recommendations had significant influence on the development of the federal regulations governing human subject research.

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

What is the main function of a Technology Transfer Office with respect to collaborative research?

It helps collaborative researchers to commercialize their work

What is the status of ICH in US

It is a FDA guidance

Which statement most accurately describes a conflict of conscience?

It occurs when an individual's personal beliefs could affect the performance or outcome of research

Which statement most accurately describes a conflict of commitment?

It occurs when outside activities interfere with one's responsibilities to an employer

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

According to the US Federal Research Misconduct Policy, falsification involves:

Manipulating research materials, equipment, or processes, or changing or omitting data

Which of the following statements is true?

Many institutions have conflict of commitment policies even though they are not strictly required to by federal agencies.

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

Which of the following statements most accurately describes the mentoring relationship?

Mentors teach trainees about aspects of academic life that are not covered in textbooks

A primary purpose of the ICH is to:

Minimize the need for redundant research

mild AE

Minor signs/symptoms; no specific medical interventions required; asymptomatic laboratory findings only; radiographic findings only; marginal clinical relevance An awareness of symptoms but easily tolerated

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.

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

Senior author

Normally the head of the research team, is often the corresponding author, and in some disciplines, the last author. As a result, in some disciplines, it is assumed that the last author position carries significant status whether or not it is the authors' intention.

Which of the following is the most appropriate way to handle a conflict of conscience relating to a project?

Notify relevant parties that a conflict may exist and seek advice about whether to accept or decline the project

Organizations receiving HHS funds for human subjects research must file a Federalwide Assurance (FWA) with OHRP. By filing an FWA, the institution assures OHRP that it will follow the regulations for human subject protections and ethical principles and that it will maintain and comply with required standard operating procedures. OHRP has jurisdiction over human subjects research conducted at the organization.

OHRP has a compliance division that conducts inspections, primarily of institutions, to determine whether the institution is complying with the 45 CFR 46 requirements.

Rechallenge

One method to determine causality is to discontinue the agent, allow the event to resolve or stabilize, and reintroduce the agent. If the AE recurs, it is highly likely related to the investigational agent

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

Under which of the following conditions is it appropriate to re-contact the individuals who provided biological specimens?

Original signed consent documents include provisions for recontacting subjects

U.S. Food and Drug Administration (FDA)

Oversees the use of all drugs, devices, biologics, etc. including their use in research with human subjects

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

Periodic site visits

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

Technological Issues

Pertain to the use of the available tools and processes for managing information throughout a research project's lifecycle and after the project concludes. This is sometimes called data lifecycle management. Its main goals are to ensure data confidentiality, integrity, and availability for as long as the data exists. Achieving such goals requires a combination of measures, which balance prevention, detection, and response to problems.

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

Clinical Trials: 6-7 years

Phase I: Goals: Assess toxicity, determine drug's pharmacokinetic and pharmacodynamic profiles, determine doses resulting in sufficient biological level of drug Subject Population: Normal healthy volunteers unless toxicity prevents exposure (for example, cancer drugs). In this case, patients with end-stage disease might be enrolled. Phase II: Goals: Determine drug's short-term risks (safety) (primary goal), examine preliminary effectiveness of drug Subject Population: Controlled studies enrolling limited numbers of patients Phase III: Goals: Determine drug's effectiveness (primary goal), determine long-term drug safety, confirm Phase II findings Subject Population: Controlled and uncontrolled studies (but typically placebo-controlled and double-blinded) enrolling larger patient numbers and seeking to confirm results of Phase II trials

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

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

According to US Federal Research Misconduct Policy, which of the following is considered to be research misconduct?

Plagiarism

Which type of inappropriate practice most likely occurred if a researcher takes credit for someone else's idea and does not acknowledge the original source?

Plagiarism

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.

Long-term toxicology of an experimental drug in animals most likely refers to which part of drug development?

Preclinical

For a Phase I new drug study in humans, what is the primary source of the data included in the initial IB?

Preclinical data

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

Which of the following represents plagiarism?

Presenting someone else's ideas or words and claiming them as one's own

Which monitoring visit would not include an inventory of investigational agents?

Prestudy site visit

A subject presents to the ED with complaints of chest pain and shortness of breath. Blood studies are positive for a heart attack and the subject is hospitalized. The subject has a history of coronary artery disease. The subject reports to the ED nurse that he is currently enrolled in a Phase I study of a new lipid lowering agent. Which individual should determine causality of the serious adverse event?

Principle Investigator

The use of prisoners in research is a concern under the Belmont principle for Justice because:

Prisoners may not be used to conduct research that only benefits the larger society

Broad consent

Prospective consent for unspecified future research

OHRP is an oversight body primarily concerned with:

Protection of human research subjects

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

detrimental research practices

Questionable research practices: behaviors that closely border on research misconduct but do not fall under its strict definition

What was the result of the Beecher article?

Realization that ethical abuses are not limited to the Nazi regime

Declaration of Helsinki (1964)

Recommendations guiding medical doctors in biomedical research involving human subjects

moderate AE

Requiring minimal, local, or noninvasive intervention only Symptoms interfere with normal daily activities

Under which circumstance does the FDA allow verbal consent prior to the participation in a research study?

The study is minimal risk

A subject of a research study is a passenger in a car involved in a motor vehicle crash. The subject sustained a broken wrist and mild concussion. The subject was treated and released from the emergency department. What should the investigator do when learning of the crash?

Report adverse events of both a broke wrist and a mild concussion

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

Subject 311 has had elevated WBC counts for the past 2 study visits, with no clinical signs or symptoms. Increased WBC count is not listed on the IB as an AE. The investigator should:

Report the elevated WBC to the sponsor as an unexpected AE

Investigator initiated trial (IIT)

Researchers who design and conduct their own studies assume responsibility of the researcher and the sponsor

Multidisciplinary collaboration

Researchers work on a problem within their own discipline-based perspectives in parallel with others, fitting their respective results together at the end of a project.

Which of the following are the three principles included in the Belmont Report

Respect for Persons, Beneficence, Justice

Informed consent is considered an application of which Belmont principle?

Respect for persons

What are the three principles discussed in the Belmont Report?

Respect for persons, beneficence, justice

42 CFR 50, Subpart F

Responsibility of applicants for promoting objectivity in research for which PHS funding is sought.

US Department of Health and Human Services

Responsible for 45 CFR 46

45 CFR 94

Responsible prospective contractors to NIH

When the FDA conducts an inspection, the inspectors will:

Review regulatory records

When a ________ occurs, it is always wise to stop use of the investigational agent immediately, as directed by the protocol, until the event can be evaluated and resolved.

SAE

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

Once IRB/IEC approval is obtained and other institutional prerequisites have been satisfied, the study can begin at the investigator's site. The sponsor organization will initiate a site through a _________ or other mechanism. At this initiation stage, the protocol, data-collection instructions, and regulatory obligations will be reviewed. Once a site is initiated, study product may be shipped to the site and subject recruitment may begin.

SIV

510(k) Devices

Section 510(k) of the Food, Drug, and Cosmetic Act requires a manufacturer to submit a Premarket Notification to the FDA at least 90 days in advance when the manufacturer wishes to market many Class I devices that are not exempt and all Class II devices in the US. The 510 (k) must show that the device to be marketed is substantially equivalent to a legally marketed similar device by demonstrating that the new device is as safe and effective as the legally marketed device. Occasionally, the FDA will require a clinical investigation to determine the substantial equivalence.

1) An elderly gentleman, whose wife is his LAR since his stroke several years ago, was recently diagnosed with lung cancer. He is eligible for a clinical trial using a new investigational drug that aims to treat lung cancer. He is able to express interest, shows a basic understanding of the nature of the trial, and gives his assent to participation. The subject's wife is out of town on a business trip. Which of the following is the most appropriate action to take for the investigator?

Send a copy of the informed consent via facsimile to the subject's wife. After she has had the opportunity to speak to the investigator, she can sign the informed consent and fax it back.

The ICH GCP guidelines:

Set standards for the design, conduct, monitoring and reporting of clinical research

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

Government funded research

Since the passage of the Bayh-Dole Act and the Federal Technology Transfer Act, US academic researchers and universities have been able to patent the results of federally-funded research and license the patented technology to others for commercial development. When academic researchers patent promising research findings, ownership of the patent and the income that it produces are usually divided between the researcher or research team and the university.

When should the sponsor-monitor conduct the most detailed review of the study protocol with the site's study staff?

Site initiation visit

Exempt Class I Devices

Some Class I devices are considered exempt. Premarket notification and application to the FDA for exempt devices is not required. Instead, the manufacturer is required to register its establishment and list its generic product with the FDA. Examples of exempt devices are manual stethoscopes, mercury thermometers, and bedpans.

Which of the following is most directly related to successful mentoring?

Someone who is committed to the professional development of the trainee

Evaluation of Unanticipated Adverse Device Effects (UADEs) must be reported to the FDA by the:

Sponsor

The investigator must report adverse events to the:

Sponsor

Form FDA 1572

Statement of Investigator 1) The agreement between the researcher and the sponsor assuring compliance with FDA regulations. 2) The document that notifies the FDA of relevant changes in researchers conducting clinical trials under the IND * only used in clinical investigations of drugs and biologics, not devices

Researchers may not participate in an investigation subject to IND regulations until they sign and submit to the sponsor the

Statement of the Investigation, Form FDA 1572

During the course of administration of an investigational drug, the following events occurred: On Day 7, subject 603 had an unexpected stroke that required hospitalization. On day 15, subject 415 complained of nausea, vomiting, and headache relieved by aspirin; On day 21, subject 20 has brief dizzy spells upon trying to stand. Which of these subject's events meets the FDA definition of serious and unexpected and would require the sponsor to file an IND Safety Report with the FDA?

Subject 603 only

Which of the following is an investigator's commitment to the sponsor?

Submit a new Form FDA 1572 to the sponsor as needed

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

Many universities have ______________ ___________ ________ that identify research projects with potential for commercialization

Technology Transfer Offices Tech transfer" facilities research collaborations that can make financial profit for institutions and researchers by bringing new findings to market.

Some medical devices are considered combination drug-device products because a medicinal component is coupled with the device. An example of such a combination product is a bandage impregnated with an antibacterial agent or a drug-eluting stent.

The FDA considers the primary mode of action to determine which center (Center for Biologics Evaluation and Research, Center for Drug Evaluation and Research, or Center for Devices and Radiological Health) has jurisdiction for review and regulation of the combined product. The FDA Office of Combination Products was established to assist agency reviewers and industry; it assigns an FDA center to have primary jurisdiction for review of both combination and single entity products where the jurisdiction is unclear or is dispute

Regarding subject receipt of a signed and dated copy of the consent forms, which is true about FDA regulations?

The FDA regulations allow subjects or the LAR to receive either a signed or unsigned copy

Exemption from IND submission requirements does nor mean exemptions from IRB review and approval or from the requirement to obtain informed consent.

The FDA should be consulted in there are any changes to the research that may affect the IND exemption status

The investigator's brochure (IB) is a compilation of the pre-clinical and clinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/intervals, methods of administration, and safety monitoring procedures

The IB is generated initially from the preclinical data. As new, relevant data is generated during drug development, the IB is updated. The sponsor is responsible for initiating and updating the IB and making it available to investigators participating in clinical studies of their product(s)

Before an investigational product can be shipped to an investigator, the research sponsor must file Form FDA 1571 or an Investigation Device Exemption (IDE) application

The IND and IDE application outlines the general investigational plan for the development of the drug or device. Amendments to the IND and IDE application are made as the product moves through the clinical development process

Premarket Approval (PMA)

The PMA application is the FDA's process of scientific and regulatory review to evaluate the safety and effectiveness of the Class III medical devices. Due to the level of risk, the FDA has determined that general and special controls alone cannot ensure the safety and effectiveness of Class III devices. Therefore, those devices require a PMA to obtain marketing approval, versus premarket clearance for 510(k)

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

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

If the blinding code needs to be broken in accordance with the protocol, the investigator should document an explanation of any premature unblinding and promptly report it to the sponsor.

The code should be broken only when the identify of the investigational product that the subject received will determine the treatment to be given to that subject for an emergency.

genetic determinism

The concept that the control of genes confers great power than can be used or misused

Which of the following financial conflict of interest information must be made available by institutions on a public website or within 5 business days upon request?

The financial conflicts of interest of senior/key personnel on projects funded by the US PHS

Corresponding author

The individual designated to receive the bulk of a paper's reprints and whom those interested in obtaining a printed or an electronic copy of the paper should contact. This person may or may not be the submitting author, the senior author, the first author, or the last author.

Source Document

The initial documentation of data in a clinical study and includes recorded observations, laboratory reports, medical records, etc.

An investigator is confronted with a life-threatening situation that necessitates using a test article in a human subject who is unable to provide informed consent and there is no time to obtain consent from the individual's LAR and no alternative method or recognized therapy is available. Under the FDA regulations for using test articles, which of the following describes the best course of action for the investigator:

The investigator and an independent physician agree that the situation necessitates the use of the test article. An exception or waiver for informed consent can be made under these circumstances. The IRB will be notified later.

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

IRB/IEC Submissions and Approval

The investigator is required to submit all investigational materials to the IRB/IEC for approval. These include the protocol, informed consent form, investigator's brochure, subject recruitment material, and any written information to be provided to the subjects. Each IRB/IEC may have additional requirements based on the type of investigation being conducted. Once IRB approval is obtained, the investigator notifies the sponsor organization If the IRB/IEC does not approve the study, requires additional information, or requires changes to the consent form or protocol, the investigator should notify the sponsor who will assist the investigator in responding the IRB/IEC queries

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

Which of the following is most likely to own the data resulting from a research project?

The organization that receives federal funding for a project.

When the subject agrees to the subject's participation in the trial, consent is documented by having the subject personally sign and date the consent form. It is important that the person obtaining consent use the most current IRB/IEC-approved version of the consent form

The person obtaining consent should also sign and date the consent form. The FDA regulations require the subject receive a copy of the signed and dated consent form. The informed consent process should be documented in the medical record or source file.

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

Informed consent

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

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

For regulatory purposes, the FDA categorizes medical device clinical investigations by the amount of risk they pose. The sponsor initially suggest a risk category for the device involved in the investigation, either as significant risk device or as non-significant risk device.

The reviewing IRB/IEC indicates whether it agrees with the sponsor risk category for the investigation. If the IRB/IEC does not agree with the non-significant risk category determination, the sponsor must submit an investigational device exemption (IDE) to the FDA and receive FDA approval before the investigation can begin

Identify which party is responsible for reporting directly to the FDA the investigator's financial interests with the sponsor:

The sponsor

Sponsors may perform audits as part of implementing quality assurance.

The sponsor may perform a root cause analysis and implement corrective and preventative actions if noncompliance affects human subject protection or reliability of trial results. Noncompliance findings may lead to serious consequences if the sponsor determines the noncompliance to be serious and continuing. This may include at the extreme the termination of the study at the site and notification to regulatory authorities

Who is responsible for making the initial risk determination for a device being used in a study?

The sponsor-investigator

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

Which of the following is an acceptable criterion for determining that a study of an approved drug does not require an IND?

The study is not intended to be reported to FDA to support a new indication or support a labeling change

When evaluating the causality of an adverse event, which of the following should be a consideration?

The timing of the event in relation to administration of the investigational agent

In any collaboration, data ownership is typically determined by:

The type and source of funds used to support the project

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

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.

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.

This is an unanticipated problem

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

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

Methodological Issues

Those associated with ensuring that a research study is well-deigned with respect to statistical analysis

Which choice best describes the purpose of most pharmacogenomic research?

To evaluate the association between individual genotypes and the safety and efficacy of a particular drug or class of drugs

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

Types of on-site monitoring visits:

Types of on-site monitoring visits: o The pre-study site visit: Used to determine qualified candidates for running the study The three main objectives of pre-study visits are to: 1) Assess an investigator's interest in conducting the study 2) Evaluate the facility and the staff, determining if they have the capacity to successfully conduct the trial 3) Determine whether they will be able to meet recruitment goals o Site initiation visit: the primary objective is train the investigator and study team to conduct the trial according to protocol requirements o Periodic site visits o Study closeout visit: the objective is to ensure that the site has fulfilled all of its responsibilities for the study

Issued in 1974, 45 CFR 46 raised to regulatory status:

US Public Health Service Policy

_____ _________________ typically govern collaborative research funded by US federal agencies wherever the research takes place.

US Regulations

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

Unanticipated adverse device effects

Unanticipated problems in device research

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

Unless the FDA has already determined the risk category for the study, the IRB reviews the sponsor-investigator's SR or NSR determination for every investigational medical device study. If the IRB disagrees with the sponsor-investigator determination, it will alert the sponsor-investigator that a change is required. If the FDA has already made the SR or NSR determination for the study, the Agency's determination is final.

Which of the following is most likely to be considered plagiarism?

Using materials from a source without proper citation

In the US, following the ICH E6 guideline is:

Voluntary for FDA-regulated drug studies

New Drug Application (NDA) submission: 6 months-2 years

When sufficient data has been obtained to provide evidence of safety and efficacy, the sponsor submits the results of the trials to the FDA as part of a NDA that requests a permission to market the product on the US. The FDA reviews the application. Only after FDA approval of the NDA can the drug be sold to consumers.

A 510(k) Premarket Notification is submitted:

When the new device to be marketed is substantially similar to one already on the market

In the research context, the term validity most commonly refers to:

Whether operationalized terms actually measure what they purport to measure

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

Humanitarian Use Device (HUD)

a device that is intended to benefit patients in the treatment or diagnosis of a disease or condition affecting fewer than 8,000 individuals in the US per year

· When the intent of the physician is to practice medicine and not conduct clinical research, the use of a marketed drug by the physician for a non-approved FDA indication does not require the submission of an IND if:

a physician uses a product for an indication not listed in the approved labeling, the physician has the responsibility to be well informed about the product and to base the proposed use on scientific rationale and medical evidence

The Bioresearch Monitoring Program

a program of the FDA's Office of Regulatory Affairs (ORA) was established to routinely inspect clinical investigators, investigative sites, IRB/IECs, sponsors/CROs/monitors, and nonclinical laboratories to assess adherence to regulations and protection of human research subjects. The clinical investigator inspections usually take place after the New Drug Application or Premarket Approval has been submitted to FDA for marketing approval. Additionally, extensive inspections are required when there is evidence of research misconduct.

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

The purpose of informed consent is:

a. To provide a potential subject with appropriate information in an appropriate manner and allow that person to make an informed decision about participation in research.

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.

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.

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

A serious adverse event (SAE) or serious suspected adverse reaction:

an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or sponsor, it results in an of the following outcomes: 1) Death 2) A life threatening AE 3) Inpatient hospitalization or prolongation of existing hospitalization 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect

Recognition of the contribution of individuals or groups that does not meet the criteria of authorship is usually given in the form of:

an acknowledgement

Humanitarian Device Exemption (HDE)

an application that is similar to a premarket approval (PMA) application, but for which the manufacturer does not need to provide evidence of efficacy. HDEs are subject to restrictions on profitability and can only be used in a facility after an IRB/IEC has approved their use in that facility, except in certain emergencies

Transdisciplinary research

an even more collaborative form of work, in which researchers approach a common problem from an integrated conceptual framework, identify discipline-based methods and approaches that they can take together, and redefine both the problem and its solution accordingly.

Sponsor-investigator

an individual who both initiates and conducts the clinical investigation and under whose immediate direction the investigational drug or device is being administered, used, or dispensed. The sponsor-investigator assumes all of the responsibilities of the sponsor as well as all the responsibilities of an investigator as outlined in the Form FDA 1572. Usually, the intent of the sponsor-investigator trial is to gain scientific knowledge without seeking market approval for the drug or device. These are considered investigator-initiated or sponsor-investigator trials.

SR device

an investigational device that is implanted and presents a potential for serious risk to the health, safety, or welfare of a subject; those that support or sustain human life and present the potential for serious risk to the health, safety, or welfare of a subject; is very important in diagnosing, curing, mitigating, or treating disease or preventing impairment to human health, and presents the potential for serious risk to the health, safety, or welfare of a subject; or otherwise presents a potential for serious risk to the health, safety or welfare of a subject. Examples of SR devices include: sutures, cardiac pacemakers, hydrocephalus shunts, and orthopedic implants.

Suspected Adverse Reaction

any AE for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of an IND safety reporting "reasonable possibility" means there is evidence to suggest a causal relationship between the drug and the AE.

Unanticipated adverse device effect

any serious adverse effect 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 (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. The investigator reports UADEs to the sponsor and the local IRB. The sponsor transmits evaluation of these reports to the FDA.

Unanticipated Adverse Device Effects (UADE)

any serious adverse effect 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.

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

To be "legally effective" consent must be obtained from the individual who has authority to give consent. If the individual has the ______________ to consent, it is that individual who should give consent. In situations where the individual is unable to consent on his or her own behalf, consent must be obtained from a person who has the authority in compliance with applicable law of the jurisdiction where the research will be conducted. Investigators should be aware of the local law requirements for inclusion of subjects who are unable to consent on their own behalf and any local law restrictions

capacity

Fatal AE

causing death

Medical devices are classified according to the risk they pose. The classification of a device will direct the type of _______________ required for marketing and will also determine whether the sponsor must obtain approval from the FDA to conduct a clinical trial

clearance

· 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

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.

Community partnership

collaborations between researchers and community groups, civic associations, non-governmental organizations, and local service agencies that address problems in the community.

HHS regulations at 45 CFR 46 require that information be presented to the subject in an understandable way that facilitates ______________________

comprehension

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.

Before an IRB/IEC can approve a clinical trial, the IRB/IEC must determine that the _____________ process and all written documents are compliant with regulations and ethical principles. The IRB/IEC must provide written approval for the informed consent process (including the ICF and all written materials provided to a subject) for a study before study initiation. If the trial is conducted under ICH E6, the IRB/IEC must also determine that the additional requirements found in this guideline are satisfied. Because the consent process begins with recruitment, the IB/IEC will consider the recruitment methods and materials in its review process

consent

ICH E6 has different requirements for the_________ ___________and documentation, including required signatures, required impartial witness for subject who cannot read, not allowing short form consent, required disclosure to subjects about third party access to their medical records, information about prorated payments, and include treatment alternatives' risks and benefits. ICH E6 also requires the consent form to include a description of each arm of the study, the likelihood of being assigned to each of the study arms, and an explanation of the subject's responsibilities.

consent process

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

21 CFR 803 (Medical Device Reporting)

covers reporting of AEs for approved products (and HUDs)

21 CFR 54 (Financial Disclosure by Clinical Investigators)

covers the disclosure of possible financial conflict of interest by clinical investigators

21 CFR 814 (Premarket Approval of Devices)

covers the procedure for obtaining approval to market certain devices and HDEs

21 CFR 56 (IRB)

covers the procedures and responsibilities for IRBs that approve clinical investigational protocols

21 CFR 812 (IDE)

covers the procedures for the conduct of clinical studies with medical devices, including application, responsibilities of sponsors and investigators, labeling, records, and reports.

45 CFR 46 (Protection of Human Subjects)

covers the protection of human research subjects in federally funded research projects. 45 CFR 46 was revised in 2017 and differs slightly from the FDA regulations for the protection of human subjects. It is important to know the differences and when each regulation applies in order to remain in compliance

An increasing number of US funding agencies require an overall _________ ________________plan for projects that they fund.

data management

In February 2012, the FDA also issued Guidance for Sponsors, Investigators, and IRBS- Questions and Answers on Informed Consent Elements, 21 CFR 50.25, which provides guidance on the regulatory requirement that informed consent documents and processes for applicable drug and device clinical trials include a specific statement that clinical trial information will be entered into a _________________

databank

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

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

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

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

As of January 2015, the NIH expects investigators to obtain the informed (valid) consent of research participants in NIH -funded genetic research for broad research use of data and data sharing, even if the cell lines or specimens are:

deidentified

Pharmacokinetics

describes how the agent moves through and is excreted from the body

ICH E8 Guidance on General Considerations for Clinical Trials

describes the drug development process and ICH expectations for establishing the safety and efficacy of investigational agents

21 CFR 820, Subpart C (Design Controls of the Quality System Regulation)

details requirements to ensure that specified design requirements are met

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

Investigator-oriented inspections

directed at the specific clinical investigator conducting the trial. Typically, these inspections occur when there are complaints of known or suspected misconduct, such as fraud, falsification, or data fabrication.

Study-oriented inspections

directed toward review of study data supporting a pending marketing application, such as: 1) New Drug Applications 2) Premarket Approval applications 3) Bioequivalence (for abbreviated NDAs) Although the primary objective of this type of inspection is to verify data submitted to the FDA, all other study-related practices are also inspected, such as protection of human research subjects and compliance with regulations. FDA typically inspects the top enrolling sites and randomly picks 10 percent of the remaining sites for inspection.

· When an AE is detected, it may require treatment. Generally, a medically qualified individual should recommend or administer treatment according to the standard of care. Often the protocol will anticipate certain reactions and provide guidelines for ______ _____________or specific treatment if AEs occur.

dose reductions

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

Belmont Report (1979)

ethical principles and guidelines for the protection of human subjects of research.

Conflicts of Conscience

exist when an individual's personal, religious, or other beliefs might interfere with the ability to perform job duties objectively. This can occur when service on an institutional committee might conflict with one's beliefs or when researchers are asked to collaborate on research that might conflict with their personal views.

Conflicts of Commitment

exists when individuals have difficulty balancing the effort necessary to perform their job duties while engaging in other activities that may or may not be job-related. This type of conflict can also occur when a competing influence affects an individual's research or work output. In this case, the individual would have a conflict regarding the completion of two separate yet important tasks.

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

· Public trust in the integrity of research depends upon the existence of an effective process for identifying ___________ COIs and acting to promote and maintain objectivity in the research.

financial

The investigator is also required to provide sufficiently accurate _______________ _____________ information to allow the sponsor to submit a complete disclosure statement as required by 21 CFR 54 and to update the financial disclosure information if any relevant changes occur

financial disclosure

If the trial is prematurely terminated or suspended, the institution should promptly notify subjects in the study. In addition, the investigator/institution should be certain that appropriate therapy and ________-____ are provided for the subjects. Where required by regulations, the investigator/institution may also need to inform the regulatory authorities of the premature termination or suspension of the trial.

follow-up

· The FDA's Bioresearch Monitoring Program conducts ______ ______ and _____ ______ _____ inspections of IRBs, clinical researchers, and sponsors

for cause & not for cause

IRB continuing review of a greater than minimal risk approved protocol that is currently enrolling subjects must:

occur at least annually

The ownership and sharing of data generated in federally-sponsored research is regulated by the _________ _________

granting agency

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

A life-threatening adverse event or life-threatening suspected adverse reaction means an AE or suspected adverse reaction is considered life-threatening if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at ______________ risk of death. It does not include an AE or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.

immediate

If a subject is unable to read, an ______________ __________ should be present during the consent discussion and personally sign and date the consent form as an indication that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject, and that informed consent was freely given by the subject.

impartial witness

Drug Supplier/Manufacturer

in addition to producing the drug, the company also supplies the investigator with the drug for use in the study

respect for persons

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

Three elements of the consent process

information, comprehension, voluntariness

If the sponsor terminates or suspends a trial, the investigator should promptly inform the _______________where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or

institution

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 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

If the investigator terminates or suspends a trial without prior agreement of the sponsor, the _____________________ should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension

investigator

Investigators can delegate the responsibility of product accountability to qualified personnel, such as the pharmacist or study coordinator. However, the _________________ remains ultimately responsible for the disposition of all investigational products provided by the sponsor for the study

investigator

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

· 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

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

The investigational product shipment will usually include a packaging list or shipping invoice. The ______________________ must verify that the shipment arrived intact and that the contents match the shipping invoice. This is the beginning of the investigator's paper trail detailing the control and disposition of the investigational product

investigator

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

Issued by the Office of the Secretary of the US Department of HHS and the PHS, the 1995 regulations apportioned responsibilities between institutions receiving PHS research funding and the ______________ involved in the research, to promote objectivity by disclosing, managing, and reporting, if not eliminating, significant financial interests that constitute financial conflicts of interest

investigators

Collaborative research

joint work on a research project or program that benefits from the knowledge, perspectives, and resources of many individuals, disciplines, or organizations.

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.

Facilitating _______________ relationships is one way that organizations can develop a sense of community and mutual respect

mentoring

Many organizations and governmental agencies look to _____________ to broaden the representation of minorities and women in research professionals, and may programs have been developed to correct the imbalance in mentoring opportunities.

mentoring

· 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

Periodically during the trial, the sponsor organization will contact or visit the site and________ the study's progress. During site visits, the sponsor representative will review and retrieve data, address data discrepancies, inventory drug and study supplies, and review the study records

monitor

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 The FDA regulations at 21 CFR 312.50 only states that the sponsor is responsible for ensuring proper monitoring of the investigation

monitors

Additional criteria influence site selection for inspections including the following:

o # of patients enrolled o The frequent occurrence of "outlier" data o High/low numbers of subjects responding to the study treatment o High number of dropouts o High number of AEs o High number of protocol violations o The volume of work performed by the clinical investigator o Conducting research outside of the investigator's specialty o The site's past inspection history

Institutions must review investigators' disclosure of travel reimbursed or sponsored by an outside entity and determine whether it represents an FCOI with PHS-supported research. The disclosure must include the sponsor, destination, duration, and purpose of the travel. Institutions have the discretion to request additional information from the investigators, including the monetary value of the travel. Excluded from the disclosure requirement is travel sponsored by:

o A US federal, state, or local government agency o A US institution of higher education as defined at 20 USC 1001(a) o A US academic teaching hospital o A US medical center; or o A US research institute that is affiliated with an institution of higher education

After the inspection, the FDA investigator who conducted the inspection prepares a written Establishment Inspection Report (EIR). After the EIR is filed with the FDA, one of the following letters may be sent to the clinical investigator:

o A letter that the FDA observed basic compliance with pertinent regulations and no violations were observed. o An informational or Untitled Letter that identifies deviations from statutes and regulations that do not meet the threshold of regulatory significant for a Warning Letter. o A warning Letter that identifies serious deviations from statutes and regulations. Warning letters will include a request for correction and a written response to the agency. FDA Warning letters are posted on the FDA website

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

The principles of being a responsible researcher alone impose obligations to stare data with others, provided there are no legal or regulatory constraints that apply to the research. The primary motivation for sharing is the same: o Allows for the replication of research

o Allows for the replication of research o Enables others to confirm if data support a conclusion o Allows them to build on prior research more easily and accurately

Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any AE caused by a drug. Examples of evidence that the drug "caused" the AE include:

o An event that is uncommon and known to be strongly associated with drug exposure such as angioedema, hepatic injury, or Stevens-Johnson Syndrome. o One or more occurrences of an event that is not commonly associated with drug exposure, but is uncommon in the population exposed to the drug such as tendon rupture o An aggregate analysis of specific events that indicates that a specific type of event occurs more frequently than previously known

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

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

The FDA places medical devices into 3 general classes for regulatory purposes: Class I, Class II, and Class III. Devices are classed according to the level of control needed to ensure their safety and effectiveness, as described below. This in turn affects the regulatory pathway that must be followed to gain marketing approval

o Class I devices: lowest risk devices and are governed by general controls (that is, Establishment Registration, Device Listing, Compliance with Good Manufacturing Practice (GMP) regulation, labeling, and Medical Device Reporting (MDR) of death or serious injuries). Examples of Class I devices are surgical gloves and tongue depressors o Class II devices: moderate risk devices and are subject to both general controls and special controls such as specific FDA performance standards, post-market surveillance, or special control guidance to ensure their safety and effectiveness. Examples of Class II devices are flexible laryngoscopes and surgical drills. o Class III devices: highest risk devices. General controls and special controls alone are not adequate to ensure their safety and effectiveness. These devices therefore require a stringent premarketing approval application to be filed before they can be sold in the US. They generally are devices that: Support or sustain life Are of substantial importance in preventing impairment of health Present a potential, unreasonable risk of injury or illness Examples of Class III devices are artificial organs, replacement heart valves, and pacemakers

Compliance with GCP includes IRB review and approval and obtaining informed consent from subjects. There are exceptions to conducting an investigation in accordance with GCP, and a sponsor may request a waiver under certain circumstances. · This rule applies to:

o IDE application o Premarket notification (510(K)) submission o Request for De Novo classification o Premarket approval application o HDE application o Product development protocol (PDP) application

International Council for Harmonisation (ICH)

offers GP guidelines

21 CFR 11 (Electronic Records) was intended to enable the use of electronic documents in the regulator process for drugs and devices. Part 11 specifies processes that must be in place assuring that electronic documents and signatures are equivalent to paper documents and handwritten signatures. For systems to comply with Part 11, a number of requirements must be met:

o Computer systems utilizing electronic records and signatures must ensure accuracy, reliability, and consistence performance. SOPS, audits, testing, and training are required o 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 o Computer systems must use system checks ensuring that only those individuals authorized to use the system are allowed access to the system, alter records, and perform operations. o 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

Planning out a research study may also include the purely technological information technology aspect of data management. It is common to pursue three main goals:

o Confidentiality: preventing inappropriate users or uses of the data. It is usually discussed within the context of protecting the privacy of research subjects, which is a regulatory and ethical requirement if those subjects are human beings. Confidentiality also involves protecting intellectual property related to the research. o Integrity: The responsibility to record, store, and preserve data appropriately during the full lifecycle of a study, which helps to improve the accuracy of data analysis o Availability: refers to ensuring that the appropriate users have access to data whenever necessary. As with integrity, availability concerns can extend past the formal end of the study, to ensure access by others who wish to replicate the work

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

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.

Investigational drugs are dispensed and administered in many ways, some of which are listed below:

o Dispensed directly to the subject from the research pharmacy o Given to the study coordinator to dispense to the subject as directions for use are discussed o Administered in subject-patients o Given to the pharmacist to prepare for administration, such as IV formulations

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

During the inspection, the FDA investigator will:

o Evaluate the facility o Review regulatory records o Review subject records o Have discussions with key ancillary personnel (lab techs, pharmacists, coordinators, sub-Is) as needed o Evaluate investigational product accountability and control o Conduct an exit interview with the clinical investigator by reviewing Form FDA 483 (Inspection Observations) if applicable, and providing feedback about the inspection observations

At the end of the inspection, the FDA investigator will conduct an exit interview. If the FDA investigator determines the observations represent deviations from applicable statutes and regulations, he/she will issue a written Form FDA 483 (Inspectional Observations). Some common deficiencies noted during FDA inspections include:

o Failure to follow protocol or investigator statement on the Form FDA 1572 o Protocol deviations o Inadequate recordkeeping o Inadequate accountability of the investigational product o Inadequate subject protections including informed consent issues

According to ICH E6 all SAEs should be reported immediately to the sponsor except for those SAEs that the protocol or other document identifies as not needing immediate reporting

o ICH E6 goes on to note that the immediate reports should then be followed promptly by detailed, written reports. All reports should identify subjects by unique code numbers assigned rather than other identifiers o Investigators must also comply with applicable regulatory requirement(s) associated with the reporting of unexpected serious adverse drug reactions to the regulatory authorities and the IRB/IEC o The investigator's report of an SAE must include an assessment as to whether there is a reasonable possibility that the drug caused the event o If the SAE is a study endpoint, the investigator must report the event according to the requirements of the protocol. However, if there is a causal relationship between the drug and the event, the investigator must report the event to the sponsor immediately o The protocol will usually include additional reporting requirements, and investigators must be familiar with these requirements and submit the required reports whether or not the event meets the definition of serious as defined by the regulation. Generally, events that are non-serious are reported on the case report form (CRF)

· The following documents are generally required for drug or device studies during monitoring visits:

o IRB/IEC membership list/roster o IRB/IEC correspondence must be kept, including: 1) Submittal package 2) Initial and all subsequent approval letters 3) All study-related correspondence 4) Progress reports 5) Annual renewals/continuation reports 6) Protocol amendments 7) Safety reports 8) Reports of unanticipated problems 9) Final reports 10) Recruitment material/advertising o The IB o Investigator CV and medical licenses o All versions of the protocol and all amendments to the protocol o Form FDA 1572 (Statement of the Investigator) o All versions of the informed consent form o All completed informed consent forms signed by subjects o All correspondence o Investigational agent records o All shipping records o Accountability records o Disposition records o Signature list o Site delegation of authority list/log o Monitoring log o Screening list o Subject enrollment log o Subject identification code list provides contact info for all subjects o CRFs (blank) as a record of the variables collected for a study o CFRs (completed) for all subjects o Source records o Laboratory certifications o Laboratory normal value ranges

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

Investigators who are planning to participate in PHS-funded research must disclose the following AFIs to their institution no later than the time of applying for funding:

o Income in excess of $5,000 from a publicly-traded entity during the past 12 months o Stock valued in excess of $5,000 at the time of disclosure in a publicly-traded entity o A combination of the above two items that exceeds $5,000 o Any amount of equity in a non-publicly traded entity o Compensation that exceeds $5,000 from a non-publicly traded entity in the past 12 months o Income related to intellectual property rights paid by any source other than the investigator's current institution. o Reimbursed or sponsored travel paid by an entity, including non-profit organizations, but excluding travel sponsored or reimbursed by a US government agency, a US institution of higher education, or one of the following US institutions affiliated with a US institution of higher education: a research institute, a medical center, or an academic teaching hospital. The specific details that investigators must disclose are the name of an entity sponsoring the travel and the purpose, destination, and duration of the travel.

More serious violations may result in any of the following actions by the FDA:

o Initiation of investigator disqualification process o Rejection of study data o Deficiency letters o Withdrawal of the marketing application o Application of the Application Integrity Policy (AIP), primarily to research sponsors o Civil penalties o Seizure of the product o Injunction o Prosecution

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 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 4) The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial 5) Clinical trials should be scientifically sound, and described in a clear, detailed protocol 6) A trial should be conducted in compliance with the protocol that has received prior IRB/IEC approval/favourable opinion 7) The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist 8) Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s) 9) Freely given informed consent should be obtained from every subject prior to clinical trial participation 10) All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. This principle applies to all records referenced in this guideline. 11) The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s) 12) Investigational products should be manufactured, handled, and stored in accordance with applicable Good Manufacturing Practice. They should be used in accordance with the approved protocol 13) Systems with procedures that assure the quality of ever aspect of the trial should be implemented o Section 3: IRB/IEC o Section 4: Investigator 1) This section covers the role of the investigator regarding qualifications, resources, medical care of research subjects, interactions with IRBs/IECs, compliance with protocols, management of investigational products, informed consent of subjects, recordkeeping, and reporting. Any investigator conducting clinical research under ICH guidelines must comply with these standards. 2) The investigator is responsible for supervising any individual or party to whom the investigator delegates study tasks conducted at the trial site. If the investigator/institution retains the services of any party to perform study tasks they should ensure this party is qualified to perform those study tasks and should implement procedures to ensure the integrity of the study tasks performed and any data generated. o Section 5: Sponsor 1) This section lists specific requirements by the sponsor including implementing a quality management system throughout the design, conduct, recording, evaluation, reporting, and archiving of clinical trials. The ICH E6 guideline recommends the quality management system use a risk-based approach. 2) Although a sponsor may transfer any or all of their responsibilities and functions to a CRO, the sponsor should ensure oversight of the CRO and specify in writing what responsibilities are transferred. Further, the sponsor retains any trial-related duties not specifically transferred to the CRO. Sponsor responsibilities include: quality management, quality assurance and control, trial design, trial management, investigator selection, compensation to subjects and investigators, confirmation of review by IRB/IEC, supplying and handling the investigational product, adverse drug reaction reporting, monitoring, and auditing, among other responsibilities o Section 6: Clinical Trial Protocol and Protocol Amendment(s) 1) This section includes specific content standards for clinical trial protocols, including trial design. This section also suggests topics to be covered in the protocol, including: selection and withdrawal of subjects, treatment of subjects, safety and efficacy assessment, statistics, direct access to source data/documents, quality control and assurance, ethics, data handling and recordkeeping, financing and insurance, publication policy, and supplements o Section 7: Investigator's Brochure 1) This section includes specific content standards for the IB o Section 8: Essential Documents for the Conduct of a Clinical Trial 1) Summarizes the requirements for essential documents including the purpose of each record type, and the parties responsible for maintaining the records

For multicenter device investigations conducted inside and outside the US, the investigator/sponsor must state whether the:

o Investigations in the US complied with FDA regulations 21 CFR 50, 56, and 812 o Investigations outside the US complied with GCP and provide supporting information

According to 21 CFR 812.3(m) (Investigational Device Exemptions 2014), a SR device study is a clinical trial of a device that:

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

According to 21 CFR 312.2(b), investigations using a marketed drug or biologic do not require submission of an IND if all six conditions below are met:

o It is not intended to be reported to FDA in support of a new indication for use or to support any other significant change in the labeling for the drug o It is not intended to support a significant change in the advertising for the product o It does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risk(or decreased the acceptability of the risk) associated with the use of the drug o It is conducted in compliance with the requirements concerning the promotion and sale of drugs o It does not intend to invoke 21 CFR 50.24(exception from informed consent for emergency research)

Sponsors must have a systematic approach for accumulating and evaluating safety during a clinical investigation. This approach should include collection of data from various sources, including those listed below:

o Reports of events from investigators o Data from animal or in vitro studies o Reports in the scientific literature, and unpublished scientific papers (sponsors are required to conduct literature reviews at least annually) o Reports from foreign regulatory authorities and from foreign commercial marketing experience for drugs

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

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.

The FDA regulations require the label for investigation drugs to contain specific information. Labels on investigational drugs may differ in design but all such labels should contain the following minimum primary information:

o Name of the study o Name of the study drug (even the placebo is labeled with the study drug code) o Subject study number o How supplied (the number of tablets per container) o Dose per unit o Lot # o Batch # o A federal statement limiting use to experimental studies

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 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

· 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

Methodologic issues include choices about:

o Population and sample selection o Group assignment o Data collection o Data analysis o Data presentation

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 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

During the initial visit, the sponsor organization typically provides a study document storage unit. Site personnel must maintain the study records in this storage unit throughout the study. Examples of the records that must be maintained include:

o Protocol and any amendments o Investigator's Brochure o Sample and all approved versions of informed consent forms o Data-collection instructions o IRB/IEC submissions, correspondence, and approvals o Copy of Form FDA 1572 o Copies of FDFs o Subject recruitment and retention records o Investigational agent accountability records o Correspondence

· Organizations can facilitate the creation of productive mentoring relationships by implementing measures such as:

o Providing rewards to good mentors o Identifying poor mentors and taking steps to improve their behavior o Establishing procedures for reporting grievances or misconduct, and protecting those who report problems o Promoting a diverse, psychologically safe, and nondiscriminatory work environment

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

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)

The cornerstone of managing COI is transparency, which begins with the investigator's disclosure of SFIs that relate to the institution. An SFI is anything of monetary value, whether or not the value is readily ascertainable, that:

o Relates to the investigator's professional responsibilities on behalf of the institution including, professional practice, institutional committee memberships, and service on panels" o Belongs to the investigator or the investigator's spouse or dependent children

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:

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

Sponsors 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 determines that information received must be reported. In the US, these reports from the sponsor 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 receives the information

o Safety endpoints are not usually reported except as outlined by the protocol, unless the event occurred as a result of exposure to the study drug o Information that should be included in the report can be found in the applicable regulations and in ICH E2s Attachment 1 o ClinicalTrials.gov also requires reporting of summary information of AEs for registered trials per 42 CFR 11. The responsible party must submit information summarizing the number and frequency of AEs experienced by subjects in 3 tables, including: 1) One table summarizing all serious AEs 2) One table summarizing other AEs that occurred with a frequency of 5 perfect or more in any arm of the study 3) One table summarizing all-cause mortality by arm or group of the study

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

· Two categories of studies involving sponsor-investigators

o Studies involving investigational drugs or devices developed by the investigator Some investigator-initiated IND/IDEs that are submitted to the FDA apply to studies of drugs or devices that were developed by the investigators themselves. In these cases, an IND/IDE must always be submitted to the FDA before the study can begin. The sponsor-investigator then becomes the holder of the IND or IDE. o Studies involving a manufacturer's investigational or approved drug or device The majority of investigator-initiated and sponsor-investigator INDs submitted to the FDA are to investigate new uses, routes of administration, dosages, or patient populations, for currently approved drugs. When an investigator wants to study a new use of a significant risk device that has been cleared for use under a 510(k) or approved for marketing under a Premarket Approval (PMA), an IDE must always be submitted to the FDA before the study can be conducted

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 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

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

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

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 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

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?

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

§ The sponsor is required to obtain financial disclosures before an investigator can participate in the trial and is required to receive updated information for _________year following completion of the trial. Investigators are required to promptly update this information if any relevant changes occur during the course of the trial and for one year following the completion of the trial at a particular site.

one

__________ _______________ is purported to improve the quality of published papers as well as to conserve the amount of space available for the most selective and deserving papers in a given journal. The goal behind the __________ ______________ of grant proposals is to select the highest quality proposals for the limited amount of dollars available.

peer review

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

Conflicts of commitment can be just as problematic as FCOIs but are not as easily recognized or regulated. Federal regulations require institutions to have policies on FCOIs, but they do not require a policy on conflicts of commitment. Many institutions have their own _____________ and researchers should familiarize themselves with the requirements at their institutions.

policies

· 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

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

protocol

21 CFR 50 (Protection of Human Subjects)

provides the requirements and general elements of informed consent.

· 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

To be considered research misconduct, the behavior must have been performed "intentionally, knowingly, or _______________"

recklessly

Ethical, Legal-Regulatory, Professional, and Organizational Policy Issues

refer to what is required, recommended, discouraged, or prohibited by governmental entities and other organizations that have oversight over research activities, including an employer's standards

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.

Duplicate publication

republishing a significant portion of a paper or the paper in its entirety.

The FDA recommends that informed consent must be obtained before the subject participates in any procedures that are done solely for _____________ purposes, including determining eligibility for the study and withdrawing medication. However, procedures that are to be performed as part of the subject's medical care, and which would be done whether or not the participation in the trial were being considered, may be completed. The information may be used for determining eligibility, without first obtaining informed consent from the subject.

research

Investigational New Drug (IND) Application

research involving a drug or biologic that has not yet reached the marketplace or that studies a new use of the marketed product requires this per 21 CFR 312 This is submitted by the sponsor to the FDA

International research collaboration

researchers or sponsors from one country conducting or funding work in another

The consent document should be ___________ whenever there are changes or new information that might affect the subject's willingness to continue to participate. When the consent is revised, IRB/IEC approval of the revised document must be obtained. The revisions should be discussed with the subject. If the subject consents to continue participation, the subject should sign and date the revised document, and they should be given a copy of the signed and dated document.

revised

All responsibilities of the IRB/IEC according to 21 CFR 56 apply when reviewing clinical investigations of medical devices. In addition, if the sponsor plans to conduct the trial under the abbreviated IDE procedure, the IRB/IEC is responsible for verifying the _______ ____________ for the device being investigated. If the IRB/IEC finds that the device falls into the significant risk category, the IRB/IEC must notify the investigator and, if appropriate, the sponsor. In this situation, the investigation cannot begin until the FDA has reviewed and approved the research plan.

risk category

For reporting purposes, AEs are classified as life-threatening, ______________, or unexpected events

serious

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

The regulations require that devices be classified as:

significant risk or non-significant risk devices

severe AE

significant symptoms requiring hospitalization or invasive intervention Symptoms are incapacitating, with the inability to perform daily activities

Deferential vulnerability

similar to institutional vulnerability but the authority over the prospective subject is due to informal power relationships rather than formal hierarchies

An entity submitting an application to the FDA must submit the financial information listed above together with any significant payments or provision of items valued at $25,000 or more made by the ____________ to an investigator or the institution except for the costs of conducting the clinical study or other clinical studies.

sponsor

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

As data is accumulated, the __________ must have systems in place to evaluate and report the data. In most instances, the sponsor will submit a report when the analysis of accumulated data reflects new safety information. In rare instances, however, the sponsor will report a single event when it is evident that the event was caused by the drug and indicates previously unknown risk

sponsor

If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial, the investigator should inform the institution where applicable and the investigator/institution should promptly notify the _______________ and provide the sponsor with a detailed written explanation of the termination or suspension

sponsor

It is often unclear whether individual signs and symptoms should be recorded instead of grouping them into syndromes or general diagnosis such as rhinitis, cough, fever or cold. There is no standard guidance for recording these types of events. The _______________ of the research should specify what is appropriate to record for the particular protocol, so that the data are consistent across research sites.

sponsor

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

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 ____________-________________ and they must follow requirements for both investigators and research sponsors.

sponsor-investigators

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

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.

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

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

For research subject to 21 CFR 312, the sponsor cannot begin a clinical investigation until the UND is granted by the FDA and

the IRB approves the study

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.

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

Pharmacodynamics

the effects of the agent while in the body

Sponsor

the entity who takes responsibility for and initiates a clinical investigation. The sponsor can be any legal entity, including a company, an academic organization, or an individual. The intent of the sponsor's IND/IDE is to allow testing for marketing approval of the drug. These are generally considered commercial or corporate IND/IDEs. Note: the sponsor is often but not always the entity that funds the clinical research

Sponsor

the individual or company that takes responsibility for and initiates a clinical trial

Investigator

the individual who actually conducts the trial

Sponsor

the person who takes responsibility for and initiates a clinical investigation. They develop a research plan for the clinical investigation, which is then evaluated by the FDA. A sponsor can be a drug company, cooperative group, or even an individual physician

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.

Case Report Form (CRF)

the tool that is used to record data collected during a clinical trial. The CRF is submitted to the sponsor

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

Non-significant risk (NSR) Device studies

those that involve a device that does not pose a significant risk to subjects. Examples of NSR devices include: most daily-wear contact lenses and lens solutions, ultrasonic dental scalers, and temporary urinary catheters

The consent process should be conducted in the language spoken by the subject, and the consent form should be ____________ into that language. An IRB/IEC may require independent confirmation of the accuracy of translation if a consent form is translated. There should also be an interpreter available to translate questions and answers between the subject and the person obtaining consent.

translated

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

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

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.

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

IRB review and approval is required in all circumstances if the researcher:

wishes to use the data for research purposes

Subjects who cannot _________ their names can "make their mark" in the informed consent document, as long as it is consistent with applicable state laws.

write

nterdisciplinary collaboration

· More intentionally collaborative, with researchers working together on a common problem from their respective disciplinary perspectives.

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.

Adverse Drug Reaction (ADR)

· when identified before market approval means any noxious and unintended response to a medicinal product related to any dose; causal relationship between the medicinal product and an ADR is at least a reasonable possibility. ADRs identified after market approval are defined as any noxious and unintended response to a drug that occurs at doses normally used in individuals to prevent, diagnose, or treat disease or to modify physiological function