Good Clinical Practice

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

(3) there is a reasonable possibility that the drug caused the event. * The sponsor must submit an IND Safety Report to the FDA and all participating investigators if an adverse event is serious; unexpected; and there is a reasonable possibility that the drug caused the event (there is evidence to suggest a causal relationship between the drug and the adverse event). Whether the event resolves quickly is not a consideration for reporting. Events that are reasonably expected to recur could be considered "expected." Likewise, events listed in the Investigator's Brochure would not be unexpected.

The packaging of investigational drugs should ideally:

• Be designed to help with subject compliance * Packaging is an important part of the clinical research process. Many studies use specifically designed blister packages which can help subject compliance by providing packages that are easy to use, place one treatment under each dome, and have specific written instruction on the card so that subjects know exactly when to take their study drugs.

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

A systematic and independent examination of trial-related activities and documents. * A systematic and independent examination of trial-related activities and documents is "an audit" and the act of overseeing the progress of a clinical trial is "monitoring." An inspection is defined as the act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources related to a clinical trial.

According to the FDA and ICH, which entity has the responsibility for monitoring a clinical trial?

According to FDA regulations and ICH E6 Section 5.18.7, the sponsor is responsible for developing a monitoring plan that is specific to the human subject protection and data integrity risks of the trial.

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

Both of the subjects * While subject 603 was admitted and discharged from the emergency department which is not considered meeting the SAE criteria of a hospitalization, the life-threatening nature of the symptoms does meet SAE criteria. Subject 20 was hospitalized which is reportable as an SAE.

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

Ensure the protection of human research subjects and data integrity. * The overall goal of monitoring, audits and inspection activities is to insure the protection of the human research subjects and the integrity of the data. Conflicts of interest management plans are developed prior to the initiation of the trial. Research-related publications may require review by the sponsor. Resolution of disputes between the sponsor and the investigators would not be the focus of routine monitoring, audit, and inspection activities.

Accurate reporting of adverse events is most important for:

Ensuring subject safety. * The sponsor of the research should specify what is appropriate to record for the particular protocol, so that the data are consistent across research sites. Accurate reporting is essential for subject safety. Adverse event reporting might affect the informed consent document, but is unlikely to change recruitment materials.

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

Evaluation of the site's capacity to conduct the study * The prestudy visit is an assessment of the site's ability to conduct the study. Regulatory documents would not be generated until the site is accepted as an investigative site.

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 * An investigator's agreement is signed by an investigator conducting a study of a medical device under an IDE. There is no standard FDA form for investigator agreements. The other choices are not specified in investigational device regulations.

The first Investigator's Brochure IB for a proposed clinical trial of a new drug is based primarily on which of the following?

• The IB is generated initially from the preclinical data. Phase II study data would inform updates to the IB, but not the first version.

Consider a study conducted a regional hospital where the investigator is one of the on staff physicians. The study focuses on smoking habits among the hospital's nurses and its relationship to lung cancer. Does this research involve subjects potentially vulnerable to coercion or undue influence? Yes or no.

The answer is yes. Because the nurses are members of a hierarchical structure within the study facility, the nurses are considered to be vulnerable to coercion or undue influence.

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

• FDA * The investigator signs the Form FDA 1572 and provides the signed form to the sponsor for filing with the FDA. By signing this form, the investigator agrees to conduct the study according to the protocol and FDA regulations.

Who is ultimately responsible for product accountability at the study site?

• Investigator * The investigator agrees to this responsibility in signing Form FDA 1572. Investigators are responsible for every individual unit of product received. The investigator may delegate some responsibility for product accountability to qualified personnel, such as the pharmacist or study coordinator, but the investigator retains ultimate responsibility for product accountability.

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

• Respect for Persons • Beneficence • Justice

The investigator must report adverse events to the:

• Sponsor * The investigator initially reports all adverse events to the sponsor The sponsor transmits reports to the FDA. Local institutions may require additional reporting.

At which study visits can the site expect the sponsor to review subjects' signed informed consent forms?

Periodic and termination site visits * The subject informed consent forms are reviewed at the periodic site visits and the termination site visit. Subjects are recruited and enrolled in the study after the prestudy and site initiation visits, therefore, no informed consent documents would have been signed and available for inspection at those visits.

When the FDA conducts an inspection, the inspectors will:

Review regulatory records. * During an inspection, the FDA inspector would review regulatory records, review subject records, compare data submitted to the FDA with the actual source records and evaluate investigational product accountability and control. An inspector may issue a Form FDA 483 but not a warning letter.

When must the investigator update the IRB about the progress of a trial?

• During the conduct of the study and at termination. * Investigators must provide periodic updates to the IRB in accordance with its policies. This typically occurs at least once per year, but may be required more often by the individual IRB.

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

• The sponsor * The investigator provides the sponsor with a completed form for reporting financial interests to the FDA. The sponsor is responsible for providing the FDA with this information. This includes potential financial interests in the sponsor's company or financial interests that might be influenced positively or negatively by the outcome of the clinical investigation.

Which party submits the completed, signed Form FDA 1572 to the FDA?

• The sponsor submits the FDA Form 1572 to the FDA.

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

• The sponsor-investigator. * The sponsor-investigator is responsible for making the initial risk determination and presenting it to the IRB. The FDA is available to help sponsor-investigators and IRBs in making the risk determination. The drug manufacturer is not involved in the risk determination for a sponsor-investigator study.

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. * The number of subjects in a study is not a consideration for IND exemption. Any study that significantly increases risk to subjects or invokes an exception from informed consent for emergency research (21 CFR 50.24) does not meet one of the criterion for an IND exemption. Investigations that are not intended to be reported to FDA do qualify as meeting one of the six required conditions for an IND exemption.

In the informed consent process, the subject must be informed if they will receive no clinical benefit from their participation in study.

• True. ICH (2016) E6 Section 4.8.10(h) requires an explanation of "the reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this."

ICH provides guidelines that are divided into the following four topic areas: Quality, Safety, Efficacy, and Multidisciplinary Topics.

• True. ICH has developed guidelines in four categories: Quality, Safety, Efficacy, and Multidisciplinary topics.

A 510(k) Premarket Notification is submitted:

• When the new device to be marketed is substantially similar (equivalent) to one already on the market. * A 510(k) Premarket Notification is submitted when a manufacturer wishes to market a qualified medical device in the U.S. without conducting clinical trials. To do so, the manufacturer must demonstrate to FDA that the device is equivalent to one already marketed. An IDE must be submitted when clinical trials of investigational devices are needed to determine the safety and effectiveness of a new device or when studying substantial modifications to or new intended uses for devices already on the market. A Premarket Approval (PMA) might be submitted for the FDA to evaluate the results of a completed clinical trial of a Class III device.

The ultimate responsibility for the disposition of the investigational product lies with:

• While the investigator can delegate duties to qualified staff, the ultimate responsibility for the investigational product lies with the investigator.

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

• Information • Comprehension • Voluntariness * Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to choose what shall or shall not happen to them. This opportunity is provided when adequate standards for informed consent are satisfied. While the importance of informed consent is unquestioned, controversy prevails over the nature and possibility of an informed consent. Nonetheless, there is widespread agreement that the consent process can be analyzed as containing three elements: information, comprehension and voluntariness.

What is the status of ICH in U.S.?

• It is a FDA guidance * After the ICH E6 guideline was finalized, several countries adopted it as law. In the United States, however, the FDA adopted the ICH E6 only as guidance. Therefore, the ICH E6 guideline does not have the force of law in the United States and is not a regulation. In the Federal Register notice, FDA stated that the ICH E6 guideline "does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both" (HHS and FDA 1997, 25692). Therefore, compliance is voluntary, but as with any published FDA guidance, compliance is considered part of good clinical practice.

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

• Sponsor * The investigator reports UADEs to the sponsor and the local IRB. The sponsor transmits evaluations of these reports to the FDA.

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

• Submit a new Form FDA 1572 to the sponsor as needed * The investigator must submit a new Form FDA 1572 to the sponsor when an investigator is participating in a new protocol that has been added to the IND or when a new investigator is added to the study. The IRB, not the sponsor, provides ongoing approval for study continuation at the site. The investigator submits the financial disclosure document to the sponsor and the sponsor submits financial disclosure information to FDA. Study record retention is two (2) years after drug approval, disapproval, or study termination.

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 legally acceptable representatives (LARs) to receive either a signed or unsigned copy. * The FDA regulations allow subjects to receive either a signed or unsigned copy. ICH E6 Section 4.8.11 requires that the subject or the legally acceptable representative (LAR) receive a copy of the signed and dated written informed consent form. The FDA (1998) regulations allow subjects to receive either a signed or unsigned copy. To be in compliance with ICH E6 guideline, 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.

An inspection is conducted by:

A regulatory agency (such as the FDA) conducts an inspection. The sponsor, CRO, and monitor perform monitoring and audits.

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. * An inspection is defined as the act by a regulatory authority of conducting an official review of documents, facilities, records, and any other resources related to a clinical trial. A systematic and independent examination of trial-related activities and documents is "an audit" and the act of overseeing the progress of a clinical trial is "monitoring."

The FDA requires retention of investigational drug study records for:

At least two (2) years after the investigational drug's approval by the FDA * The FDA requires that sites maintain study-related records for at least two (2) years after the drug has been granted marketing approval in the U.S. for the indication tested in the study or, if no application will be filed or if the application is not for the indication, for at least two (2) years after the investigation is terminated and the FDA is notified. For devices, the investigator or sponsor shall maintain the records for a period of two (2) years from the date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval (PMA) or a notice of completion of a product development protocol.

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

Discuss the pros and cons of both the investigational drug and the commercially available drug and then allow the subject to decide whether to withdraw from the research to take the new drug. * Informed consent is not a one-time procedure but a continuing and ongoing process. 45 CFR 116(b) and 21 CFR 50.25(b) requires that the informed consent document include a statement indicating that if significant new findings are developed during research which may relate to the subject's willingness to continue they will be explained to the subject. The informed consent document must also describe the process whereby subjects will be notified of significant new findings.

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. * "I waive any possibility of compensation for injuries that I may receive as a result of participation in this research." is exculpatory language. Exculpatory language is language in the consent document through which the subject is made to waive or appear to waive any of his/her legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence. Such language is specifically prohibited. The other choices provide information without asking the subject to waive any of their rights.

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

Identification of protocol violations * Initial assessment takes place at a prestudy visit. It is the prestudy visit that will determine if the site will be asked to participate in the study. Once the study is active, protocol violations would be identified at periodic site visits or at the termination visit.

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

Periodic site visits * Although some outstanding verification of CRF data may take place at the termination site visit, the majority of verification is done during the periodic site visits.

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

Prestudy site visit * At the prestudy visit, the site has not yet been chosen for participation in the study and would not have received any investigational agents.

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

Principal Investigator * Determining the relationship of the investigational agent to an adverse event requires medical decision making and expertise. The person making this determination should be medically qualified to do so. The Principal Investigator of the Phase I study is responsible for assessing and reporting adverse events.

OHRP is an oversight body primarily concerned with:

Protection of human research subjects * The OHRP assurance process is designed to have institutions and IRBs register and agree that they will comply with requirements to protect human research subjects (45 CFR 46).

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 broken wrist and a mild concussion. * The broken wrist and mild concussion are changes from the subject's baseline and are unexpected and untoward medical occurrences and therefore reportable as adverse events. The motor vehicle crash is the cause of the adverse events, not the adverse event itself.

Subject 311 has had elevated white blood cell (WBC) counts for the past two (2) study visits, with no clinical signs or symptoms. "Increased WBC count" is not listed in the Investigator's Brochure (IB) as an adverse event. The investigator should:

Report the elevated WBC to the sponsor as an unexpected adverse event * The investigator should notify the sponsor according to the sponsor's requirements. The laboratory tests already were repeated at the second study visit and remained abnormal. MedWatch reports may be used to notify the sponsor of the event, but the investigator would not file the report with the FDA. The sponsor would notify FDA.

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

Site initiation visit * The site initiation visit focuses on in-depth training of the study staff which includes detailed review of the study protocol requirements. The site's ability to conduct the type of study proposed is assessed primarily during the prestudy visit.

Sponsors must notify regulatory authorities and all participating investigators in writing of events that are both unexpected and serious, and associated with the use of the investigational drug no later than:

Sponsors must notify regulatory authorities and all participating investigators in writing of events that are both unexpected and serious, and associated with the use of the investigational drug not later than 15 calendar days after the sponsor determines that information received must be reported.

During the course of administration of an investigational drug, the following events occurred: On Day 7, subject 603 had an unexpected stroke that requires 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 * The incident for subject 603 meets the FDA definition of "serious" and "unexpected." The incidents for subjects 20 and 415 do not meet the FDA definition of "serious."

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

Termination site visit * At the end of the study, final disposition of all the remaining investigational agents at the site must take place. The investigational agents will be shipped back to the sponsor unless the sponsor allows an alternative disposition.

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 team agree that the situation necessitates the use of the test article and the IRB will be notified later. * The life- threatening situation requires a timely decision so that the test article can be used. It would be unethical to withhold emergency treatment until a research protocol is submitted and approved by the IRB. Not using the test article in a situation where it might save a life is also unethical. 21 CFR 50.24 provides the option of using the test article in a life-threatening condition involving an individual subject.

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

The study is minimal risk. * In limited circumstances, the FDA regulations at 21 CFR 56.109(c)(1) allow the investigator to obtain verbal informed consent without a signature on the consent form. The FDA requires IRB approval for this anomalous consent process, and it can only occur when study participation presents minimal risk. An illiterate person can place a mark on the consent document. An impartial witness should be present during the consent discussion and should also personally sign and date the consent form. If the subject has the capacity to consent, consent should be given by the individual, not the LAR. If the subject is unable to provide consent, the LAR must personally sign and date the consent. Please note, ICH E6 Section 4.8 does not include a similar provision for waiving the requirement for a signature on the consent form.

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 * Whether or not an event qualifies as serious is a regulatory determination and would not be a consideration in assessing the causality of the event. The timing of the event in relation to the administration of the investigational agent should be considered in determining the causality of the event.

When evaluating the causality of an adverse event and the investigator determines that there is a likelihood that the investigational product is the cause of the event, but other causes cannot be ruled out, this is called:

When there is a likelihood the investigational product (IP) is the cause, but other factors cannot be ruled out, this is deemed "possibly related." When there a certainty that the event is related to the IP, this is termed "definitely related." When evidence exists that the event is related to something other than the IP, this is documented as "unrelated."

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

• Case report form * When a drug is dispensed or administered to a subject, it is necessary to record this information for the sponsor's use and analysis by completing the case report form. Form FDA 1572, insurance claim forms, and informed consent forms do not include this information.

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

• Clearly disclose to subjects in the informed consent form that the monitor, auditor, IRB/IEC, and the regulatory authorities may have access to the subject's medical records. * ICH (2016) E6 Section 4.8.10(n) states that the informed consent should indicate that "the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) 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 legally acceptable representative is authorizing such access." The FDA regulations at 21 CFR 50.25(a)(5) (Protection of Human Subjects 2016) state only that in seeking informed consent, the following information shall be provided to each subject:. . . (5) 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 Food and Drug Administration may inspect the records. While it is true that data sent out of the U.S. loses certain federal protections, this statement is not required. The possibility of hacking data is a risk that should be addressed in the study design and conduct. Non-disclosure forms are not required for communications with primary care providers.

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

• Conduct or supervise the investigation personally * All investigators agree to personally conduct or supervise the investigation when they sign the Form FDA 1572. They must report adverse events to the sponsor, not the FDA. Records must be retained for two (2) years after drug approval, disapproval, or study termination. Maintaining a contract is not a requirement.

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

• Determining that the study has maximized benefits and minimized risks. * The Belmont Report's principle of beneficence includes the two general rules as complementary expressions of beneficent actions (1) do not harm and (2) maximize possible benefits and minimize possible harms. Providing detailed information about the study and obtaining the subject's consent to participate would be an example of the principle of respect for persons. Ensuring that the selection of subjects includes people from all segments of the population would be an example of the principle of justice. Finally, ensuring that confidentiality is maintained is a regulatory requirement per HHS regulations 45 CFR 46. Ensuring confidentiality could be supported by respect for persons (extending the idea that the subject's right to autonomy could include their right to privacy and confidentiality) and beneficence (that maintaining privacy and confidentiality helps to protect subjects from potential harms of a breach of confidentiality with sensitive information), but it is not the best response for this question since it is not directly an example of the principle of beneficence in human subjects research.

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

• Drug shipping and disposition records * Drug accountability includes tracking of the receipt and return/destruction of the investigational product and dispensing/administration records showing subject usage of the product. Although environmental controls should also be documented, they are not considered part of accountability tracking. Compounding procedures and patent expiration dates are the responsibility of the sponsor.

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. * ICH (2016) E6 Section 4.8.10(c) states that "Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include the probability for random assignment to each treatment;" however, it does not specify how the information should be presented. The FDA has no such requirement about including probability for random assignment to each treatment, but does require an identification of any procedures which are experimental. 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 study arms.

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

• IND report * The sponsor-investigator is required to keep the FDA updated through IND Safety Reports, IND amendments, and annual IND reports. IND Safety Reports are filed throughout the study, not just annually. There is no requirement for an annual submission of an IND renewal application or marketing plan.

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. * ICH (2016) E6 Section 5.0.4 states that the sponsor should decide which risks to reduce and/or which risks to accept. The approach used to reduce risk to an acceptable level should be proportionate to the significance of the risk. Risk reduction activities may be incorporated in protocol design and implementation, monitoring plans, and agreements. Routine scheduled audits of study documentation whether on-site or remote are not considered fully responsive to the need for continuous monitoring of data under a proactive risk-based approach. While data from Case Report Forms may be selected for ongoing monitoring, there is no ICH template and a "one-size-fits-all" approach is not appropriate for study-specific monitoring. The use of any specific method of analysis quality improvement is not required and routine annual review may not be sufficient for monitoring the study-specific risks that have been identified.

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

• In the study protocol * Investigational products must be stored according to protocol specifications and the manufacturer's directions. Sponsor requirements for this are usually found in the study protocol.