GCP for Clinical Trials Involving Drugs and Devices
In the United States, following the ICH E6 guideline is:
Voluntary for FDA-regulated drug studies.
Development of most new drugs, from discovery to marketing approval, usually takes:
9 years or more. Development of a new drug requires a detailed and lengthy research process. Preclinical studies can take 3-6 years and Phases I-III clinical trials can take another 6-7 years.
The FDA requires an IND if the use of the drug in the trial significantly increases the risk (or decreases the acceptability of the risk) due to...
(1) the route of administration; (2) the dosage level; (3) the subject population, or other factor.
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.
Severity of AEs are by:
Mild, moderate, or severe. By number. Or by its effect on activities of daily living. There is also the Common Terminology Criteria for Adverse Events (previously called Common Toxicity Criteria) scale used by the National Cancer Institute, an elaborate, specific scale that encourages consistency in rating the severity of AEs.
A primary purpose of the ICH is to:
Minimize the need for redundant research. The goal of the ICH guidelines is to standardize voluntary 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.
The FDA requires the sponsor to obtain an IND for studies of approved drugs when the data are intended to be reported to the FDA so support...
(1) a new indication for the drug; (2) any other significant change in the labeling for the drug; or (3) a significant change in the advertising for the drug.
According to ICH E6, an "audit" is defined as:
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.
In completing Form FDA 1572, Statement of Investigator, the investigator agrees to
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.
What are AEs categorized as?
By body system and by individual or by grouping. It is important to distinguish AE from a sign or symptom of the disease or condition being studied
Investigational product dispensing or administration information for the sponsor is recorded on the:
Case report form
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
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.
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?
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.
Which of the following should take place during periodic site visits?
Identification of protocol violations
Which of the following best describes the principle of Respect for Persons as described in the Belmont Report?
Information, comprehension, voluntariness.
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?
Informed consent is 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.
What is the status of ICH in U.S.?
It is a FDA guidance. 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.
At which study visits can the site expect the sponsor to review subjects' signed informed consent forms?
Periodic and termination site visits
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
OHRP is an oversight body primarily concerned with:
Protection of human research subjects
When the new device to be marketed is substantially similar (equivalent) to one already on the market
Sponsor
Regarding subject receipt of a signed and dated copy of the consent forms, which is true about FDA regulations?
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. 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.
Which of the following is an investigator's commitment to the sponsor?
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.
Who is responsible for making the initial risk determination for a device being used in a study?
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 required at a prestudy site visit?
Evaluation of the site's capacity to conduct the study
Form FDA 1572, Statement of Investigator, is legally binding between the investigator and the:
FDA
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
True
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."
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." 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.
An inspection is conducted by:
A regulatory agency (such as the FDA) conducts an inspection. The sponsor, CRO, and monitor perform monitoring and audits.
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
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.
The FDA requires retention of investigational drug study records for:
At least two (2) years after the investigational drug's approval by the FDA
What happens to investigational agents at the end of the study?
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.
The packaging of investigational drugs should ideally:
Be designed to help with subject compliance. 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 drug
Whenever a trial involves a new drug that has not been approved by the FDA the sponsor-investigator (or, in some cases, the sponsor) must submit the following information to the FDA to obtain an IND:
Cover letter Form FDA 1571 (Investigational New Drug Application [IND]) Form FDA 1572 (Statement of Investigator) Introductory statement and general investigational plan Investigator's Brochure Protocol(s) Chemistry, manufacturing, and controls information (CMC) Pharmacology and toxicology information Previous human experience with drug Additional information Relevant information
Which of the following is an important component of drug accountability?
Drug shipping and disposition records
When the FDA conducts an inspection, the inspectors will:
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
The overall goal of monitoring, audits, and inspection activities is to:
Ensure the protection of human research subjects and data integrity.
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.
Under which circumstance does the FDA allow verbal consent prior to participation in a research study?
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.
Where is information on storage requirements for the investigational product usually found?
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.
Adults with more than a twelve (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 efficacy measure was the reduction in severity of the migraine attacks. Enrollment was twelve-hundred (1200) subjects. Which of the following best describes the clinical phase of this study?
Phase III
Long-term toxicology of an experimental drug in animals most likely refers to which part of drug development?
Preclinical
For a Phase I new drug study in humans, what is the primary source of the data included in the initial Investigator's Brochure?
Preclinical data
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
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
Which of the following are the three principles included in the Belmont Report?
Respect for Persons, Beneficence, Justice
The ICH GCP guidelines:
Set standards for the design, conduct, monitoring and reporting of clinical research. Compliance with ICH E6 does not guarantee that the drug will be approved and marketed. ICH guidelines do not supersede nor contradict FDA regulations.
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.
ICH E6 describes standards that apply to:
The ICH standards apply to clinical research. Sponsors, IRBs/ethics committee, and investigators are each involved in aspects of clinical research.
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?
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.
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?
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."
Who is ultimately responsible for product accountability at the study site?
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.
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.
Identify which party is responsible for reporting directly to the FDA the investigator's financial interests with the sponsor:
The sponsor
Accurate reporting of adverse events is most important for:
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 party submits the completed, signed Form FDA 1572 to the FDA?
The sponsor submits the FDA Form 1572 to the FDA.
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?
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.
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.
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 addition to, known effects of the drug or drug class. Other factors to consider are chronic effects, cumulative effects, late effects, and re challenge.
For blinded studies, the code should be broken only when the identity of the investigational product that the subject received will determine the treatment to be given to that subject for the emergency.
True
An investigator from the FDA contacts the PI's site. What should the PI ask the FDA investigator?
Usually, a PI will want to know what day the FDA will arrive, how many investigators will participate in the inspection, how long the inspection is expected to last, the studies the FDA will inspect, and whether the inspection is routine or for cause (study-oriented or investigator-oriented.)
A 510(k) Premarket Notification is submitted:
When the new device to be marketed is substantially similar (equivalent) to one already on the market
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."
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:
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 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.
