Please create a high-level masters level PowerPoint (13 slides) with speaker notes on each slide for the following 2 questions
Topic: Conducting Research Remotely
Please comment on the following questions:
1. How can remote work be a challenge and an advantage to study teams that are implementing clinical research studies?
2. What steps do you think might need to be taken to ensure that patient safety, protocol deviations, and study monitoring continue to be robust? Are there steps, tools, or systems you would use to manage these and other ongoing study processes?
Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others In this Chapter n Why adverse event data are important n Definition of adverse events n Unanticipated problems involving risks to subjects or others n Investigator and sponsor responsibilities when events or problems occur 6 “Sweet are the uses of adversity, Which, like the toad, ugly and venomous, Wears yet a precious jewel in his head; And this our life exempt from public haunt Finds tongues in trees, books in the running brooks, Sermons in stones, and good in every thing.” William Shakespeare (1564–1616), English poet and playwright From As You Like It, Act II Scene 1 A Clinical Trials Manual From The Duke Clinical Research Institute: Lessons From A Horse Named Jim, 2nd edition. By Margaret B. Liu and Kate Davis. Published 2010 by Blackwell Publishing 9781405195157_4_C06.qxd 11/16/09 15:23 Page 123 A Clinical Trials Manual from the Duke Clinical Research Institute: Lessons From A Horse Named Jim, Second Edition Margaret B. Liu and Kate Davis © 2010 by Duke Clinical Research Institute. ISBN: 978-1-405-19515-7 One of the most important responsibilities of the site investigator is the accurate, timely, and complete reporting of adverse events (AEs). The safety of research subjects is best served when investigators and their staff take a systematic approach to collecting and reporting adverse event data. However, investigators sometimes face chal- lenges in identifying events that must be reported. It is important for investigators to be aware of the difference between AEs in the context of a clinical trial as opposed to events that occur in clinical practice. In clinical trials, the identification and reporting of AEs must meet regulatory requirements; however, this is not the case in clinical practice. Because AEs must be reported according to the definitions provided in the protocol, a given clinical trial may be characterized by the recording and reporting of AEs that in the opinion of the investigator are not of clinical significance. For example: 1) a creatinine measurement of 2.1 mg/dL may not be considered clinically significant by the health care provider, but the protocol requires reporting of creatinine values >2.0 mg/dL; 2) a slight worsening of congestive heart failure may be considered part of the usual disease progression by the clinician, but must be reported as an AE in the setting of a clinical trial. Inconsistent terminology in the regulations adds to the challenges of reporting AEs. Some regulations provided in the U.S. Code of Federal Regulations (CFR) refer to “adverse events,” while others use the term “adverse effect” and “adverse experience.” Device regulations use the term “unanticipated adverse device effect” [21 CFR 812.3(s)]. The regulations in 45 CFR 46.103(b)(5) and 21 CFR 56.108(b)(1) require written procedures for reporting to the Institutional Review Board (IRB) “any unanticipated problems involving risks to subjects or others . . .” The glossary in the International Conference on Harmonisation (ICH) E6 guidelines for Good Clinical Practice (GCP) provides definitions for “adverse events,” “adverse drug reactions,” and “serious adverse events.” Reporting requirements are mentioned in ICH, Section 4.11: “all serious adverse events should be reported immediately . . . except those that are designated in the protocol or investigator brochure as not needing reporting immediately.” Why Collect Adverse Event Data? AEs are collected in clinical trials to: 1 determine the safety profile of a drug, biologic, or device; 2 evaluate the benefits and risks of a product; and 124 Adverse Events in the Regulations Adverse Event (AE) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including any abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. (ICH E6 Consolidated Guideline: 1.2) Safety Reports An investigator shall promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately. (21 CFR 312.64) Investigator Commitment I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64. (Form FDA 1572) 9781405195157_4_C06.qxd 11/16/09 15:23 Page 124 125 6. A d ve rs e Ev en ts a n d U n an ti ci p at ed P ro b le m s Benefit versus Risk: “Take AZT, for example,” said Robert Temple, MD, former director of the Office of Drug Evaluation at the FDA’s Center for Drug Evaluation and Research. (AZT, marketed as Retrovir, is used to treat AIDS.) “It has significant toxicity. If you weren’t quite sure it had a benefit, it would be hard to describe it as ‘safe.’ But we know from well-controlled studies that it has a benefit. In the first large clinical study with the drug, there were 19 deaths in patients taking a placebo, but only one death among those on AZT.” 3 provide information for the package insert if the product is approved for marketing. Safety Profile The safety profile of a drug, biologic, or device is carefully monitored in clinical trials to determine whether there are any significant con- cerns that would prevent the product or test article from being used in its intended patient population. The Investigator’s Brochure con- tains all AEs reported in trials of the test article to date, and describes the number of times specific events were reported. Sometimes test articles are found to be effective but have such serious unwanted effects that further studies are discontinued. Benefits and Risks Evaluation The U.S. Food and Drug Administration (FDA) recognizes the need for a medical risk-benefit judgment to be made as part of the process of approving a test article for marketing. In this evaluation, the FDA considers whether the benefits of the test article outweigh its known and potential risks, as well as the need to answer remaining questions about its effectiveness.1 Included in the FDA assessment of the risk-benefit ratio is a careful evaluation of all AEs reported during clinical trials. Package Insert Sponsors use AE information to prepare package inserts and user instructions for marketed drugs, biologics, and devices. Package inserts, based on scientific facts gleaned from clinical trials, are writ- ten to instruct health care providers in the appropriate use of the product for patients and to inform health care providers and patients of potential side effects. The package insert also serves as a reference by which the FDA can evaluate additional AEs reported after market- ing. When postmarketing AEs not listed on the package insert are reported, additional investigations may be required and/or the product may be recalled. Adverse Events An AE in a clinical trial is generally defined as any unfavorable change in a subject that may occur during or after administration 9781405195157_4_C06.qxd 11/16/09 15:23 Page 125 of the test article. This change does not have to be caused by the treatment to be described as an AE. AEs can include: n physical signs or symptoms; n abnormal laboratory values; n changes in vital signs, physical examination, or on an electrocardiogram; n an increase in the frequency or intensity (worsening) of a condi- tion or illness that was present before study enrollment; n complications from a surgery or procedure; n device malfunction or failure; n device user error; n psychological harm. AEs are NOT: n procedures or surgeries (the medical condition that caused the need for the procedure or surgery is the AE); n pre-existing events or illnesses that do not worsen during the study period. Internal and External Adverse Events In the context of multi-center clinical trials, internal AEs are those that occur to subjects at one investigative site. The investigator usually learns about an internal AE directly from the subject, from the subject’s health care provider, or from another investigator at the same site. External AEs are those events that occur at other sites participating in the study, or that may be events occurring in other studies of the same test article. Site investigators are often not aware of external AEs since they occur to subjects at other institutions. If an external AE or series of events is determined to be unexpected or to represent an increased risk to subjects, the study sponsor noti- fies all investigators of the event. This may also result in a change to the protocol via a protocol amendment and/or changes to the con- sent form; these changes must receive IRB approval before imple- mentation. Serious Adverse Events A subset of AEs is considered to be serious when events meet any of the six defined criteria, regardless of the relationship of the adverse 126 9781405195157_4_C06.qxd 11/16/09 15:23 Page 126 127 6. A d ve rs e Ev en ts a n d U n an ti ci p at ed P ro b le m s Unanticipated Problems Involving Risks to Subjects or Others All three questions must be answered YES for the event or problem to be considered an unanticipated problem involving risks to subjects or others: 1 Was it unforeseen or unexpected? 2 Is it related or possibly related to study participation? 3 Did it cause harm or lead to a possible increased risk of harm (for subjects or others)? event to the test article. A serious adverse event (SAE) is defined as any experience that meets one or more of the following conditions: 1 results in death; 2 is life-threatening and puts subject at immediate risk of death; 3 results in persistent or significant disability/incapacity; 4 requires or prolongs inpatient hospitalization; 5 results in a congenital anomaly/birth defect; 6 is an important medical event that may not lead to death, be life- threatening, or require hospitalization if, based upon appropriate medical judgment, the adverse event jeopardizes the subject’s health and may require medical or surgical intervention to pre- vent one of the other outcomes listed in this definition.2 (For example, allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the develop- ment of drug dependency or drug abuse, would be considered important medical events.) Unanticipated Problems Involving Risks to Subjects or Others As noted earlier, the regulations refer to unanticipated problems involving risks to subjects or others, without providing a clear defini- tion. However, the current working definition of “unanti- cipated problems involving risks to subjects or others” comprises any incident, experience, or outcome that meets all of the following criteria: 1 unexpected (in terms of nature, severity, or frequency) based on the research procedures that are described in the