In this section, we will be going through the roles and responsibilities for all of the players in the data collection process for each of these protocol events. One of the responsibilities of the investigator or sponsor is a balance of the risks and benefits to the participants in the trial. This means both treatment groups and as a study population overall. One of the tools to do that is collecting data on protocol events. To do this effectively, investigators must ensure that the procedures are comprehensive enough for complete data collection and that they are communicated to everyone on the study team. Oftentimes, it may not be the lead investigator who is collecting these data, so it's really important that each member of the study team is aware of what is needed and when it is needed. In the case of multicenter clinical trials, this also means clear and uniform communication to all of the site investigators and their study teams. In the end, the investigator bears the responsibility for timely reporting of protocol events to both the ethical bodies and the relevant regulatory agencies. They are also held accountable for adhering to the reporting timelines. These timeline clocks typically start at the point that the study team learns of a particular protocol event. The investigator may or may not be masked to the treatment groups in the reporting of protocol events. That is usually determined preemptively with a discussion with the study team and study oversight bodies such as the medical monitor or DSMB. The medical monitor is typically an expert in the field who is independent of the study and can advise the study investigator on protocol changes. Their main concern is participant safety throughout the trial. The medical monitor may evaluate safety data as they accumulate, as well as in an aggregate form throughout the trial in an ad hoc manner. Because of their independence and focus on safety, they do not threaten the integrity of the trial. For some studies, the medical monitor may adjudicate the severity, relatedness, and seriousness of adverse events if necessary. The masking of the medical monitor is typically determined before the trial begins via a discussion with the study investigators and/or the DSMB if there is one. It is also important to identify backups for the medical monitor and evaluate the implications of their unmasking if that is deemed possible for a particular trial. In the case of a prevention trial, unmasking the medical monitor may have implications for data integrity and should therefore be carefully considered. This is primarily because your outcome data is in fact safety data. The DSMB is another external body that assesses accumulating safety data in addition to efficacy data and performance metrics. At the interim meetings, they assess protocol deviations, adverse events, SAEs, and unanticipated problems to inform their recommendations about the continuation of the trial or any necessary protocol changes. The DSMB may also choose to review these data in light of external emerging data about the study population or even the intervention under study or alternative treatments. Similarly to the medical monitor, the DSMB or DSMC as they may be called in certain trials, may be masked or unmasked. This is also decided before the start of the trial. Unmasking the DSMB to the accumulating safety data can also be done at their request if they decide to remain masked. Let's go through a couple of examples to see how this would play out in an actual trial. In this first example, we're looking at a trial that's comparing a new drug X to the standard of care for the treatment of pancreatic cancer. One of the participants, a 67-year-old female, was given the higher dose of everolimus than indicated. She started to cough up blood. In this particular situation, this event would be classified as an unanticipated problem as well as an adverse event. It would be considered severe, related, and expected, and that is primarily because coughing up blood is considered a very severe adverse event. It is related because we know from the product label for everolimus that it is an expected side effect and it is directly related to this particular product. In our second example, we'll be looking at a trial comparing citalopram to placebo for the treatment of agitation in Alzheimer's patients. Let's suppose that during an audit of one of the clinical sites in this multicenter trial, it was discovered that the treating physician had not completed all of the ethical certifications that were required of all study investigators. In this case, this particular event would be considered an unanticipated problem. It may or may not be an adverse event or an SAE if this caused harm to the participants. For instance, he completed a study procedure in a way that he thought was clinically superior to the way it was specified in the study protocol. This may result in an adverse event. It's important in this case to follow up and report to the Office of Human Research Protection, in addition to the IRB, if this is conducted in the United States. In our final example, we'll be looking at a trial that is investigating the use of vitamin D for the prevention of falls in the elderly. In this example, we have a 72-year-old participant who was male, enrolled in the trial and he was randomized to the active treatment group. He experienced a car crash on the way to his first appointment for the baseline assessments and had to be admitted to the hospital to treat his injuries. He had not received his first treatment, but he was on his way to the study facility to get that baseline assessment completed. In this case, this particular event would be considered an SAE. It would also be considered related because he was on his way to a study visit and the expectedness may or may not be determined based on what the medical monitor might think. Are car crashes more prevalent in the elderly population? I think we can say that the answer would be yes. If he's going to travel to the clinical site, then that is to be expected. Depending on where your study is being conducted, you may have multiple regulatory and ethical bodies to report to. In the design phase of your trial, it is important that you consider all of the reporting requirements so that your data collection instruments can accommodate these different needs. In most cases, they will be quite similar. Additionally, planning data collection and verification procedures around the required reporting timelines is critical. In this lecture, we have discussed the various players in this process. Each of them may or may not be privy to protocol event data. I'm going to go through some of the key players on this slide. The Institutional Review Board, the IRB, typically sees protocol deviations and all adverse event reports at pre-planned reporting times. This is usually annual. They also receive reports of unanticipated problems and SAEs on an expedited timeline through ad hoc reporting, and these reports typically have a bit more information than you would normally provide for any other adverse event. The Office of Human Research Protection, the OHRP, and funding bodies, they typically receive information on unanticipated problems on an expedited ad hoc reporting timeline as well. The regulatory agencies typically follow similar timelines to IRBs for SAEs and unanticipated problems resulting in SAEs. Depending on whether or not the investigational product is approved or not, they may require interim reporting of adverse events and protocol deviations. If there's a significant risk to participant safety that is discovered through the unanticipated problem or aggregated adverse event data, study participants may also be notified. This notification may or may not involve unmasking of study participants. Finally, adverse event data are typically reported in trial registries at the conclusion of the trial. You'll notice that on this slide, I don't specify specific timelines for each of these expedited and standard reporting procedures. That is primarily because all regulatory agencies have their own specifications and some of them do conflict with others. Please be sure to check with the reporting agencies that you are responsible to report to.
