Location where subjects will be seen: a factor to consider in monitoring activities

The recently issued draft guidance recommends that the location where subjects will be seen (and how the data will be collected) relative to where sponsor oversight activities will be conducted, should be a factor you consider when determining the timing, types, frequency and extent of monitoring activities. The guidance was issued in response to questions. It is likely that inspectors have identified this as an issue.

Why the location matters

The more complex the setting (in-patient vs outpatient) and the more health care providers (HCPs) interacting with the study participant, the more likely a protocol deviation will occur. If it is a protocol for subjects with a long-standing chronic condition, they might be seen at a doctor’s office once a month. Interactions may be limited to the receptionist checking the patient in, the practice nurse, the research coordinator and the Principal Investigator (PI). For subjects with end-stage renal disease (ESRD), study visits can be monthly, but subjects might be treated thrice-weekly at a dialysis center. Study subjects will interact with multiple HCPs between study visits in this scenario. In-patient studies, by virtue of their location, are inherently challenging.

How the data is collected

Depending on the patient population, there might be multiple ‘sources’ of data. It is a good idea at study start to map the study procedure on the Schedule of Events to the original source i.e. where the data point was first documented. This can serve as a resource for back up coordinators as well as for any new CRAs monitoring the study. Some sites create their own ‘source document’ templates. While they might be useful as a memory aid, there is the risk that an inexperienced CRA will rely on that as ‘source’ and not make the effort to review the electronic medical records. Source documentation for adverse events is not limited to doctors’ notes. They might be documented in a dietitian’s note or that of a social worker. If you do decide to use a visit template and the temperature, for instance, has been documented by another caregiver, indicate on the visit template ‘see nurses notes for vital signs.’

An example of multiple ‘sources’ which led to an FDA finding

I recall one FDA inspection where the protocol called for labs to be drawn before dialysis started. The time noted on the lab requisition for the lab draw was after the start time of dialysis noted on the dialysis flow sheet (generated by the dialysis machine). The labs had been drawn by a patient care technician prior to initiating dialysis but the research coordinator, who processed the labs for shipping, used the time on a wall clock when completing the requisition…which differed from the machine settings. The finding, one of several such instances, was listed by the inspector on the 483 as a failure on the part of the PI to follow the investigational plan (i.e. to draw labs prior to initiating dialysis). That same inspector wanted to see documentation that all the patient care technicians had been trained on the study protocol, even though drawing labs is standard of care.

Where oversight activities will be conducted

In my experience, in both in-patient and outpatient studies, the CRA reviewed the consents, training records and the Delegation of Authority log when on- site. With RBM methodology and fewer on-site visits, Sponsors need to ensure that key activities are being performed by adequately trained resources. The right people need to perform the right task at the right time. Oversight needs to be commensurate with risk. If it is a complex study population with multiple co-morbidities and numerous interactions with HCPs, training is critical and needs to ongoing for the duration of the study. I would argue that sick, complex study populations need more on-site monitoring visits, especially if the CRA does not have remoted access to the electronic medical records. At a minimum a visit should take place soon after the first trial subjects are enrolled to ensure that the HCPs caring for a study patient have been trained on the study and are aware of their reporting obligations.