Early Protocol Assessment for Increased Patient Centricity

Emily Mitchell, Executive Director, DCT Operations, ICON plc

As our knowledge on study design for decentralized clinical trials (DCTs) continues to grow, the foundational considerations of protocol development have expanded to include patient burden and technological innovations in addition to addressing the scientific question and regulatory compliance. Set against a background of increasing complexity within clinical trials, getting protocols right the first time is essential. Retrofitting a clinical trial protocol to be more patient-centric and to leverage new technologies or digital solutions can cost sponsors a great deal in time and resources.

Thorough assessment of protocols, whether DCTs or hybrid clinical trials that incorporate decentralized components, can ensure the study is designed to minimize patient burden while optimizing opportunities to leverage data on a wider scale. This assessment is most impactful early in the process and follows key stages of trial design development.

Not all trial phases are equal

Not every trial can accommodate decentralized and digital components. The first indication of whether decentralized components may be suitable is the trial phase. For example, first-in-human trials are not typically decentralized due to the high level of control and intensive schedule of assessments required, while at the other end of the scales, non-interventional trials and observational studies are generally good candidates. Marketed products seeking to expand their labels make excellent candidates for DCTs and the patient centricity they afford because the safety profile is already known.

Indication and appropriate representation

This is a critical point in the protocol assessment to ensure patient centricity. During the assessment of the indication and participant population, we can infuse the patient voice to ensure this perspective is central during development. Here, it is possible to crack open the protocol and pull in multidisciplinary teams to provide holistic and diverse considerations. Incorporating patient insights and other voices like patient advocacy organizations (PAOs), surveys, and focus group feedback from representative populations will help to ensure the protocol provides the optionality patients desire and that participation will fit into their daily lives.

Engaging with diverse voices at this stage of assessment is crucial to capture and account for the range of cultural implications that may impact patient populations and their carers. Making assumptions or generalizations can lead to false understandings of patient needs, and, therefore, generate irrelevant solutions.

True patient centricity is multilayered, requiring framing the protocol assessment from patient points of view and examining diverse population barriers and preferences to determine the most impactful solutions (see Figure 1 below). Ultimately, the protocol should be flexible enough to provide personalized optionality for the target patient population.

Figure 1.True patient centricity should be multilayered, allowing for protocol flexibility and personalized optionality.

Source: ICON plc

Safety first

During the safety profile review, consultation with therapeutic experts ensures the investigational product is appropriate to utilize the decentralized components that would service the needs and desires of patients as identified in the earlier step. This ensures that the delivery of the investigational product, remote observation, and follow-up will protect patient safety.

If a condition or disease requires more intensive, on-site observational periods with the patient, it is unlikely to be suitable for full decentralization of services. For example, oncology is not typically decentralized as these studies require scans and frequent labs. Though for some of these studies, additional analysis may reveal a hybrid model as a more palatable option whilst maintaining patient safety.

Analyzing endpoints

Recent Tufts Center for the Study of Drug Development (CSDD) data reflect increasing numbers of endpoints in clinical trials, adding to the overall complexity and operational challenges. Capturing data for a multitude of clinical endpoints complicates data collection and integration, often requiring the management of separate vendors with discrete scopes.

Importantly, it can also pose an additional burden for patients. In this stage of assessment, the key is to analyze the proposed endpoints to streamline data collection or identify opportunities to collect it in less interventional ways.

Let’s review the six-minute walk test, for example. This is an intensive on-site assessment conducted in a controlled, clinical environment. Patients are burdened with traveling to sites for the test, and the results do not necessarily reflect real-world outcomes. Alternative solutions could utilize technology that fits into their normal lives, such as an actigraphy monitor or a heart monitor to gather real-world data and avoid unnecessary site visits.

There are two accepted alternatives to the six-minute walk test; one is accepted by the FDIC, the other is in the submission process to the FDA for acceptance as a digital equivalent endpoint. Advances in technology allow for continuous innovation in digitizing endpoints; so considering how and when to incorporate them can greatly benefit the data collation and patient experience in the appropriate trials. They can also generate more meaningful data outside of a controlled clinic setting, as in the case of the six-minute walk test.

Planning for varying guidelines and regulations

The adoption of DCTs is growing and, similar to traditionl trial designs, these often involve multi-national or global footprints. However, there is no single global set of regulations governing DCTs. It’s important to carefully consider the country-specific regulations that may impact the protocol as it is operationalized across geographies.

Innovation and the use of technology may be regulated differently across countries, especially regarding data privacy and remote data collection. Assessing the protocol for the flexibility to remain operational within different regulatory environments will avoid the need for mid-trial amendments. Tufts data also show how the increase in protocol amendments in recent years has added costs and resulted in timeline disruptions.

Ensuring that the language used in the protocol includes strategic flexibility will benefit the regulatory process. For example, if a country’s regulations restrict the use of eSource, remote consent, wearables or in-home nurses, then the protocol should be worded to allow trial implementation under these conditions.

It is also beneficial to engage with regulators early to align expectations and minimize the amount of time that it would take for an agency to approve. Contract research organizations (CROs) with experience in this early engagement can provide lessons learned to help smooth the process. For example, when we submit informed consent for an institutional review board (IRB) approval, we know what elements need to be included. We are familiar with the questions regulators will ask, what they want to know, and the intended purpose of their questions—which is ultimately to ensure patients will have a full understanding of the trial.

Mapping the patient pathway: Schedule of assessments

The schedule of assessments essentially maps key touch points in the patient pathway and is, therefore, a critical phase for aligning patient centricity. Patient perspectives and initial burden assessments were initially incorporated at the patient population assessment phase to build the protocol, and the schedule of assessments reflects the results of this consideration.

At this stage, assessing and anticipating where the roadblocks are likely to occur will help to develop a plan that balances minimizing burden with the necessity to engage patients on a one-to-one basis on-site to ensure patient safety. Offering options to replace site visits with remote data capture, for example, may require the addition of concierge services to more fully support the patient and support compliance. Again, the solutions devised for the schedule of assessments must provide options for the wide range of patients and their varied cultural or personal preferences.

Novel possibilities

Designing a study that minimizes patient burden and simultaneously optimizes opportunities to leverage data on a wider scale means investing time into early protocol assessments and incorporating multidisciplinary insights. Innovation and advancing technologies open up novel possibilities for patient-centric, data-rich, and operationally efficient trials, though the balance of these elements will vary between clinical trials depending on their specific scientific requirements, patient populations, and regulatory restrictions.

Novel trial designs reflect the flexibility and adaptability needed to provide patients with the necessary options to make trial participation a more convenient and positive experience.

Emily Mitchell, executive director, DCT operations, ICON plc