Introduction
Innovative approaches in clinical studies
Innovative approaches to reduce the need for study participants to visit trial sites
Term | Definition |
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Mobile (home) nursing | Nursing services that visit the patient at home and can provide certain activities described in the trial protocol. Possible activities may include drug administration, blood draws, biological sample collection, drug accountability, physical exam and patient safety check. |
Investigational medicinal product (IMP) home delivery | IMP home delivery refers to courier services that transport the IMPs from a site or a depot to the patient’s home or to a local facility (e.g. local pharmacy). |
Home/local infusion services | Intravenous or subcutaneous administration of drugs or biologicals to an individual at home or local infusion centre. |
Alternative laboratories and imaging centres | |
Mobile laboratory | Laboratory that is either fully housed within or transported by a vehicle. |
Local laboratory | Local laboratories are located at the local investigator site or close to the patient. They may not be a lab that the sponsor has an agreement with and could be selected by the investigator based on their preference/experience or patient location. The lab could be used to perform diagnostics/tests that are required per protocol. |
Local imaging centre | Located close to the patient and used to collect imaging that is required per protocol. |
Digital health technologies to reduce patient visits to the trial site | |
Telemedicine/telehealth | Practice of medicine using technology to deliver care at a distance. A physician in one location uses a telecommunication infrastructure (e.g. video or phone calls) to deliver care to a patient at a distant site. Telehealth is the broader term to refer to technologies that provide care and services at-a-distance. |
Remote assessment of patients by the observer (i.e. traditional clinical outcome assessment [COA] conducted remotely) | Remote assessment of patients by the observer (i.e. COA conducted remotely): performance outcome assessments (PerfOs), patient-reported outcomes (PROs) and clinician-reported outcomes (ClinROs) can be evaluated via telemedicine/telehealth. The assessment method itself cannot be modified to be employed remotely, e.g. 6-min walk test can be administered by a clinician using a video interface. |
Remote data collection using digital tools for different purposes | Digital health technologies (DHT) such as sensors and wearables can be used to capture patient data remotely within a clinical study. The data captured may be a measure of physiology, function and/or behaviour, e.g. blood pressure (physiology), e-diary (behaviour), step counter (function) and sleep tracker (function). The non-invasive monitoring devices can be connected to a wireless network through Bluetooth, Wi-Fi or cellular connection to transmit a patient’s measurements directly to their health care provider or other monitoring entity. |
Remote collection of physiologic data for remote patient monitoring through DHT | Remote monitoring devices (e.g. wearables, hand-helds, stationary in-home monitoring and digital interfaces) can be used to measure the physiology of patients. The devices can also apply algorithms to transform a patient’s physiological parameters into a novel index or alarm that may aid a health care professional in the diagnosis of a particular condition or disease state/severity. Most use cases will fall under the medical device definition (defined in local regulations) and be classified as Software as a Medical Device (SaMD)/Medical Device Software (MDSW). |
Remote collection of outcomes data through DHT | DHTs can be used to collect digital measures that can construct a COA or a biomarker and be used as endpoints in trials. |
Key considerations to evaluate innovative approaches in clinical studies
CONTEXT | Clinical context | • What are the patients’ needs in this clinical context and disease setting? • What are the site and healthcare provider’s needs in this clinical context and disease setting? • Has the clinical context changed since the initiation of the study requiring the introduction of a new solution? • Did a COVID-19 infection change the clinical context and risk for patients within their primary disease? |
Context of use A. Related to the use of the innovative approach | • How will the innovative approach address the patient’s needs? • Will the approach address an important gap in access or equity in care? • Will the approach improve the patient experience in this study and is it feasible for this patient population? ◦ Has this been confirmed with patients/and or caregivers? • What are the benefits/downsides of using the approach for site/investigators/other healthcare providers in the study? • Will the innovative approach improve the site experience in this study? ◦ Has this been confirmed with the sites? • Will the innovative approach address a key gap in operational challenges? | |
B. Related to the use of the final study results | • What is the intended use of the study results? e.g. as proof of concept, or regulatory submission of the medicinal product and/or innovative approach. | |
EVIDENCE | Technical validation | • What data supports the use of the approach? i.e. are the data relevant and of adequate quality? • Has the approach been validated both in this patient population and disease setting? • What are the data gaps and mitigation steps? • Is the level of validation appropriate for how the innovative approach will be used in the study? And for the intended objective of the study? |
Clinical validation | • What are the benefits/downsides of using the solution for patients in the trial? • What data show that it can be used safely in patients and that it performs according to its specifications (if applicable)? • If the approach encompasses the use of a technology, is it safe for patients to use it? i.e. are there any risks associated with its use? Are there mitigation plans in place to ensure care continuity? | |
FEASIBILITY | Regulatory | • Is the approach and available documentation acceptable according to the local regulations? And what regulatory actions are needed to support implementation? • If digital tools are used, do they qualify as medical devices and do they have the required national certification/clearances? (e.g. CE mark in EU, FDA clearance in the US) • If the trial is already ongoing, does the incorporation of the approach need a protocol amendment? |
Data | • Does the approach introduce any risks related to data privacy? e.g. data access to unauthorised individuals or identification of study participants. • Does the approach support the collection of critical data to address the main objective of the study? • Does the approach pose risks related to the collection of reliable, consistent and complete data? i.e. any potential risks on the integrity of the study. • Are there any specific legal considerations? e.g. General data protection regulation in EU on data privacy. Are there any national restrictions on to use of the solution in specific countries beyond regulatory? • Is this technology collecting safety data? Consider the specific requirements. • Does the data collected follow the principles of FAIR (i.e. findability, accessibility, interoperability and reusability) data? | |
Ethical considerations | • Are there any ethical concerns about the use of the approach and in particular, could it enhance health inequity? e.g. introduces a technology that not all study participants have access/familiarity. • Does the informed consent form give enough information on the approach and its use? | |
Compliance | • Is the approach/technology compliant with the key international and national guidelines (e.g. GCP) and regulations related to privacy, accessibility, monitoring and patient inducement? • Is the approach/technology consistent with the sponsor’s standard practices and standard operating practices? If not, how will deviations be managed/recorded? • What are the potential risks if the patient does not know how to use the approach? • For approaches incorporating local labs/imaging, what are the related risks to data integrity and avoiding bias? What risk mitigation measures can be implemented to reduce the impact on data integrity? • If an external service provider will be used, what measures will be taken to ensure adherence to sponsor procedures? e.g. clearly defined responsibilities within contracts with sponsor oversight. • If local facilities are used, ensure collecting their certification and list of normal ranges (as applicable). | |
Operational | • How long (on average) would it take to implement this approach? For example, are contracts with specific vendors already in place? • Is the approach/technology easy to use by the site/investigator/patient? • Is training required to deploy the approach? Who requires the training? (e.g. principal investigator, patient, caregiver, nurses). Can the same training modules be used for all, or do we need to develop specific training for each group? How much time is required to organise the training? Is training available in the required languages? • Can this approach be implemented in all sites and countries? Is there appetite and interest from patients and sites in all countries? Can the approach be integrated into existing systems? • Can the approach/technology be widely deployed if necessary? • Is there enough vendor capacity and coverage? • Is special hardware needed to implement the approach, or can available hardware from patients/sites (e.g. smartphone) be used? • Can the study team procure and provide the hardware or other materials needed on time? Can the materials/resources be sourced locally to accommodate potential global supply issues? • Is there a process to solve issues identified by patients with the hardware (e.g. call centre)? • Is the approach cost-effective? What is the average cost (and cost model)? i.e. cost per patient, per site and per study. • If the approach is newly introduced into an ongoing study, how will the team document its introduction? Will the data be flagged with regard to how it was collected (e.g. remote collection of outcome data) to facilitate necessary sensitivity analysis? Can the change be flagged within the case report form? • Is there a way to monitor patient compliance through the study and a way to course correct if non-compliance is identified? • Is the data collected through the approach/technology easily accessible for the study teams to use and analyse? In what format? Can the data be integrated into company systems? • Are there any long-term considerations in deploying the approach? For example, what is the impact on subsequent studies? • Identify upfront the process for data flow to ensure integration into appropriate databases. |
Roche/Genentech experience: select cases
Telemedicine
Home administration and mobile nursing
Use of local laboratories
Digital health technologies to reduce patient visits to trial site
Proposed regulatory framework for fit-for-purpose approaches in clinical studies
Context
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Evidence to support its use
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Feasibility
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Insights on the use of the framework or whether this was a fit-for-purpose approach
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Clinical context/need:
Continuous remote heart rate monitoring for an experimental treatment for patients with breast cancer (BC).
Context of use:
-Related to the approach: Beyond routine, periodic monitoring of vital signs at study sites, digital health technology (DHT) could provide continuous heart rate data during treatment in a phase Ib study for patients with BC. This study was intended to pilot the use of this DHT in studies with BC. -Related to the study results: Safety and efficacy results from the phase Ib study could provide supportive evidence for a potential marketing authorisation application of the molecule. |
Technical validation:
The approach (commercially available DHT) is approved/cleared in the proposed countries for measuring heart rate in the general population.
Clinical validation:
Justification (or data) that this DHT can be used in breast cancer studies is needed.
Data relevance and integrity:
As indicated above. |
Regulatory and compliance:
There is limited regulatory guidance related to the use of DHTs in clinical studies and necessary evidentiary requirements when used in different settings making broader implementation (e.g. in studies for breast cancer or other indications) challenging. Data privacy: Different national and trial site data protection laws/guidelines presented a major operational challenge for using the DHT. Operational: Differences in local data protection laws, ethics committee acceptance of DHTs, and non-harmonised regulatory guidance made global implementation of this DHT in this (and potentially future) studies very challenging. | In conclusion, the framework could have been very helpful in raising awareness earlier of anticipated challenges. Such earlier awareness could have saved time and facilitated risk mitigation. |
Context
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Evidence to support its use
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Feasibility
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Insights on the use of the framework or whether this was a fit-for-purpose approach
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Clinical context/need:
Enable accurate and reliable cough measurements in respiratory disease
Context of use:
-Related to the approach: Collection of cough counts during treatment in a clinical trial -Related to the study results: Efficacy endpoint for a potential regulatory submission for marketing authorisation application |
Technical validation:
No technical validation of the DHT is available at this point in time; however, it is planned and required.
Clinical validation
Cough frequency is one of the recognised clinically meaningful measures [14] in the respiratory disease under investigation. Considering that the DHT will be technically validated for this disease, no further clinical validation is needed.
Data relevance and integrity:
Cough count is recognised as a relevant clinical endpoint in respiratory disease. Technical validation is needed to demonstrate that the tool can accurately and reliably capture cough counts. |
Regulatory and compliance:
Insufficient and non-harmonised regulatory and ethics committee guidance/position on the regulatory identity of the DHT, for example, is the product classified as a medical device and what are the required validation approaches. This makes global implementation of the approach challenging.
Data privacy:
Because cough count is an audio-based measure, care has to be taken to anonymise the data and prevent exposing personal health information (PHI).
Operational:
The addition of a DHT in this clinical trial adds complexity, e.g. the need to identify experienced vendors and related resources. | The issue of non-harmonised regulatory guidance/position standards was recognised at an early stage in the project. In conclusion, early awareness of anticipated challenges could save time and facilitate risk mitigation. This could be supported by the framework we are proposing in this publication, as it provides key dimensions that development teams need to consider, as in this case. |
Context
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Evidence to support its use
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Feasibility
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Insights on the use of the framework or whether this was a fit-for-purpose approach
|
Clinical context/need:
Safety follow-up of patients (paediatric and adults) at home to reduce travelling to sites and therefore patients’ burden/or in case travelling to sites was not possible during the COVID-19 pandemic.
Patients’ needs:
Mobile nursing was applied to conduct safety follow-up procedures as well as the collection of weight in the paediatric population to help determine the dose (IMP dosing is weight-dependent). Direct-to-patient IMP shipment was used to support patients that lived far away from sites to avoid unnecessary travelling/or if travelling was not possible.
Context of use:
-Related to the approach:
Mobile nursing and direct-to-patient IMP shipment. -Related to the study results: Supportive safety data for regulatory submission of a marketing authorisation application of the medicinal product. |
Technical validation:
N/A
Clinical validation:
Mobile nursing:
This approach was already used prior to the pandemic. Data collected by the nurses is the same as in the clinic. Further clinical validation is not needed. Essential aspects: training for nurses and site staff, contract with a vendor, PI oversight and good documentation practice.
Direct to patient IMP shipment
This approach was already used prior to the pandemic. Good documentation practice consistent with GCP principles are key (e.g. shipment conditions and confirmation of receipt), as well as adequate training of patients on IMP handling.
Data relevance and integrity:
N/A |
Regulatory and compliance
No regulatory issues (both the approaches were included in the initial clinical trial application). Both studies were part of the marketing authorisation application for a product which is now approved. The use of both approaches was only fully implemented during the pandemic. For this reason, re-training of the site staff was a key success factor. Data privacy: Additional language was included in the patient informed consent forms to make it more explicit.
Operational:
Enabled through the availability of global vendors that had experience in the application of the innovative approaches. Clear and proactive communication to regulatory authorities and ethic committees, during the clinical trial application process, on the mobile nursing and direct-to-patient shipment approaches was identified as key to success in approval. |
At study initiation (i.e. prior to the pandemic):
Uncertainties on patient preference for at-home safety follow-up led to limited adoption of the approaches in the adult population. Therefore, at study initiation, the framework would have helped to identify questions on patient preference regarding these innovative approaches. During the pandemic, the clinical context (i.e. patient needs) changed, and mobile nursing uptake for both adults and paediatric patients increased, as well as the use of direct-to-patient IMP to prevent COVID-19 exposure. Fortuitously, the provisions for mobile nursing and direct-to-patient IMP shipment enabled fast implementation during the pandemic showing how upfront strategic planning of appropriate approaches, as called out in the framework, is key. |