Regulatory considerations for successful implementation of digital endpoints in clinical trials for drug development

Abstract

Regulatory acceptance of Digital Health Technology (DHT) -derived endpoints can be a long, multifaceted and costly process. Success relies on establishing a global strategy as part of the development program including health authority consultations to ensure alignment with regulatory requirements. In this manuscript, the authors provide stepwise guidance for successful implementation of DHT-derived endpoints in clinical trials for drug development.

Introduction

Advances in Digital Health Technologies (DHTs) have opened new opportunities in clinical trials by providing innovative methods to collect information from participants¹. DHTs consist of hardware and/or software and can be used on various computing platforms, such as mobile phones, smartwatches, etc.^2,3. More advanced DHTs also leverage artificial intelligence and machine learning for data processing and analysis⁴. The use of DHTs in clinical trials offers several potential advantages by providing richer data sets (e.g., continuous data collection in participant’s home environment vs. snapshots/episodic recordings during clinical visits) or performing objective measurements without recall bias that flaws Patient Reported Outcomes, leading to a better understanding of the efficacy and safety of the interventions studied^1,3,5,6. Via remote data acquisition, DHTs can also decrease the number of clinical trial sites and follow-up visits and potentially increase diversity and inclusivity in clinical trials⁷. For these and other advantageous reasons, we have seen the use of DHTs in clinical studies increase significantly over the years^1,8–10. Recently, the first example of digital outcome assessment used in a pivotal study was completed, the Phase III REBUILD clinical trial of INOpulse for the treatment of fibrotic interstitial lung disease, the primary endpoint was the change in moderate to vigorous physical activity, as measured by actigraphy (NCT03267108). Unfortunately, the study failed to meet its primary endpoint.

Regulators and legislatures have recognized the potential of DHTs in clinical trials and provided guidance and documents to help support the development of these new tools^3,5,6,11,12. As part of the US Food and Drug Administration’s (FDA) work to fulfill the Prescription Drug User Fee Act (PDUFA) VII commitments, FDA has recently published the Framework for the Use of DHTs in Drug and Biological Product Development and established the DHT Steering Committee which consists of senior staff from the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH) to support the implementation of the framework for the use of DHTs in drug and biological product development^12,13. Additionally, the US FDA has created the Digital Health Center of Excellence, based in CDRH, which is intended to provide scientific expertise on DHTs for all of FDA and connect internal and external stakeholders to FDA in the DHT space. To further this mission, the US FDA created the Digital Health Advisory Committee in October 2023 to advise the Commissioner of Food and Drugs on scientific and technical issues related to DHTs. As part of the PDUFA VII commitments FDA has also agreed to hold a series of five public meetings to discuss the use of DHTs in regulatory decision making and identify three demonstration projects to further progress the evaluation of DHTs.

The recent landmark qualification of the stride velocity 95^th centile as a primary endpoint for ambulatory Duchenne Muscular Dystrophy studies by the European Medicines Agency (EMA) demonstrates the regulatory utility of DHT-derived endpoints in drug development and approval processes¹⁴. This endpoint is also currently under review by the US FDA as part of the Drug Development Tools, Clinical Outcome Assessment (COA) qualification pathway^15,16. In addition, US FDA qualified the first DHT under the Medical Device Development Tools program, as a biomarker to help evaluate estimates of atrial fibrillation burden as a secondary effectiveness endpoint within clinical studies intended to evaluate the safety and effectiveness of cardiac ablation devices¹⁷. This qualification is for a specific context of use (CoU) in medical device development and is not directly applicable to clinical studies for drug development in atrial fibrillation.

Regulatory acceptance of DHTs can be a rigorous and lengthy process. It necessitates results from multiple prospective studies to demonstrate the validity and reliability of DHT, and clinical relevance of the DHT-derived endpoint^1,3,6,18,19.

While this manuscript focuses on the regulatory considerations of using DHTs for capturing COAs and biomarkers in clinical trials, it is crucial to consider other important aspects such as technical, operational, and ethical considerations. These topics are beyond the scope of this manuscript, but readers are referred to previous publications^9,20,21.

Considerations for the use of DHTs in clinical trials

DHT-derived endpoints can complement accepted endpoints or provide new ways to capture existing endpoints for a more granular and holistic disease monitoring or awareness. If DHT is used for digital acquisition of an accepted endpoint (e.g., to measure blood pressure in a participant’s home), demonstration that DHT is fit-for-purpose (the level of validation associated with a DHT is sufficient to support its context of use³) is likely to be adequate for regulatory acceptance. If the DHT is a medical device, the clearance/approval of the DHT by FDA and/or CE marking under EU MDR for the intended purpose would be highly recommended to demonstrate that the device is fit-for-purpose. In many cases a DHT also measures a novel endpoint addressing unmet measurement needs in clinical development. In such cases, additional considerations as outlined in the following sections are required.

Concept of interest, context of use and conceptual framework

Incorporation of DHTs into a drug development program is a complex process. As outlined in Fig. 1, first, the Concept of Interest (CoI), a health experience that is meaningful to patients, and represents the intended benefit of treatment should be defined^6,19,22. If the proposed measure is a novel endpoint, it would be advisable to establish early on whether the novel endpoint is addressing a core aspect of the disease and is meaningful to patients. Subsequently, the CoU should be delineated and include how the DHT will be used in the trial (i.e., endpoint hierarchy), the patient population, study design and whether the measure is a COA or a biomarker^2,6,19,23 (Fig. 1).

Fig. 1. Demonstration of DHT is fit-for-purpose.

Steps for showing DHT is fit for purpose for use in a development program as an endpoint measure.

It is important to design a conceptual framework for the DHT-derived endpoint visualizing the relevant experiences of patients, the targeted CoI, and how the proposed endpoint fits into the overall assessment in a clinical trial³. This becomes particularly important when the disease of interest has multiple health aspects, and the proposed endpoint does not address all of them. Figure 2 provides an example of a conceptual framework that outlines the different types of COAs proposed for each health concept of a disease and how a novel DHT-based electronic performance outcome assessment (ePerfO) fits within the model. In this example, the new ePerfO is proposed to be added to a traditional cognitive battery of tests to capture aspects of cognitive function that are not adequately captured in clinical trials for early Alzheimer’s Disease (AD). The Clinician Reported Outcome Assessment (ClinRO) and the Observer Rated Outcome Assessment (ObsRO) are validated measures. The ePerfO has multiple components and combining these individual components in validated machine learning-enabled models has been shown to enhance sensitivity in detecting cognitive impairment compared to traditional assessments in patients with mild cognitive impairment and dementia. A Type C meeting was requested seeking the FDA’s advice on the acceptability and validation of the ePerfO for demonstrating treatment effect on cognition in early AD (in 2022, under an investigational new drug (IND) application). The Agency provided feedback that it was unclear how the individual components of the ePerfO data would contribute to a meaningful assessment of cognition. The Agency communicated that even though the ePerfO might be a sensitive instrument for detecting subtle changes in cognition, there may be challenges in interpreting the clinical significance of any effects of an intervention on that instrument. The Agency recommended to consider the ePerfO to be most appropriate only as an exploratory endpoint. The Agency did not comment on the proposed ClinRO and ObsRO.

Fig. 2. An example conceptual framework for an Alzheimer’s disease (AD) clinical trial.

The framework outlines the relevant experiences of patients related to meaningful health concepts in AD and corresponding CoI within the Conceptual Model. Measurement Model then links each CoI to a COA assessing the severity or impact of the corresponding aspect of the disease. ePerfO (Electronic Performance Outcome Assessment) is a novel ePerfO measured by a DHT; *: ClinRO (Clinician Reported Outcome Assessment) and ObsRO (Observer Rated Outcome Assessment) are broadly used and validated outcome assessments.

This feedback highlights the importance of demonstration of the meaningfulness of the new measures to the patients. However, establishing clinical meaningfulness for abstract concepts, such as cognitive domains (e.g., executive functioning, processing speed) represents challenges. Additionally, in diseases with cognitive impairment like AD, patients often suffer from a lack of insight, making it difficult to rely solely on their self-reported assessments. Instead, care partner input is often used, but it is subjective and may not accurately reflect how patients truly feel and function. Moreover, in AD, when treatments are directed towards slowing cognitive decline, it can be difficult to demonstrate the meaningfulness of the change when improvement is seen in the form of slowed decline. As such, the assessment of the meaningfulness of the treatment effect on cognitive decline in early AD remains an unresolved issue. Early HA consultations are advisable to ensure that the endpoint is accepted by the HAs (also see Figs. 3 and 4).

Fig. 3. Decision tree for a clinical study based on whether DHT is a medical device, it is used for the intended use and fit-for-purpose.

1: The definition of medical devices is provided in Section 201(h) of the Food, Drug, and Cosmetic Act and Regulation in the US and (EU) 2017/745 (Medical Devices Regulation) and Regulation (EU) 2017/746 in Europe. *: In cases where DHT is a medical device, CE marking is provided by a Notified Body (NB); HA: Health Authority; IRB: Institutional Review Body, EC: Ethics Committee.

Fig. 4. Health Authority (HA) consultation strategy.

The key time points for HA consultations include prior to starting clinical studies to align on CoI and CoU and prior to progressing from early exploratory studies to registrational studies to align on whether the evidence package would support method finalization.

Fit-for-purpose/ fit-for-the intended use

After defining the CoI and CoU, the minimum technical and performance specifications of the prospective DHT should be established to guide selection of a fit-for-purpose DHT (Fig. 1). These specifications could also be used as reference to ensure the DHT remains fit-for-purpose for the duration of the trial³. Further information on the DHT can be obtained from the manufacturer(s)/vendor(s) directly (Table 1).

Table 1.

DHT information from manufacturer/vendor(s)

DHT information from manufacturers/vendors
Intended use of the DHT per the manufacturer. • Validation and verification data to demonstrate the DHT is fit-for-purpose for the intended use. • Ensure contract covers the obligation of vendors to provide supportive documentation to address HA/IRB/EC requests for information (e.g. validation/verification reports etc.). • If the intended use of the DHT differs from the CoU, perform gap analysis to determine what additional verification/validation studies are needed to ensure DHT is fit-for-purpose (Fig. 1).
A copy of IFU/Manual and labeling • Assess for changes in the DHT version described in the IFU vs. what was originally cleared/approved. • If the IFU and intended use do not match, check whether the manufacturer have additional validation data to back up the expanded intended use and discuss with the vendor the reasons for the discrepancy and HA/EC/IRB questions may be addressed.
According to the manufacturer, is the DHT a medical device or not? If not, what is the rationale? • If it is a medical device, all applicable registration/approval documentation for all countries where the device is to be used (e.g., FDA 510(k) clearance, PMDA approval; EU CE Certification under medical device regulation ((EU) 2017/745), UKCA marking, and other relevant registration approvals/licensing).
If the DHT is associated with an algorithm, has the algorithm been validated for the CoU? Can it be made available to the sponsor and/or to HAs/ECs/IRBs? • If the algorithm cannot be made available due to IP restrictions, request for validation of the algorithm on multiple unrelated data sets to show both accuracy and robustness.
Request all technical specifications of the DHT (both hardware and software) to be evaluated as part of the fit-for-purpose evaluation.
Is the DHT including data transfer measures compliant with data privacy regulations (e.g., GDPR regulations in EU25).
What are the experiences with importing the DHT into countries where clinical studies will be carried out.
A list of clinical trials in which the DHT has been used.
Any HA and/or IRB/EC feedback for the DHT and its use in clinical trials.

EC Ethics Committee, HA Health Authority, IFU Instructions for Use, IRB Institutional Review Board, UKCA UK Conformity Assessment.

The DHT must be fit-for-purpose/ fit-for-the intended use. The evidentiary burden to demonstrate the DHT is fit-for-purpose for regulatory acceptance varies depending on how the DHT is used^18,19. The highest bar will be for use as a primary endpoint or to support label claims in a pivotal trial. For all DHTs regardless of whether they are medical devices or consumer grade, it is recommended to review the technical specifications, available verification, and validation information even if the DHT will be for use in an exploratory endpoint for internal decision making and/or hypothesis generation.

Figure 3 describes a decision tree based on whether the DHT is a medical device, whether it is fit-for-purpose for the intended use and recommended HA consultations. The intended use and indications for use of the DHT determine whether it meets the definition of a medical device. In the US, FDA adopts a risk-based least burdensome approach for DHTs that are medical devices but are not cleared or approved for the proposed intended use: for a non-significant risk device (21 CFR 812.3(m)) an Investigational Device Exemption (IDE) application to FDA is not generally required if the investigation complies with the abbreviated requirements in 21 CFR 812.2(b); for a significant risk device, when all information required in an IDE application under 21CFR 812.20 is provided in the IND, a separate IDE submission is unlikely to be needed³. The regulatory and legal framework for DHTs in Europe differs from that of the US^4,6,11. EMA’s remit is limited to the specific use of a methodology in the development, use or monitoring of medicinal products pre- or post-authorization^4,6. EMA and National Competent Authorities (NCAs, the medicines regulatory authorities of the Member States that are primarily responsible for the authorization of medicines available in the EU that do not pass through the centralized procedure) in Europe are likely to expect the technical validity of DHTs to be demonstrated, ideally through CE marking for the intended COU in the trial. The DHT should be deemed “suitable and valid” and supporting data should be presented in the in the Marketing Authorization Application (MAA)^14,24.

In Europe, the responsibility for assessing medical device submissions and granting CE marks lies with Notified Bodies (NBs, an organization designated by an EU country to assess the conformity of certain products before being placed on the market). NBs, however, do not participate in drug medicinal product review or provide advice on device development unless the sponsor submits an application to the NB for the device approval. Additionally, in Europe, not all NCAs have medical device expertise, thus when technical information for DHTs is submitted to NCAs for review, differences in opinions among NCAs may arise. This can create a bottleneck for the use of DHTs that are not CE marked under Medical Device Regulation ((EU) 2017/745) for the intended use but are deemed fit-for-purpose. In the Regulatory Science Strategy to 2025, EMA recognized the potential impact of DHTs on drug development and committed to establishing a multi-stakeholder platform to gather feedback on the use of DHT-derived measures and endpoints⁵. This new platform is aimed to complement the existing qualification and scientific advice procedures and provide an additional avenue for obtaining input from various stakeholders, including NBs. By bringing together relevant competencies and expertise, the platform is expected to streamline the regulatory evaluation of DHTs while minimizing unnecessary delays. It is not yet clear how the new platform could help to streamline advice from NCAs that have different opinions or how the existing bottlenecks for non-CE marked DHTs could be addressed. It is encouraging, however, that proposals for new EU/EEA pharmaceutical legislation includes provisions for the EMA to use device expertise when developers are seeking scientific advice for medicinal products to be used with a device.

Changes to the DHTs during the clinical trials

Changes to the DHTs such as software or hardware updates during the clinical trials, could occur for various reasons (e.g., to implement improvements that enhance the patient’s experience or add new features to the device etc.). Sponsor may be forced to consider changing the DHT while the study is ongoing due to issues with the supplier. These changes could have significant implications, up to the invalidation of results from a clinical study. Ideally, the ability to freeze the algorithm prior to the start of the study should be one of the minimum technical requirements as part of the DHT fit-for-purpose assessment.

For medical devices it is expected that the manufacturers have change-control plans. For consumer grade technologies, these changes and their timing are likely to be driven by market needs. It would be advisable to collaborate with the manufacturers to address the potential mismatch between market needs and clinical trial use by establishing a predetermined change-control plan whereby intended modifications to the technologies are proactively specified. Contingency plans should be put in place to address planned and unplanned changes to minimize the impact on the ongoing study. Sponsors are recommended to put a risk mitigation plan around this in advance. When changes occur, the sponsors should assess the change and its implications (e.g., whether the data obtained by different versions are significant, whether the changes result in data integrity or safety issues) and document it as part of the audit trail system. Additional verification and validation studies may be required^3,11.

Considerations for missing data

Missing data and how it is minimized is an important aspect of DHT-based measures as it may occur during remote data acquisition. During the DHT development or selection of a DHT for use in a clinical trial, the design features of DHTs such as data storage capacity, battery life as well as trial design and operational aspects (e.g., patient population, timing, frequency and duration of data collection, and suitability of the data acquisition and transfer methods) should be considered to minimize missing data. Sponsors should also ensure that site personnel, study participants and their care providers are adequately trained. However, despite all efforts, the missing data is unlikely to be fully eliminated. How much missing data can be tolerated would depend on the purpose of the DHT-driven measure in the study. Sponsors should have a plan in place to reduce the potential for missing data as part of the risk management plan. How to handle missing data should be discussed and aligned with regulators early on³.

Data protection and privacy

Clinical trial sponsors need to ensure transparency, lawful collection, transfer and retaining of the minimum required personal information, to be used for the purposes specifically communicated to clinical trial participants. Following the applicable laws and regulations (e.g., General Data Protection Regulation (GDPR) in the EU²⁵), this could be achieved through less intrusive ways, ensuring sufficient information is provided to the participants allowing them to make informed decisions. Prior to implementation of a DHT, a privacy assessment should be done to assess risks and potential harm to the individuals and third parties involved in data collection. This assessment should include cybersecurity requirements. Adequate data transfer measures including measures for the transfer of personal data to a third country or to an international organization according to Chapter 5 of GDPR²⁵ should also be in place^3,11.

Additional considerations for measuring a novel endpoint

When the DHT is measuring a novel endpoint, in addition to demonstrating that it is fit-for-purpose, a strong justification on how the new measure adds value compared to existing measures is needed³. Principles around the development of novel DHT-derived endpoints are the same as those for any other endpoint development³. Early in the development process, it is crucial to define whether the new measure is a COA or a biomarker, as part of COU delineation²⁶. This distinction is important because it can influence the evidentiary requirements for its acceptance by regulators. The authors strongly recommend against considering a COA as a biomarker (and against the interchangeable use of those terms), even for internal decision making. Also note that the type of the biomarker and how it is used in the trial would also influence the evidence requirements for its acceptance²⁷. A novel biomarker must be demonstrated to be accurate (i.e., analytically validated). There should be a discussion with the HAs as to what level of accuracy is necessary for the novel biomarker prior to the initiation of an analytical validation study. In the US, for biomarkers used as surrogate endpoints for accelerated approval the sponsor must demonstrate that the surrogate is reasonably likely to predict clinical benefit^28–31.

Sponsors should provide a robust rationale for developing the new endpoint. For instance, the novel digital endpoint (i) could be more sensitive and accurate than existing endpoints, (ii) can directly measure the patient’s disease symptoms rather than a distal concept of the disease. In disease areas where there is clearly an unmet need for new endpoints, HAs may take a risk based approach to the benefit:risk assessment for use of novel digital endpoints. For more details on endpoint development including demonstration of clinical meaningfulness and applicable statistical approaches readers are referred to FDA publications^18,19,27.

Health authority submissions and consultations

Discussions with HAs should begin early, before beginning clinical studies to gain agreement on the COI, path towards validation of the DHT and endpoint (Fig. 4). At this early stage during the conceptualization of the COI and COU, if relevant data from literature and the DHT manufacturer are available, those should be presented to the HAs.

There are multiple ways to engage with HAs to receive feedback on the desired endpoint and/or the DHT being developed, depending on the goal of the development program. FDA and EMA have voluntary qualification processes for drug development tools (DDTs) and methodologies, which provide options to obtain advice and qualification of a specific context of use of the proposed method in a clinical trial context (Table 2). Qualification as a DDT is not mandatory and requires a comprehensive evidentiary package with certain aspects of submissions being publicly disclosed. Once a DDT is qualified, it can be utilized for the development of any product for the qualified COU. However, to date there have been no successful DDT qualifications for DHTs to be used in drug development clinical trials in the US. The “cost, complexity, and multidisciplinary nature” of qualification may create challenges for individual stakeholders²³. Instead, qualification programs are encouraged to be used by collaborative entities, such as consortiums or other public-private partnerships. Innovative Science and Technology Approaches for New Drugs (ISTAND) pilot program is an exciting new opportunity for DHTs to be qualified by the FDA and may be suitable for qualification of DDTs that are out of scope for existing DDT qualification programs but may still be beneficial for drug development²³. For DHT use in individual drug development programs, use of HAs’ scientific advice meetings provides sponsors with more targeted, and confidential sources of advice and guidance (Table 2)^13,32,33.

Table 2.

Options for HA consultations

	Early dialog	Use with a specific drug program	Qualification for a specific COU
US FDA	CPIM (Critical Path Innovation Meeting)a • For discussions outside of an individual drug development program. • Suitable for early stages of development, e.g., conceptualization stage. • Discussions are informal & the Agency’s feedback is non-binding.	ND Path (e.g., INTERACT, pre-IND, Type C, or D meetings)32 • Advice for a particular drug development program incorporating DHTs, and/or medical devices. • Option to request for focused Type C meetings on the Clinical Outcome Assessment or biomarker. • Type D meetings are for discussions focused on a narrow set of issues and may be suitable for a general discussion about an innovative development approach that does not require extensive, detailed advice • Initial Targeted Engagement for Regulatory Advice on CDER and CBER producTs (INTERACT) meetings are intended for novel products and development programs that present unique challenges in early development and may be suitable for early discussions on novel endpoint measures among other aspects of the development program. • Confidential	COA (Clinical outcome assessment) or Biomarker Qualification Programs (under the Drug Development Tool (DDT) Program)b33 • Not specific to a particular drug development program. • Potential to result in formal qualification of new COA for use across multiple drug development programs. • Requestors may ask for a meeting with the relevant DDT qualification program at any time to discuss the qualification pathway for their specific DDT and COU. • Qualify and make DDTs publicly available for a specific context of use to expedite drug development and review of future regulatory applications. • Qualification of DDT tools likely to be time and resource intensive and may be more suitable for public-private partnerships • Innovative Science and Technology Approaches for New Drugs (ISTAND) pilot program • May be suitable for qualification of DDTs that are out of scope for existing DDT qualification programs but may still be beneficial for drug development. • Includes methods, materials, or measures to facilitate drug development, • Qualified by FDA to have a specific interpretation and application within the stated COU. • Publicly disclosed.
EU EMA	ITF (Innovation Task Force) • Early stages of development, conceptualization stage, before confirmatory clinical data • Non-binding.	Scientific Advice33 • Advice for a particular drug development program incorporating DHTs, and medical devices. • Confidential	Qualification of Novel Methodologies5 • Qualification Advice process at the endpoint development stage, or • Qualification Opinion process when the endpoint has been validated by the sponsor for use across multiple drug development programs. • Publicly disclosed.
EU National Competent Authorities		Scientific Advice • Scientific Advice from a single NCA or Simultaneous National Scientific Advice (SNSA) from multiple NCAs. • Advice for a particular drug development program incorporating DHTs, and medical devices. • Confidential
FDA & EMA	Parallel Scientific Advice (PSA) Program7 • Raise questions or issues involving the development of a medicinal product, especially those lacking development guidelines • Single meeting
National Health Authorities	MHRA, Health Canada, Swiss Medic, PMDA, etc. • Advice for a particular drug development program incorporating DHTs, and medical devices. • Confidential

^aFDA Critical Path Innovation Meetings: provides an early source of feedback from FDA which allows Center for Drug Evaluation and Research (CDER) and investigators to discuss potential scientific advancements in drug development. But it should be noted that the CPIM is not a venue for entities to market commercial products to or seek endorsement from the FDA and CPIM does not permit an in-depth review of data by the FDA.

^bFDA Qualification Process for Drug Development Tools see also, section 507 of the Food, Drug and Cosmetic Act; FDA’s program provides qualification when FDA has made a determination that a DDT and its proposed context of use “can be relied upon to have a specific interpretation and application in drug development and regulatory review.” This means that a “qualified DDT used within the [context of use] may be applied to support or obtain approval or licensure (as applicable) of any drug, provided that the qualification has not been rescinded or modified.”

It is important to plan for multiple engagements with HAs to allow for the implementation of the feedback received into the study design and set up follow-up meetings to discuss results and determine next steps. Because HA consultations are resource intensive, sufficient resources should be allocated as part of the program plans and objectives. Engaging with HAs and incorporating their feedback into the study design increases the likelihood of ultimate regulatory acceptance and facilitates smooth implementation of DHT-derived endpoints in clinical studies. Since these technologies will support global projects, it is essential to consult major HAs, such as the EMA, US FDA, UK Medicines and Healthcare Products Regulatory Agency (MHRA), or Japan Pharmaceuticals and Medical Devices Agency (PMDA), to ensure alignment with regulatory requirements across different regions and to obtain broader acceptance. Differences in requirements for validation of DHT-based measures from different HAs could delay and in some cases prevent the successful implementation of these measures. Harmonization of requirements for validation/qualification of DHT-based measures by achieving scientific consensus with regulatory and industry experts and other stakeholders is key to advance the field.

In summary, successful integration of DHT-derived endpoints requires a comprehensive regulatory strategy as part of an overall development plan. This strategy should be tailored to the specific program objectives, endpoint hierarchy, target product profile and include planning for global HA consultations. Engaging with HAs early on allows alignment with regulatory requirements, identification of potential gaps and implementation of strategies to address them effectively in a timely manner.

Author contributions

G.E., T.M. and S.W. equally contributed to the writing and reviewing of the manuscript, read and approved the final manuscript.

Competing interests

G.E., T.M. and S.W. are employees of Novartis and may hold shares in the company but have no non-financial competing interests.