What are real-world evidence studies?

This refers to studies outside the constraints of a clinical trial setting. Real-world evidence (RWE) studies usually look at how drugs/interventions work in the real world or explore burden of disease. One type of RWE study could be a long-term registry and another a short gap-filling study. Essentially, the studies could involve one country or many countries, be short or long in duration, with participants recruited via sites, in the community, or a mixture of the two. A vital element is being able to tailor study design to the research questions and then the audiences for the evidence (e.g., health technology assessment, regulators, publication in scientific literature).

What are future uses of real-world study data?

Study data are useful, in addition to our clinical trial data package, for discussions and submissions to health technology assessment (HTA) bodies. When designing a real-world evidence study, it is worth engaging with those bodies to make sure this type of data would be acceptable to them. If no new products are available for a certain indication, these data will be useful to help payers understand the disease, and how it impacts patients. This could be European HTA bodies, but also US bodies such as ICER.

How useful is it to work with key opinion leaders and patient advocacy group representatives when conducting real-world evidence studies?

It is invaluable to work closely with clinicians experienced in treating patients (with a particular condition) and patient advocacy groups as it helps to ensure we are asking the right questions, in the right way. For digital registries with scientific advisory boards, including patient advocacy group representatives (many of whom are patients themselves) helps reassure participants that the registry is not just to collect data, but also for participants to track their condition (e.g., via a symptom diary) in a meaningful and patient-friendly way.

How can the data from a patient RWE registry be used?

For discussions and submissions to health technology assessment (HTA) bodies. When we help design the study, we engage with those bodies to make sure this type of data would be acceptable to them. Such data is really useful to help payers understand the disease, and how it impacts patients.

Why do you think patients are motivated to participate in real-world evidence studies?

There are multiple reasons which vary depending on the individual. We have had feedback that some participants want to give something back, and want to be part of new or innovative research to improve future management of their condition. Some find completing the questionnaires therapeutic, or find the features in the study useful to them (e.g., a symptom diary), or wish to keep up to date with the latest research information. If a study is not designed in a patient-friendly way, all these motivational factors can be lost, with a lack of engagement potentially leading to poor retention and completion rates.

Disease registries are often linked to a sponsor's clinical development plans for a product. At what stage of product development should an accompanying real-world evidence study begin?

This should be done prior to a pivotal study, as it can inform its design. If you are going to invest, invest early: set-up costs will be the same, and it is cost-effective to keep it running, plus there is often significant value in capturing longitudinal data. To allow for a seamless transition when the product is approved, we have a safety reporting module which can be added, meaning a pre-approval disease study can transform into a post-approval/phase IV study, opening the possibility of building data after initial discussions with regulators (PASS, REMS) and health technology assessment bodies/payers.

Why are rare disease registries invaluable?

The use of disease natural history studies prior to initiation of clinical trials can help guide the design of clinical studies and recruitment of patients into trials of new therapies. When designed carefully, registries create an engaged cohort which can also be contacted for future studies. Generally, digital registries can provide granular data, while also leveraging relationships with stakeholders. For rare disease registries in particular, the patients can be spread out geographically, making site-based studies harder to conduct. With a digital registry, the reach can be much wider and easier to recruit for.

What type of data can be gathered from a rare disease registry?

A broad range of data can be collected from a registry – here are a few examples: • Treatment patterns • Treatment preference/satisfaction • Quality of life • Diversity • Demographics • Healthcare-resource use • Patient experience • Physical function • Productivity losses • Burden of disease • Adverse events.

How do you build the best patient-reported outcomes strategy for a real-world evidence study?

The strategy is built in a similar way to RCTs as we still need to be confident that we are measuring the right thing in a robust way so the data will be credible and well received by a variety of stakeholders. The strategy can vary depending on the real-world study type. For example, in a registry we usually have a blank canvas to start with: we speak to patients/carers and look at the literature to explore what it is like to live with the condition of interest and identify the issues that are most important to patients in relation to their disease and treatment. Then we look at suitable patient-reported outcomes (PRO) instruments/questionnaires to be able to capture this information in a reliable way; sometimes we need to develop new instruments from scratch. For a real-world study with a narrower approach, such as a patient preference study or an online survey type methodology to assess one particular construct (e.g., health-related quality of life), our strategy is more focused. We look at the particular issues within that construct and then identify suitable instruments to measure them. Then there is the challenge of thinking about the practical implementation – how will the data be collected and how often? How will the data be analyzed? This is where our Analytics team comes in.

How do real-world evidence studies compare with patient-reported outcomes (and patients) that a sponsor might have in their RCT?

Similar instruments are used in RCTs and real-world studies as we want to ensure we capture data in a reliable and valid way. We often have more flexibility in a real-world study with the questions we ask patients and how we ask them. This is especially true if it is in electronic format as we are not burdening patients with having to come into a clinic for a study visit. Data are not scrutinized by regulators in the same way as RCTs so we have more flexibility in how we present information – infographics, charts, etc. There is also the option to validate instruments within the real-world study itself.

How has working with key opinion leaders and patient advocacy group representatives helped with the success of rare disease registries?

It has been invaluable to work closely with clinicians experienced in treating patients with rare conditions and patient advocacy groups (PAGs) as it helps to ensure we are asking the right questions, in the right way. In particular, the involvement of clinicians ensures rigor from a clinical perspective and that the data we collect will be meaningful and credible to other clinicians. For digital registries with scientific advisory boards, including PAG representatives helps reassure participants that the registry is not just to collect data, but also: •To better understand what it is like to live with a particular condition •To enable participants to track their condition (e.g., via a symptom diary) in a meaningful and patient-friendly way •To provide information about the study through articles, data-sharing, etc. The involvement of PAG representatives also helps us to establish whether certain patient-reported outcomes measures are unsuitable, e.g., in a recent online workshop during registry creation, patients told us there were some key symptoms missing from one of the shortlisted measures.

How do you ensure RWE data are published?

There are rich publication opportunities and we have been very successful in helping sponsors publish, but it is not always guaranteed. External stakeholders frequently expect publications as part of their involvement, with patient advocacy groups taking an active role in the review processes of publication content. There are abundant opportunities for publications with real-world studies, so we frequently build publication plans in parallel with studies.

Benefits of collaborative approaches to real-world evidence studies are obvious, but who owns the data? Presumably it is better if advocacy groups or even patients themselves own the data?

This is one important aspect of the governance framework for any study. We have had lots of discussions about “distributed” models of data ownership with patient advocacy groups (PAGs). However, many PAGs are not set up to discharge responsibilities of data ownership, e.g., having a Data Protection Officer, meeting GDPR requirements, etc. These discussions have concluded that the key driver in rare diseases is actually access to the data rather than ownership. So we have set up systems whereby non-commercial researchers can access study data, and such access is decided upon by a scientific advisory board.

In many rare diseases caregivers play a significant role, which is often undervalued and poorly understood. Can this also be measured in digital studies?

Yes, absolutely! The impact on caregivers can be measured in its own standalone study or could be added to an existing patient registry. We ask all our registry participants for “consent to contact” about further research, with a good opt-in rate, so this can be an excellent means of identifying potential participants for a caregiver study. More generally, the impact of conditions on families and caregivers is a growing area of interest, recognizing that the burden of living with a condition extends beyond the patient, with caregivers experiencing a wide range from emotional impacts to having to take time off work, for example.

Many rare diseases affect pediatric patients. What are the challenges with this population?

We have conducted several studies in pediatric populations. It is not as simple as taking an adult study and making a few changes – there are specific considerations and challenges to be addressed during the design of the study. It is important to select patient-reported outcomes measures and design questions that are appropriate for children. Due to developmental differences between age groups, we cannot just apply the same questionnaire to all children as we might for adults. It is important to consider the requirements and cognitive understanding in narrow age bands, e.g., under-5s, children aged 6–11, and teenagers. These groups will have different needs. In some cases, particularly in the youngest groups or those with a condition which causes cognitive impairment, it may be more appropriate to carry out a proxy measure. There are also greater limitations in terms of the number of questions we can ask children before they lose concentration/get bored, so it is especially important to prioritize effectively and design the data collection platform in an engaging, user-friendly way; usability testing is also a very important step in the development process. Ethical and regulatory considerations include consent and assent, which vary between age groups, and the need to obtain parental consent first, for which separate consent forms/information sheets, etc., need to be developed.

How much does a real-world evidence study cost?

There is a lot of variability, as with an RCT. The key drivers are complexity (e.g., data capture), number of countries, duration, recruitment method (e.g., site vs. community), incentivization, age groups, and licensing for patient-reported outcomes measures.

What are the building blocks for user-friendly study app content?

With our Vitaccess Real™ platform, we can deploy studies very quickly – so fast that other workstreams are often the limiting factors, e.g., licensing for patient-reported outcomes measures or site contracting. Three months is typically the minimum, with data available in real time after study launch. We have had pre-registered participants as quickly as three weeks after contract signature, which we think is exceptional! Community recruitment is also very fast: we have recruited hundreds of participants in under 3 months for a rare disease study.

Is a meeting with the FDA generally needed before investing in a long-term real-world evidence adverse event reporting plan?

No, if the study currently conducted does not support a marketing application. According to the attached FDA draft guidance “Considerations for the Use of Real-World Data and Real-World Evidence”, the sponsor should engage with the FDA in the early stages of designing a non-interventional study intended to support a marketing application. So, should the real-world evidence (RWE) study you are currently conducting be used to support a marketing application, then the answer is yes. Note that the FDA can always be asked for input on a voluntary basis, even when it is not required – this is a sponsor’s decision. According to the same draft guidance, applicants of NDAs and BLAs, and other responsible parties are subject to regulatory requirements regarding post-marketing safety reporting so this legislation needs following. As per the guidance, no pre-meeting with the FDA required. Also, given that non-interventional studies examine the use of a drug in routine medical practice, the FDA requires that relevant adverse events be submitted to it in accordance with post-marketing safety reporting regulations. So as per the regulations, no pre-meeting is needed. Only when using innovative trial designs where RWE is combined with an interventional trial for efficacy and safety reporting purposes would we recommend a pre-meeting because this is an unexplored area and the FDA should state upfront to what extent they will allow RWE for the marketing application. If there is no pre-meeting, expensive and long trials might not yield the desired results.

Should sponsors avoid longitudinal studies that continue pre- and post-approval of a drug, as it will increase the chances of having events to report?

This type of study has no impact on the safety profile of a product. Fulfilling obligations by modifying an existing study will be far more cost-effective than starting separate programs and, of course, here you have the significant benefit of longitudinal data.

Are there any design considerations pre-launch to ensure post-launch safety can be implemented?

Causality is important, so it is useful to be able to link the event to a specific treatment, and if there are lots of treatments and causality is unclear, that can be a problem. It’s also important to be able to flexibly evolve the design, e.g., by adding safety reporting, or amending the informed consent.

Have you already implemented safety reporting in real-world evidence studies?

We have done pre- and post-marketing studies, as well as safety reporting with the dedicated Vitaccess Real™ safety reporting module, which has showed the continuous use case. We haven’t yet built a continuous study with reporting added at launch, but this is still a relatively new area, so we think it will grow. As an example of one deployment, in addition to the mandatory data requirements, we worked with a sponsor to specify data capture and work flows, plus obtain the necessary ethical approvals. User interface/user experience (UI/UX) were also considered to ensure the result was user-friendly for participants.

Can pre-approval data from real-world evidence studies be of interest to regulators?

Yes. Of course, their priority will be the data arising from clinical development to adjudge safety and efficacy. However, regulators such as the FDA and EMA have issued guidance showing that they are interested in real-world evidence to help understand diseases and the patient perspective.

What is the value of longitudinal data?

Its range – natural history of disease, disease progression, as well as establishing the burden of disease prior to the introduction of a sponsor’s new treatment.

Can you specify different data capture for different regulators/ audiences? (e.g., FDA vs. EMA)

Not only can we do that, it’s vital! The flexibility of a digital platform is a key advantage for compliance with local requirements. And, of course, we would encourage engagement with regulators, as with other audiences.

So a pre-approval natural history study can evolve to comply with post-marketing safety reporting?

Yes. As always, we suggest engaging with the regulators to get advice on the design of the study, and ensure that they are satisfied with the data you will be providing them. Any post-marketing real-world evidence safety reporting will be informed by understanding developed during clinical development.

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