RARE DISEASES

Many drug developers have now turned their attention to rare and orphan diseases, making this a dynamic development space with a predicted CAGR of 12.3% by 2024, approximately double the rate for non-orphan drug markets.1

However, many challenges characterise rare disease (RD) drug development, including a lack of established data, low number of KOLs globally, small numbers of patients who may be geographically dispersed, and a scarcity of research assets such as natural history data, registries, and biobanked samples.

Yet, sponsors pursuing treatments for rare diseases have one key advantage in overcoming these challenges: the ability to collaborate with patient communities through rare disease patient advocacy organisations (PAOs) ‒ nonprofit groups that aim to improve the lives of those impacted by a given disease.

A PAO’s mission may include a variety of efforts, such as patient support, education, political advocacy, and advancing research into the condition, including clinical research support.

The rare disease advocacy landscape is highly sophisticated and includes disease-specific and umbrella organisations at national, regional and global levels. Disease-specific PAOs exist at every stage of the PAO life cycle, from recently formed to legacy organisations. Often, recently formed PAOs can rely on umbrella organisations for capacity-building support.

Many rare disease PAOs are highly experienced in collaborating with sponsors throughout the drug development process, from the preclinical stage to beyond commercialisation. An effective partnership, working towards the mutually beneficial goals of the sponsor and the PAO, is a critical success factor in this space.

Such partnerships can hold a great deal of value for sponsors and stakeholders, and are important in the implementation of rare disease clinical trials. This article will explore the powerful potential of collaboration with PAOs for clinical trials, particularly how PAOs can inform trial design and the creation of patient registries.

In the rare disease space there is often not the same abundance of information available to researchers and developers as there is for more common indications. However, PAOs are often repositories of knowledge gained from first-hand and shared patient experiences, collected informational materials and involvement with clinical research. For those looking to develop treatments for rare diseases, PAOs present an invaluable resource.

Additionally, in many cases, a PAO is a community. While patients with a given rare disease may be geographically dispersed, a PAO can bring them together. Building a relationship with such a group of people, many of whom are motivated to take action concerning the disease in question, can be incredibly beneficial, as it can help with finding those who are interested in participating in clinical trials and make it easier to gather information and input about what patients and caregivers value and need. Engaging with the PAO to understand the disease is typically the most direct and cost-effective way for a sponsor to gather information critical to the clinical programme strategy, including preferred/acceptable product formulation, desired benefits, connection to KOLs, understanding geography of patient communities, protocol design considerations, barriers to participation in a clinical trial and support that can effectively address these barriers.

As a result, working with a PAO can help to improve the patient-centricity of clinical trials, and ultimately benefits sponsors and patients.

When sponsors collect and, where possible, act on input from PAOs, patients will be more likely to participate and stay involved with clinical trials. If the perceived burden of the trial is too high compared to potential benefits, enrolment will be low. Therefore, considering the patient perspective early in the clinical trial design process is critical to trial success. Multiple studies have reported that enrolment and retention rates are higher when patients are able to contribute to trial design, and avoid costly timeline delays, protocol amendments, and other common study risks.2

There are several ways in which PAOs can contribute meaningfully to the design of clinical trials. Many stem from the ability of patient groups to advise researchers on patient needs and experiences. For example, PAOs can provide input on trial protocols and suggest ways in which procedures and materials can be better adapted for the patient population involved. Elements as simple as using equipment that is better suited to patients can improve the patient experience and provide more accurate data, for example using paediatric silicone spirometer mouthpieces for adult patient groups that, due to their condition, have difficulty forming a seal with rigid adult mouthpieces.

There are also broader trial design elements on which PAOs are well positioned to comment, one of which is clinically meaningful outcome measures. Measures which researchers implement without consulting patients, such as surrogate markers, do not necessarily guarantee a study is assessing results that are meaningful to the patient’s experience of the disease. In fact, a lack of evidence showing that outcomes are clinically relevant to patients may impede a treatment’s regulatory approval. However, PAOs have a wealth of first-hand knowledge of the patient experience and what outcomes they view to be important.

Therefore, PAO input in this regard is highly constructive, particularly in the case of rare diseases, where existing measures may not be directly applicable.

Sponsors may wish to consider the use of patient-centred outcome measures that focus on how patients survive, feel, or function, and can ensure a clinical trial is measuring outcomes that are relevant to the patients’ experiences and priorities. When patients have input regarding outcome measures, it is much clearer that a treatment has meaningful patient benefit and effectiveness. These measures can be informed through focus groups, interviews, audio or written diaries and a variety of other methods. As communities of impacted individuals, PAOs can guide and meaningfully contribute to such research, and help researchers understand disease context and areas of interest.3

Another area that may benefit from PAO collaboration is developing inclusion and exclusion criteria. Heterogeneity within rare diseases, as well as limited information, means that patients and patient groups may have information that can help sponsors determine which groups should be included in a clinical trial. For example, one scleroderma study revised its exclusion criteria after input from a patient group provided insight on ulcerative manifestations. This allowed investigators to better ensure patient safety.4

Establishing patient registries is another invaluable way that sponsors can collaborate with PAOs. As mentioned previously, due to the limited number of patients, data on a given rare disease is often incomplete and inadequate. Patient registries, which are organised systems to collect information on a given disease, can help alleviate these difficulties.

Identifying rare disease patients can be challenging for many physicians due to the specialised knowledge or equipment required for diagnosis. This means that finding these patients through typical avenues, such as electronic health records, is not always a reliable option. As communities of patients that have already been established, often with increased geographic reach via the internet, PAOs can be instrumental partners in creating these registries. Access to a registry, in turn, can help identify qualified participants for a clinical trial, speeding up rates of enrolment as a result.

Registries can actually accomplish a wide variety of goals, including measuring disease burden and incidence of major health events, identifying diagnostic and treatment pathways to establish best practices in disease treatment and management, and generating real-world follow-up data after clinical trial participation. Registries can also be used to conduct natural history studies. These can help to gather much-needed data about the progression of a disease over time; data that is often lacking for rare diseases. In some cases, this data can be used for an external control arm in clinical trials, in place of a placebo group.

Because patients with rare diseases often have few options for treatment, many are more likely to participate in a clinical trial if they can be sure they will receive treatment.

Therefore, reducing or eliminating the need for a placebo group can support recruitment efforts.

Effective engagement with a PAO requires a deep understanding of the rare disease patient advocacy landscape and best practices for drug development collaboration. Partnerships in this space are not transactional but rather highly strategic and robust. Sponsors are sometimes surprised to find that meaningful relationship building and collaboration, not sponsorship dollars, are the key to a productive partnership. Having a highly experienced patient advocacy professional to guide these endeavours, and maintaining flexibility to adapt clinical development processes to the rare disease dynamic, is key for sponsors developing treatments.