Enabling repurposing

Enabling repurposing involves laying the groundwork to be able to successfully repurpose a treatment for a rare disease.

Early on in the repurposing process, it is important to take certain steps to set up the project for success. This can involve creating a rare disease non-profit organization (if one doesn't exist), setting up research infrastructure, fundraising or applying for grants to support research, building a patient contact registry, creating a network of researchers and physicians, and developing resources such as a biobank or natural history study/registry.

Rare disease nonprofit organizations can play a critical role in this process by serving as powerful intermediaries between patients, researchers, physicians, regulatory agencies, and pharmaceutical companies. Through their passion and perseverance, these organizations can help create and foster the right ecosystem to drive forward drug repurposing efforts for rare diseases.

The ways that a rare disease organization can support drug repurposing projects fall into four somewhat overlapping categories:

1. Funding support
2. Research support
3. Partnering & collaboration support
4. Patient support

Click the text for the corresponding sections in the tool on the left to learn more about each support type.

Identifying the drug

Drug identification is an important early step in the process of drug repurposing. It involves identifying existing drugs that may have the potential to treat a particular rare disease. This can be done through various methods. We believe these approaches can be separated into five categories:

1. Drug Screen approach (High-throughput Drug Screening)
2. Pathogenesis targeting approach (Preclinical/Translational research)
3. Data from similar diseases approach
4. Computational approach
5. Data from off label use approach

In the ROADMAP survey, 94 (76 unique) drugs were found to be in the process of being repurposed by 40 organizations. The most common drug identification method was preclinical/translational research (66 drugs), which can also be referred to as pathogenesis targeting (research identifies a potential problem underlying a disease [e.g., mTOR activation is increased in Castleman disease] and then matches a drug to reverse the problem [e.g., using an mTOR inhibitor to treat Castleman disease], which is then studied further in the laboratory). The other top choices were looking at drugs used in similar diseases (29), analysis of off-label drug use (25), high throughput drug screening (HTDS) (21), and literature review/meta-analysis (16). The least common approach involved computational/machine learning/artificial intelligence (2), which may speak to the novelty of this approach and its slow integration into the existing research/repurposing processes or that it is mostly being utilized without the involvement of rare disease nonprofit organizations.

Benefits of multiple methods

These methods of drug identification can be done simultaneously or in sequence, depending on the organization's resources and priorities. For example, an organization may choose to perform a high-throughput drug screen and conduct a literature review to identify a list of candidates and look for overlap between “hits”. Preclinical/translational research can help to identify candidates and help to refine the list to the most promising ones. As each method has certain limitations, using multiple methods can help to increase the chances of success in the drug repurposing process.

In our survey, 57 drugs were identified by more than one identification method. The most common combination of methods was HTDS and Preclinical/Translational research (11 cases) and looking at drugs used in similar diseases and Preclinical/Translational (9 cases). This speaks to the value of pursuing multiple avenues at once and triangulating the findings from one method with another. It is also interesting to point out that the 11 drugs were identified as promising by utilizing different identification methods for different rare diseases.

Roadblocks & Opportunities

Rare disease nonprofits are often small, volunteer-led organizations. They are susceptible to several internal limitations, which, though applicable to almost all stages of the process, in early stages of the drug repurposing process can become critical roadblocks that can prevent an organization from ever getting to identifying a drug candidate for repurposing:

Lack of financial resources

Not having a sufficient budget limits the ability to conduct necessary research or support certain important resources such as biobanks or natural history studies. See “Funding Support” for suggestions on how to overcome this roadblock.

Lack of resources

Without having access to or creating ways to support systematic data collection and analysis organizations may struggle to identify potential drug candidates or assess their safety and efficacy in clinical trials. See “Providing data/samples for research” for suggestions on how to overcome this roadblock.

Lack of staff

Organizations that are have little to no full-time staff can have difficulties juggling their primary mission of supporting patients with some time-consuming aspects of early-stage drug repurposing, such as engaging with external collaborations, setting up data and sample collection, and bringing together both the patient and researcher community to identify both the overall research strategy and promising off-label drugs. See “Partnering & Collaboration“ for suggestions on how to overcome this roadblock.

Lack of time / prioritization

If organizations focus on too many projects at once, this can divert attention and resources away from targeted drug repurposing efforts, limiting the overall impact of these initiatives. See “Patient-centered research agenda” for suggestions on how to overcome this roadblock.

Lack of an existing researcher network

Without having an established researcher network, it may be challenging to attract researchers to apply for a grant or pursue specific research questions in relation to identifying a drug to repurpose. See “Research Network” for suggestions on how to overcome this roadblock.

Lack of medical expertise among the rare disease nonprofit leaders

Organizations relying on external advisors to provide guidance on which drug identification is best for their rare disease and budget may face difficulties in securing an advisor that has the level of expertise and commitment to engage with the organization and their mission. See “Partnering & Collaboration“ for suggestions on how to overcome this roadblock.

Lack of understanding of the steps towards successful drug repurposing

Not knowing how best to approach drug repurposing, an organization to be stuck in “limbo”, not knowing how to identify a promising drug or how to proceed once a drug has been identified. It can also lead to mistakes or oversights that may compromise the project's success. The CDCN hopes that this ROADMAP tool and associated data helps at least partially fulfill this need and help rare disease nonprofits move forward in their drug repurposing journeys.

There is evidence in the ROADMAP data that some organizations have been able to overcome some of these limitations and still be successful. For example, looking at staff limitations: among our 147 organizations, 52 (38.78%) do not have any full-time staff. This includes 34/111 (30.63%) of the organizations that support research and 20/58 (34.48%) of those that are pursuing drug repurposing. Looking at the organizations that have been successful in drug repurposing: 1/5 (20%) of the organizations who have had a drug FDA approved, and 6/12 (50%) of organizations which are using a drug off label with some measure of success do not have any full-time staff. This means that even if you’re a newer or smaller organization, you can bring treatments to patients through repurposing that have an impact on their quality of life in various ways.

Additionally, many RDNPs are able to achieve success outcomes without their leadership team having medical expertise. 79 of the 147 RDNP leaders that participated in the ROADMAP survey (53.7%) noted that they are also either patients themselves or loved ones (often parents) and not researchers or physicians, and 1 (1.27%) of these organizations was able to make it to FDA approval with a repurposed drug, while 4 (5.06%) have been able to get a repurposed drug available off label with some measure of success.

Validating the drug

The validation stage of drug repurposing is a crucial step in determining whether a drug candidate is likely to be safe and effective in treating a specific rare disease and whether it should progress forward to more research. This stage typically involves conducting additional studies, prior to moving forward with giving the drug to patients and/or performing clinical trials. This stage can be separated into in vivo and in vitro studies, as well as preliminary validation through real-world evidence. Once the validation stage is completed, the organization often moves forward with clinical trials to gather more robust data on the drug's safety and efficacy in human subjects with the rare disease. In some cases researchers move straight from identification of a promising repurposing approach directly to treating patients in a clinical trial and/or outside of a clinical trial (off label), bypassing this stage.

Roadblocks & Opportunities

The validation stage of drug repurposing for rare diseases faces several challenges in addition to the ones described in the prior stage. These roadblocks are more specific to the requirements of preclinical data and collaboration with external partners, such as academics, researchers, biotech companies, pharmaceutical companies, etc.

Limitations of preclinical models

Preclinical models, or studies conducted in cells, tissues, or animals, before testing in humans, can provide valuable information on the potential effectiveness and safety of a drug. However, preclinical models may not accurately reflect the human version of the rare disease, which can limit the understanding of the drug's potential effectiveness.

Limited patient samples

Rare diseases, by definition, affect a small number of individuals, which can make it difficult to obtain a large enough sample size to conduct meaningful research. Additionally, rare disease patients’ samples can also be limited, or access to them may be difficult; they may be spread out geographically, or not available for certain types of research studies. This can make it difficult to conduct research that is representative of the patient population, and can limit the understanding of the drug's potential effectiveness for validation. See “Providing data/samples for research” for suggestions on how to overcome this roadblock.

Lack of real-world evidence (RWE)

RWE refers to data collected in routine clinical practice, outside of the controlled environment of a clinical trial. This type of evidence can provide valuable preliminary information on the safety and effectiveness of a drug in a real-world setting, in a broader patient population and with longer follow-up. In the case of repurposed drugs, there may be limited RWE available, which can make it difficult to gain these insights. See “Providing data/samples for research” for suggestions on how to overcome this roadblock.

Data sharing

Academic researchers conducting the in vivo/in vitro research for drug validation may be hesitant to share their data, as they may want to be the first to publish their findings. This can slow down the drug repurposing process and make it difficult for the organization to access the information they need. See “Partnering & Collaboration“ for suggestions on how to overcome this roadblock.

Differing priorities/timelines

Academics may prioritize publishing their research findings in scientific journals, which can be important for their career advancement and for the advancement of their field of study. However, this can make it difficult for organizations to access the information they need and delay the timeline of moving forward with the next stages of repurposing. See “Partnering & Collaboration“ for suggestions on how to overcome this roadblock.

Intellectual property concerns

IP refers to the legal rights associated with an invention or discovery, such as patents, trademarks, and copyrights. These rights can be used to protect the creators of the invention and to prevent others from using the invention without permission. In the context of drug repurposing research, IP concerns can arise when academics or organizations have discovered new indications for a repurposed drug, and they want to protect their rights to the intellectual property. This can make it difficult for other academics or organizations to access the information or resources they need to conduct additional research, as they may need to obtain permission or license the IP. See “Partnering & Collaboration“ for suggestions on how to overcome this roadblock.

To overcome these challenges, it is important to supplement preclinical models with other types of research, establish partnerships with other rare disease organizations, various academic institutions and research labs, establish transparent communication channels between stakeholders and clear data ownership and licensing agreements. Open-access platforms and data-sharing agreements can also facilitate greater access to research findings and resources, as well as establishing continuing to fund and support systematic data and samples collection resources.

Utilizing the drug clinically

Once the drug is shown to be promising and potentially safe and effective for a given rare disease, it must be tested in humans to demonstrate whether it is effective or not. This is traditionally done either through clinical trial testing and/or real world off-label use. Clinical trials provide robust data on the drug's safety and efficacy in human subjects with the disease, and are necessary for obtaining FDA approval and making the drug available to patients, while off-label use tracking can provide additional data on the safety and efficacy of the drug in real-world settings.

Roadblocks & Opportunities

Supporting drug repurposing can include a number of challenges related to the clinical trial process itself, which is complex, costly, time-consuming, high-stakes, and requires close coordination of many different stakeholders of varying levels of commitment and interest. Some important roadblocks to keep in mind and be prepared for include:

The cost and complexity of clinical trials

Clinical trials can be expensive and time-consuming. Locating the appropriate clinic and/or physician to conduct the clinical trial may be especially challenging for rare diseases, particularly those that lack a disease expert who is also a clinical trialist. See “Funding Support” for suggestions on how to overcome this roadblock.

The design of clinical trials

The design of the trial poses particular challenges with rare diseases, as the selection of appropriate endpoint measures can present challenges due to limited data available or a small patient population. Many rare diseases lack a measurable biomarker, which may make endpoint selection more difficult. When studying a drug in a new disease population, there may be a requirement to redose or reformulate the drug, adding complexity to the clinical trial design and potentially requiring additional safety studies. See “Supporting clinical trials” for suggestions on how to overcome this roadblock.

Lack of a sufficient patient population to study

There are very few patients who are officially diagnosed with the rare disease, and/or the small patient population may already be receiving the repurposed drug off-label, which can make it difficult to conduct robust clinical trials and gather enough data to support the repurposing of drugs. There might also be limited awareness about the trial, or lack of understanding of the risks and benefits involved. Patients may be hesitant to participate in a trial if they have a distrust of the medical system in general or they fear losing access to the treatment they are currently receiving or go on a treatment during the trial which they might not have access to afterwards. There also may be clinical trials already ongoing, which may further reduce the patient population eligible to enroll in new trials See “Patient Network” for suggestions on how to overcome this roadblock.

International patient population

Working with an international patient population can also present challenges in terms of coordinating care and communicating effectively with patients and families with different language needs, different religions and cultural backgrounds. There is also variation in regulations, drug access, research standards and regulatory requirements, and other factors across different countries, which can make it difficult to conduct clinical trials in multiple sites and ensure that all patients have access to the same treatment options during the trial and after its completion.

Complexities of rare diseases

Many rare diseases have several subtypes, symptoms across multiple organ systems, severity of the symptoms, speed of disease progression, or co-occurring conditions which can make it difficult to discern the effects of a repurposed drug in the clinical trial. Due to the rare disease itself, it may be difficult for patients to understand the trial, comply with its requirements, or travel to a trial site; patients who are particularly sick may not enroll in a clinical trial, particularly if the drug is available off-label outside of the trial. See “Supporting clinical trials” for suggestions on how to overcome this roadblock.

Lack of physician support

Physicians may not be interested in serving as Principal Investigators (PIs) for a rare disease-focused clinical trial, or otherwise support patients during the clinical trial process. See “Partnering & Collaboration“ for suggestions on how to overcome this roadblock.

Lack of pharmaceutical company support

Pharmaceutical companies may not be willing to provide the drug needed to conduct clinical trials, due to lack of financial incentives even if the trial is successful. See “Supporting clinical trials” for suggestions on how to overcome this roadblock.

Blood-brain barrier penetration and other disease-specific considerations

The blood-brain barrier (BBB) is a specialized system of blood vessels and cells that surrounds the brain and spinal cord that helps protect the brain from harmful substances. This barrier is selectively permeable, which means that some substances can pass through it, while others can't. This means that even if a drug has been repurposed and has been shown to be effective in treating a certain condition, it may not be able to reach the target area in the brain, making it less effective.

Regulatory requirements

Navigating the complex requirements for conducting clinical research can be a huge roadblock for organizations who do not have a core team member who has a research background and/or experience with clinical trials. This is important to consider if the organization is planning to submit the results of the clinical trial to the FDA for approval, as there are certain clinical trial design requirements that need to be implemented. See “FDA approval” for suggestions on how to overcome this roadblock.

Other

There are other external limitations, such as COVID-related challenges, which caused disruptions to clinical trial recruitment and the ability to conduct in-person study visits.

These limitations can make it difficult for a rare disease nonprofit to support large-scale clinical trials for repurposing. However, by establishing collaborations among rare disease nonprofits, physicians, researchers, and pharmaceutical companies, organizations can work to overcome some of these challenges: pooling resources and expertise, identifying potential trial sites, and creating networks to connect with patients and families affected by rare diseases with ongoing trials for which they are eligible for.

Another strategy is to leverage innovative trial designs, such as basket and umbrella trials, which allow for testing multiple treatments for multiple rare diseases or subtypes in one trial. Furthermore, utilizing digital health technologies, such as telemedicine and remote monitoring, can help overcome geographic and logistical barriers to patient recruitment and retention, while also reducing costs. Regulatory agencies may be more receptive to innovative clinical trial designs for rare diseases, and engaging with them early in the process can help ensure that trial design and data collection are aligned with their requirements. By leveraging patient and community engagement and various types of partnerships, rare disease nonprofits can work to overcome these barriers and advance progress in their rare disease space.

Reaching an outcome

There are many ways we can conceptualize “success” in a drug repurposing project. One obvious and traditional marker is receiving FDA approval, but it is important to note that there are many factors that affect whether a drug can ever get FDA approval that do not depend on its safety, efficacy and are beyond the control of a researcher or a rare disease nonprofit organization supporting a drug repurposing project. Notably the most important of these is that pharmaceutical companies may choose to not invest time and money into supporting the FDA approval application. Thus, we consider FDA approval as one metric among others. The ultimate goal is to ensure that drugs that can be effective and safe for a rare disease are used for that rare disease, regardless of if it’s following an FDA approval, treatment guidelines changes, or off label use with some efficacy/safety data and measures of benefit.

Some of these outcomes are final endpoints for a repurposing project, such as FDA-approval, while the others - off-label use and abandonment - can be reached at earlier stages in the process. A project can be abandoned at any stage, whereas off-label use can be considered a sufficient success endpoint whenever there is sufficient evidence on a drug’s safety and efficacy data, and it’s integrated into treatment guidelines. In some cases, this can be achieved without formal clinical trials.

Roadblocks & Opportunities

Even if a drug shows promising results in preclinical and/or clinical studies, it may still face roadblocks in the final outcome stages.

FDA approval process requirements

The FDA approval process for repurposed drugs can be challenging and time-consuming. The FDA may require additional clinical trials and data to establish the safety and efficacy of repurposed drugs for new indications, the overall document which needs to be submitted can be hundreds of pages and can take months of work to put together. Without the support of a pharmaceutical company, the avenue for FDA approval is limited to a “citizen’s petition,” which does not have a good track record of being successful often. There is little/no FDA guidance for how rare disease nonprofits can best spearhead drug repurposing initiatives and many have had difficulty navigating the regulatory requirements for repurposed drugs. Repurposed drugs for rare diseases may qualify for orphan drug designation, FDA breakthrough designation, and other similar programs, which could provide financial incentives and expedited review. However, the criteria for qualifying for these statuses can be restrictive, and not all repurposed drugs may qualify.

Additionally, even if the drug is FDA-approved or if available off-label with with some efficacy/safety data and measures of benefit, there are still some important roadblocks to consider:

Drugs may not work for everyone

Even if drugs are successfully repurposed, they may not work for all patients, even if they have the same rare disease or even the same rare disease subtype. This can be due to a variety of factors, such as genetic variations, differences in the underlying causes of the disease, or other individual patient characteristics. See “Patient Support” for suggestions on how to overcome this roadblock.

Side-effects

As with any treatment, repurposed drugs may have side effects, which can vary in severity. Some side effects may be minor and manageable, while others may be more severe and have a significant impact on the patient's quality of life. This can be particularly challenging for rare disease patients, as there may be limited treatment options available and the side effects of the repurposed drug may outweigh the benefits for some patients. See “Off label use” for suggestions on how to overcome this roadblock.

Limited supply

The supply of repurposed drugs can be a challenge as they were originally approved and manufactured for a specific indication. If the demand for the drug increases for a new indication or several new indications, it can be difficult to obtain enough supply if the manufacturing does not increase to meet this new demand. Moreover, if the drug is repurposed for more common diseases, such as COVID-19, it could affect the supply for rare disease patients.

Physician prescription

Physicians may not be aware of off-label uses of drugs for rare diseases if they do not see many patients with those conditions. Therefore, it is crucial for rare disease organizations to educate not only physicians in their network, but also the patient and loved one community about potential off-label treatment options, so that they can advocate for themselves and make informed decisions about their care. See “Patient Support” for suggestions on how to overcome this roadblock.

The cost of drugs

Whether off-label or FDA-approved, drugs can present affordability challenges for patients, particularly if they are not covered by insurance, or are covered by some insurance in some cases, while not in others. See “Patient Support” for suggestions on how to overcome this roadblock.

To work on overcoming these challenges, various strategies can be employed, such as the development of precision medicine approaches and additional biomarkers to identify patient subgroups that are more likely to benefit from the drug, as well as rigorous monitoring of patients for side effects, collaboration between drug manufacturers and rare disease nonprofits to increase drug supply, and education of physicians and patients on off-label uses of drugs for their rare diseases. Additionally, rare disease nonprofits can lobby for healthcare systems to improve insurance coverage for repurposed drugs and provide financial support to rare disease patients.

Funding support

Drug repurposing projects require financial resources. In order to support these projects, a rare disease nonprofit serves two intertwined functions, as a fundraising entity and as a fund-allocating entity.

Fundraising

There are many ways an organization can raise money. One way to think about this is to focus on different entities that can contribute funds:

1. Patients & their families
2. Individual large donors
3. Government organizations
4. Other nonprofit organizations

Fund-allocating

Once the funds are raised, there are a number of initiatives that a rare disease nonprofit can contribute funding to that can help to facilitate drug repurposing:

• Research-related activities*
  *The details will be explored in more detail in the “Research support” section.

  • Basic research studies
  • Preclinical/translational research
  • Other drug repurposing candidate identification approaches (e.g., high throughput drug screens, etc.)
  • Resource development (animal models, cell lines, biobanks, registries, etc.)
  • Clinical trials

• Community-focused activities

  • Collaborations between different rare disease organizations (pooling resources for either research, patient support, events, etc.)
  • Grants to early career researchers to help grow researcher network
  • Creation of research consortiums and meetings/events
  • Supporting patient drug access
  • Supporting a patient discussion platform

• Patient care-centered activities

  • Establishment of expert panels to create treatment guidelines
  • Creation and work of centers of excellence
  • Genetic screening

It is also important to note that there are different approaches to how a nonprofit organization can select which research and researchers to fund.

• The traditional approach involves an organization announcing a request for proposals (RFP) that invites researchers to submit a research proposal (a research question, approach to answering the question, and budget) that addresses the question or area of research described in the RFP. The organization then reviews and awards funds to the best proposal(s).
• An alternative to the researcher-centric model is the “Collaborative Network Approach” (16). It consists of eight steps and leverages and integrates the entire community of stakeholders — patients, loved ones, physicians and researchers — to identify and prioritize high-impact research questions. One of the most important steps of this approach is a crowdsourcing process, which “allows the entire community to identify the most clinically relevant and pressing questions; any idea can be translated into a study rather than limiting research to the ideas proposed by researchers in grant applications.” Read more about the Collaborative Network Approach at https://cdcn.org/about-us/our-approach.

Regardless of the amount raised or grant allocation approach, rare disease organizations can start to create a “seed” funding budget for research projects which either directly or indirectly relate to drug repurposing. Even if these are small grants that may not be enough to complete large-scale projects, these small grants can enable the first proof-of-concept studies to take place, enabling the researchers to then apply for larger grants from entities like the FDA, NIH, etc.

Research support

Drug repurposing is a research process that involves identifying treatments for diseases that they were not initially intended for. Nearly all (86%) of the rare disease nonprofit organizations that completed the ROADMAP survey support research in their rare disease in one way or another, while 58 (40%) are supporting a drug repurposing project now, or have in the past. Many organizations split up their research funding between novel drug development (including gene therapy) and drug repurposing.

Drug repurposing for some rare diseases can provide a drug that provides full remission for at least some portion of patients, while for others it can simply be a good option to reduce symptoms, slow disease progression or improve quality of life in other ways until a more targeted drug can be developed. Drug repurposing, whether it is successful or not, also helps improve understanding of rare diseases and treatments, which can help support better and potentially faster novel drug development.

Rare disease nonprofit organizations can play several important roles in supporting various types of research related to drug repurposing by:

• Leading the creation of a patient-centered research agenda
• Creating research infrastructure & gathering data/samples for future research
• Providing data/samples to researchers & supporting clinical trials

Leading the creation of patient-centered research agenda

Though researchers may be experts in their field, a rare disease nonprofit organization can provide crucial insight based on the patient experience of having a rare disease. There are things that are important to patients, which may not be prioritized from a research perspective.

For example, quality of life is more important for some populations than a marginal increase in overall survival rates; patients with chronic rare diseases may care about the effects of the rare disease or the treatments on more “everyday” things like fertility, cognitive development, as well as a decrease in overall pain or inconvenient drug delivery methods (needing to drive to a hospital to get regular treatments). This is why it is crucial that rare disease research is focused not only on filling the gaps in the literature, but also on the needs of the patient population. One example of this approach is CDCN's All In Movement, which leverages and integrates the entire community of stakeholders — patients, loved ones, physicians and researchers — to identify and prioritize high-impact research questions.

In addition to keeping the pulse of what is most important to the patient and loved one community, a rare disease nonprofit can also do extensive literature review to keep itself up to date on the latest research on its rare disease. This has a lot of potential benefits as it may:

• Create an additional value-add on the nonprofit as a potential collaborator with both academics or pharmaceutical companies
• Create opportunities to form cross-disease collaborations
• Identify new potential drugs to repurpose
• Enable the organization to learn from other nonprofits (what's already been done, what's in progress, what's planned elsewhere. You don't want to reinvent the wheel, repeat studies that have already been executed or are underway or are being planned, etc.)
• Identify researchers to collaborate with, invite to events, or to be a part of your SAB/MAB
• Learn how to model research approaches, including designs of clinical trials

Creating research infrastructure & gathering data/samples for future research

Rare disease nonprofit organizations can help fund the development of research resources, such as cell lines, mouse models, biobanks, natural history studies and patient registries. These data and research samples can then be made available to researchers to pursue various studies, including ones that can lead to a drug being identified for repurposing. The following are examples of some of the types of infrastructure an organization can set up and maintain.

Patient network

One of the most foundational ways a rare disease nonprofit organization can support research is for it to act as an intermediary between the patients and the researchers/physicians. In this way, its contact registry (a database of contact information for all your rare disease patients) becomes an incredibly valuable resource. It can be used to gather data, spread the news about opportunities to participate in clinical trials, and share research findings (including new treatment options as a result of repurposing).

Research network

There may be dozens of researchers around the world which are already researching a specific rare disease, or doing research which is related to a potential drug target or potentially important pathway. Finding them and creating opportunities to enable them to collaborate can drastically speed up the pace of innovation and treatment identification for drug repurposing.

Biobank

A biobank is a storage facility for biological samples for use in research. These samples may include human tissues of any type (blood, lymph node, etc.) These samples can be included in basic research around disease mechanisms through translational research leading to treatments. Biobanks have the potential to accelerate rare disease research by providing access for researchers to high quality biological samples for their research. The operating costs of biobanks vary widely based on the scale of the operation. Though the costs can be beyond the scope of smaller organizations, there are commercially operated biobanks which can be hired to outsource the biobanking of rare disease tissue specimens.

Among the 147 organizations surveyed in this project, 45 (31%) utilize a biobank. This includes 24 (41.38%) of the 58 organizations that are pursuing drug repurposing. Among the 5 organizations who had a drug FDA-approved through a drug repurposing project, one (16.67%) has a biobank. Having a biobank of samples can be helpful in supporting several types of research projects which may lead to identifying potentially helpful drugs for a rare disease.

Patient registry and Natural History Registry/Study

Patient registries are databases used to collect data (patient contact information, demographics, basic health information, medications, diagnosis, comorbidities, hospitalizations, etc.) and provide information to help researchers and clinicians understand the disease course over time.

Natural history studies are research studies that analyze data gathered in a patient registry over time. This type of study aims to gain a better understanding of the disease's natural course, including its symptoms, signs, and complications, as well as how it affects patients' lives. The information collected in a natural history study can be used to identify drugs for repurposing, and improve patient care.

There are hybrid “natural history registry” options as well, such as CDCN’s ACCELERATE in which patients self-enroll, the research team obtains medical records, and data collection is centralized and implemented into new and existing research priorities.

Among the 147 organizations surveyed, 59/147 (40%) utilize a natural history study or patient registry. This includes 52/111 (47%) of the organizations that support research and 30/58 (78%) of those that are pursuing drug repurposing. 3/5 (60%) of the organizations who have had a drug FDA approved utilize an NHR or NHS. These findings suggest that having a natural history study or registry can be helpful in supporting several types of research projects which may lead to identifying potentially helpful drugs for a rare disease.

Resources:

• Natural History Study (nih.gov)
• Funding opportunities for rare disease research | FDA
• IAMRARE® Registry Program - NORD (National Organization for Rare Disorders) (rarediseases.org)
• Natural History Study (nih.gov)

Tracking off-label drug use

Off-label drug use refers to the use of a drug for a disease that has not been specifically approved by regulatory authorities, such as the FDA in the US. It is quite common and is used in cases where a drug has been found to be potentially safe and effective for a new disease through research, or a physician has reason to believe it may help a patient from their own medical knowledge or anecdotal reports from other doctors. This can be incredibly helpful for patients that are not responding to the standard of care or have no standard of care for their disease. However, off-label use of drugs can also have risks. Since the safety and effectiveness of a drug for an off-label use have not been established, there is a potential for adverse events or lack of efficacy.

Tracking off-label drug use can provide information on how well the drug works in different populations or for different conditions, as preliminary data to more formal research, or in lieu of formal research. This can serve as justification to support the official integration of this treatment into treatment guidelines or help a patient gain access to a drug via letter to an insurance company, if the request for coverage was denied.

To be able to utilize off-label drug use as an avenue for drug identification, rare disease nonprofits can systematically track off-label drug use in their patient populations by implementing a few different strategies:

1. Surveys and questionnaires: Surveys and questionnaires can be used to gather information from patients and caregivers about their experiences with off-label drug use. These surveys can be distributed through the nonprofit's website, social media, or mailing list, and can include questions about the types of drugs being used, the reasons for off-label use, and the outcomes of treatment.
2. Patient registries: Registries can be used to collect and track information about patients with a specific rare disease, including information about the treatments that patients are receiving and its effects (and side effects) over time.
3. Collaboration with healthcare providers: Nonprofits can collaborate with healthcare providers to gather information about off-label drug use in their patient populations in order to identify trends and patterns in off-label drug use.
4. Literature review: Nonprofits can help identify information about off-label drug use in their patient populations by searching for articles and studies that have been published in peer-reviewed journals, and reviewing data from clinical trials and observational studies.

Among the 147 organizations surveyed, only 17 (12%) track off-label drug use within their patient populations. This includes 16/111 (14.41%) of the organizations that support research and 12/58 (20.69%) of those that are pursuing drug repurposing. Looking at the 5 organizations that have successfully received FDA approval, only 1 organization (20%) tracks off-label drug use. Of the 12 organizations that use a drug off-label with some measures of success, 5 (41.7%) track off-label drug use. 25/94 (27%) of the drug repurposing projects in the ROADMAP were first identified from off-label drug use data. Among the 17 organizations that track off-label drugs, 5 (29%) of them utilized this data in an ongoing drug repurposing project as a drug identification method.

Though these are all correlational relationships, they do suggest that tracking off-label drug use in your patient population, either informally through simple patient surveys or systematically through a natural history study, can be helpful in identifying potentially helpful drugs for a rare disease.

Providing data/samples to researchers & supporting clinical trials

Rare disease nonprofits have a crucial role to play in the support of research in early stages by facilitating researcher access to existing resources, such as patient registry data, biobank samples, contact registry information, etc.

In later stages, rare disease nonprofits can support clinical trials in various ways:

• Clinical trial recruitment: serving as a resource for researchers and clinical trial PIs to recruit participants while simultaneously actively seeking out and sharing information about clinical trials for their patient population.
• Patient education: informing patients of eligible trials and discussing the pros and cons of participation, including potential consequences such as ending up on a placebo, associated costs, or having to stop taking a drug after clinical trial completion.
• Leading or assisting in clinical trial protocol design: assisting in the design of clinical trial protocols, depending on their collaboration and expertise. They can act as the administrative PI (writing the protocol, the MOU, and the application to the FDA, even if they do not have scientific or medical expertise) and provide input on protocol design to better represent patient needs and facilitate recruitment. They can also provide expertise on important clinical measures and endpoints.
• Advocate for certain subpopulations: adding or coordinating clinical trial sites, facilitating conversations with pharma companies to expand their ongoing clinical trials to include a specific subtype of rare disease patients to a clinical trial, or to add expansion cohorts to ongoing trials.
• Collaborating with other rare disease nonprofits: creating opportunities for collaboration such as joint-funding, increasing size of clinical trials, sharing data and samples, etc. For example, basket trials can help defray costs, coordinate efforts, lean on a shared infrastructure and PIs, benefiting multiple rare disease patient populations simultaneously.
• Funding: providing either seed funding, which can enable researchers to do preliminary work to then qualify for larger grants for clinical trials, or provide extra funding if external funding is insufficient to support a clinical trial. With enough funding, a rare disease nonprofit can potentially support multiple ongoing clinical trials, i.e. have eggs in multiple baskets to raise the chances of having a successful outcome.

There are many potential benefits to patients if a clinical trial is successful, such as more data on the safety and efficacy of existing treatments for various different patient populations, or new treatment options becoming available for them. There are also other benefits for the nonprofit itself in supporting clinical trials, such as - expanding their patient network, especially internationally. It also provides a great milestone in its mission to support research, which can serve as both internal motivation and help cement the idea that a rare disease nonprofit is able to be a partner in further rare disease research with pharmaceutical companies and academic institutions.

In vitro

In vitro studies are research studies that are conducted in a laboratory dish or in a test tube, as opposed to in live animals (in vivo) or human subjects (clinical trials). These studies are used to investigate the effects of drugs, chemicals, or other interventions in a controlled environment, using isolated cells or tissues.

In vitro studies are an important tool for understanding the basic mechanisms of disease and the effects of drugs on the activity of enzymes or proteins, or to test the toxicity of chemicals on cells, or the genetic or environmental factors on cells or tissues, and to investigate the underlying mechanisms of disease.

In vitro studies are cost-effective, as they have a lower cost and less ethical considerations than in vivo studies. However, the results obtained from in vitro studies tend to be less reliable than findings from in vivo systems.

Alternatives

Off-label use

Off-label use of a repurposed drug that has been shown to be safe and effective through either preclinical and/or clinical research can provide access to treatments for patients, bypassing the regulatory hurdles, costs, and delays associated with FDA approval submissions. Additionally, the clinical trial protocol for such a drug may be streamlined as it is not intended for FDA submission, which could save resources for both the researcher and rare disease organization.

Thus, as an alternative to FDA approval, we can consider a drug to have reached a success outcome when it is available off-label, with efficacy/safety data and some subjective measure of benefit, such as:

• Drug to provide a significant reduction in symptoms
• Significant improvement in quality of life
• Increase life expectancy / decrease in mortality
• Provide cure of disease
• Provide prevention of relapse

Though it is worth considering that due to the fact that it is difficult to qualify what a “significant” reduction or improvement is, these measures are open to various biases and inaccuracies from both reports from patients as well as perceptions of benefit overall from rare disease organizations.

If we look at organizations that fit this criteria from the ROADMAP data for at least one repurposed drug, we end up with 12 organizations. They are on average 17.6 years old (range: 2 - 44); the majority ( 4 organizations, 33.3%) reported annual funding between $100,000 and $500,000; and they have the following characteristics: 11 ( 91.7%) have an SAB, 6 ( 50%) have a natural history study, 7 ( 58.33%) have a formal research agenda, 6 ( 50%) have a patient registry, 5 ( 41.67%) have a biobank, and 3 ( 25%) already have an FDA-approved drug prior to pursuing drug repurposing (one organization has two FDA-approved drugs). Interestingly, 6 ( 50% ) have no full-time staff, relying entirely on volunteer and/or part-time labor to achieve their success.

Among these 12 organizations, there are 44 unique drugs being repurposed. The most common drugs among these organizations were Sirolimus ( 3 organizations), Trametinib, Everolimus, and Bevacizumab ( 2 organizations each). The most common identification method for these drugs was Preclinical/Translational research ( 30), closely followed by data from similar diseases ( 17) and off-label use ( 17). Most of these drugs are currently in early stages or clinical trials, specifically in recruiting patients for clinical trials ( 18). Their respective rare diseases have the following characteristics: 11 ( 91.67%) have animal models, 8 ( 66.67%) have cell lines developed, 9 ( 75%) have an identified genetic mutation, 8 ( 66.67%) have an ICD code, 7 ( 58.33%) have treatment guidelines, 5 ( 41.67%) have a clear understanding of etiology or disease pathogenesis, and 3 ( 25% ) have predictive biomarkers.

It’s important to note that off-label use of drugs can serve as both a starting point for repurposing as a way of identifying a promising drug, a way of validating a drug through analyzing RWE of its during the repurposing process, and as a success endpoint for drug repurposing. It is also vital to continue monitoring the use of these drugs through natural history studies or patient surveys, to track any potential side effects or other issues that may arise.