In early 2019, the FDA released a revised draft guidance (finalized in December 2023) for rare disease clinical trials. The guidance, updated from a 2015 version, provides clarification in certain areas such as natural history studies, evaluation and validation of biomarkers as surrogate endpoints, evaluation of novel drug compounds, drug manufacturing, and safety. Well-received, the 2019/2023 guidance is intended to encourage sponsors to tackle the complex issues associated with rare disease research proactively so that research can be conducted more effectively and efficiently.
Main Challenges in Rare Disease Drug Development
Rare diseases affect a small population of people who are dispersed across the world, and it makes country and site selection, clinical trial recruitment, and long-term retention particularly complex. Furthermore, many rare diseases are difficult to diagnose leading to a possible misdiagnosis. Although more rare diseases are being identified through recent medical advancements and development of new diagnostic techniques, it typically takes time for the diagnostic and screening standards to be established. Obtaining an accurate diagnosis is often one of the first obstacles to overcome.
From a research point of view, rare disease clinical trials are usually expected to have slow recruitment, a small number of patients recruited per site, and typically low numbers of study participants overall. This poses specific challenges that you must account for in your study planning and site selection strategy; these challenges also directly impact the required budget.
Planning, Selection and Support
To start your path towards a successful rare disease clinical trial, you must seek the input of key opinion leaders (KOLs) for the specific disease. Depending on what research has been conducted to date (if any) in your targeted disease, you may need to take additional time to identify KOLs: leverage their expertise from the beginning, utilize their knowledge to aid protocol development, and determine the best methods for locating study patients. You should build your new-found information into your research program planning, site identification, and patient recruitment strategy early on.
In addition to speaking to KOLs, consider tapping into support groups (i.e., rare disease patient advocacy or parent/family support groups). There is a spectrum of organizations (specific to the disease or therapeutic area, and also ones that differ in geographical outreach: national, multinational, global, etc.) depending on the maturation of awareness for the given disease, such as its public and investigative profile. Such groups should be considered and/or approached during study planning. Not only can they help locate potential study investigators and participants, but they can also serve as valuable sources for research strategy planning, increasing disease awareness and support, or providing input into your communications with regulatory and ethics bodies.
In cases where diseases lack adequate research due to the rareness of the indication or the indication being recently defined, it may be necessary to obtain reliable information about the natural course of the disease by following relevant disease parameters over time (prospectively or retrospectively designed, protocol-driven natural history studies). If this is needed, execution of a natural history study should be part of your early planning and, if possible, in parallel with preclinical development.
Additionally, necessary product development parameters (e.g., disease-specific endpoints) may need to be defined for the first time. Be prepared to go into unknown territory while working closely with other interested parties (such as KOLs, regulatory bodies, and patient advocacy groups) to define what is most important for patients and what are measurable, clinically meaningful endpoints. Quality of life improvement is crucial in disabling diseases, and a final result on a parameter such as ‘quality-adjusted life year’ is vitally important for drug approval and market access by relevant approval bodies.
Unlike the site selection strategy in more common diseases, you will often need to include research-naïve sites in your study. It is not unusual that even KOLs lack experience as investigators; therefore, it’s important to be site-centric and patient-centric with your study strategy. Research- naïve sites will likely need additional training, support, and attention, but they also tend to be extremely motivated to learn and eager to participate. They typically have teams who are very knowledgeable about rare disease challenges and are ready to help patients and researchers find a treatment.
Clinical teams assigned to the study should have experience working on rare disease clinical trials and be prepared to provide additional, detailed training for the rare indication and assessments under study. Having KOLs involved in therapeutic training with a focus on disease-specific measurements, assessments, and scores (such as muscle scales in diseases affecting mobility) has been proven to be successful.
Spending additional time and effort early on to prepare for your study will be rewarded with successful recruitment numbers, retention of patients, and high-quality data.
Your formula for success can be broken down into these initial steps:
- Engage KOLs and investigators early during study planning
- Approach rare disease patient advocacy groups or advocates for assistance and disease insights
- Be prepared to work with research-naïve sites
Patient Landscape
Mapping your patient landscape is critical for successful patient recruitment in rare disease clinical trials. When available and accessible, patient registries or anonymized medical records can help you determine where certain patient populations are clustered. You should check globally for relevant registries or early research and keep in mind that, sometimes, due to a disease’s genetic nature, patients with that disease may be more prevalent in some regions than others (such as in an endemic pattern). The National Organization for Rare Disorders and other regional and global initiatives may have useful data available.
However, because a particular rare disease affects so few people, you must be prepared to use old-fashioned, manual investigative work to pick up where technology and available data fall short. Allotting enough time to mine all relevant data can help inform your potential patient landscape.
Raising disease awareness can also be a recruitment technique. When awareness of a disease is greater, a patient has an increased likelihood of gaining an accurate diagnosis; in turn, newly diagnosed patients will want to consider all their treatment options, including the possibility of study participation. Although this effort requires additional investment by sponsors, it can be beneficial to provide support and training for health professionals by organizing targeted trainings and seminars and contributing at relevant conferences.
Your formula for success with the patient landscape:
- Map your patient landscape by tapping into available data and research in all forms
- Take the necessary time to complete due diligence to propel your program towards an efficient study initiation
- Raise disease awareness during the study planning and setup
Patient-centric Support
In rare disease research, it is common to work with pediatric populations or with patients with debilitating conditions; for both, travel and overall time commitments are difficult to manage. Furthermore, geographic distances and financial hardships can make ongoing study participation particularly challenging for patients and caregivers. While the clinical research industry has made great strides to be more patient-centric, it is not enough to passively plan or account for these difficulties in the study plan and design. Instead, you must aggressively and proactively plan to be patient-centric in rare diseases − to take the study to these patients or to find ways of bringing them to the study.
Deploying dedicated vendors that specialize in helping participants with travel and other clinical trial-related expense reimbursement can improve participation and retention. These vendors should reduce the burden associated with travel arrangements and expenses. Additionally, patient stipends should always be offered in line with local regulations, including to accompanying parents or caregivers who may lose wages due to study participation/engagement.
You should establish mechanisms to enable home visits and remote measurements of the study parameters whenever possible. In this way, required site visits are decreased, easing the burden for patients and their caregivers. While there are specialized vendors that conduct home visits, the final decision should be left to the patient as some consider their homes ‘research free’, especially in pediatric studies. Incorporating this aspect into your rare disease clinical trials design and schedule of assessments is an important factor in your formula for success.
Be aware that patient study participation may require additional caregiver engagement, which can lead to caregiver burnout. Providing the extra support, as detailed earlier, can make a significant difference to caregivers and, ultimately, to patient retention.
Finally, patient centricity extends beyond the immediate study. Patients should be offered expanded access to the study drug, either as a compassionate use or as an open-label extension study. Prolonged access to the drug may be a requirement by the regulatory bodies and is often part of the sponsor’s commitment in the product development plan. Not only is providing continued access to the drug morally responsible, it is always appreciated by investigators and ethics committees and further promotes patients’ willingness for study participation and retention. By offering expanded access opportunities to patients, you are increasing your program’s chances of success.
Your formula for success with patient centricity:
- Continually consider how to make your study patient-centric
- Engage specialized vendors to help with travel, reimbursement, and in-home care support
- Offer expanded access to the study drug following your study, whenever applicable
Enhancing Data Quality
Study populations are so small that data quality and accuracy are particularly essential in rare disease clinical trials; every single patient and data point counts. A single, non-evaluable or ineligible patient could potentially affect study success; therefore, a centralized patient eligibility check is highly recommended.
Consider the use of electronic data capture devices to minimize data entry mistakes and ease the burden of data reporting. Electronic patient reported outcome (ePRO) tools and wearables make review of real-time data possible, including remote data monitoring for accuracy, and timely medical data review for consistency. Although these technologies add to the overall study cost, the investment will pay for itself when it saves a study or keeps a study timeline on track.
Your formula for success with supportive data technology:
- Go digital; eDiary and ePRO solutions should help enhance data quality
- Recoup your investment costs in these technologies by obtaining complete or near real-time data review and intervention
- Plan for a centralized patient eligibility check
Regulatory Agencies and Review Boards
To quickly provide treatment for an urgent unmet medical need, the drug development for rare diseases is often planned to be more efficient. While ensuring patient safety is never compromised, sponsors sometimes combine different phases of development under a single protocol (e.g., Phases I and II, or Phases II and III) to enable a quick marketing authorization application. How this is done must be agreed upon with regulatory agencies early on. There are various special considerations for speeding up development and approval; under the FDA, it may be fast track, breakthrough therapy, accelerated approval, or priority review. For the EMA, you should consider the PRIME scheme for priority medicines.
Once the study protocol is finalized and submitted, the regulatory and clinical teams should work closely with the sites to address questions or concerns that may arise during the regulatory and ethics review phase. It is not unusual to have multiple rounds of questions, sometimes with tight timelines for feedback, so you should be ready for a quick turnaround.
A review board may not be familiar with your study condition. It is usually a study investigator who communicates with review boards, so plan to support investigators with relevant scientific materials or slides. Separate questions with independent review boards or ethics committees (IRB/EC) may be received and addressed to define how patients and caregivers will be supported with travel, meals, or other compensation, in line with local regulations.
Any promotional material used in the study must be reviewed and approved by the IRB/EC, and, in the case of rare diseases, it can also be used for raising public awareness about the disease. It is not uncommon that advertising about one disease also educates the public, and sometimes even the medical community, about rare disease research overall.
Your formula for success with regulatory considerations:
- Explore your options to expedite your program early with regulatory authorities
- Be prepared to offer a quick and efficient response to review bodies
- Support investigators in conversations with review boards and ethics committees
Knowledge sharing
While it’s true that clinical trials for rare diseases present a unique set of obstacles, they can be overcome. Establishing a well-prepared plan early is key: enlist KOLs and rare disease patient advocacy groups as soon as possible, mine available data promptly, consider if a natural history study would be helpful as part of your initial planning, discuss your planning with regulatory authorities early, and, throughout all your preparations, keep patient centricity at the forefront so as not to add further burdens onto your often fragile study population.
Finally, as stakeholders in the research of rare diseases, contribute your knowledge and experiences. By passing on knowledge gained by our experiences, we can all further this important research to find better treatments and even cures for at least some of these rare diseases; these patients deserve nothing less.
As a rare disease CRO Allucent has more than 30 years of expertise successfully navigating the unique challenges in rare disease drug development including a dedicated Patient Engagement team providing strategies to support patient recruitment, engagement, diversity and compliance – working across a range of therapeutic areas and clinical study types, including on-site, decentralized, and hybrid trials.
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