Why does the diagnostic procedure take so long?
Rare Diseases (RD) diagnostic process commonly involves visits to different specialists, numerous laboratory and imaging tests, travel to tertiary health centers, moving households, several hospitalizations, including ICUs, or the performance of invasive procedures among other issues. In addition, it is complicated by the presence of widely varying non-specific symptoms that overlap between different clinical presentations. This is a result of the lack of natural history information about the individual diseases due to the low number of cases of each disease. All of this leads to a significant delay in diagnosis for most RDs. Neurogenerative disorders display a higher risk of experiencing delays as many of their clinical manifestations overlap, requiring more specific tests. Healthcare systems are not always prepared to solve complex case diagnostic dilemmas in RDs. According to the International Rare Diseases Research Consortium (IRDiRC), there has been some progress in the RD arena with respect to goals for 2027. IRDiRC hopes to achieve that all known RDs will be diagnosed within a maximum of one year from the first date when clinical care was initiated.
Why is it difficult to find the correct treatment?
There is no approved treatment for 95% of rare diseases. While access to successful clinical trials may positively impact RD patients, the cost of research and development for these rare conditions is prohibitive and the patient populations are small. It is also not uncommon that these therapies may not sufficiently treat individual patients causing them to return to an earlier point in their journey.
What is the importance of research and investigations in this field and what difficulties do those working in it face?
RDs are generally related to dysfunction of a biological pathway. Genetic mutations leading to RDs are usually located in a single gene. Studying the role of altered genes and comparing the functions of the altered protein levels in patients can provide a unique insight into the pathophysiology of the disease. These findings can help understand mechanisms that are related to more common diseases. Moreover, RDs embody personalized medicine with an approach to identifying treatments that can be tailored to the individual. Research challenges include the choice of study design and analytic concerns related to small data sets and unique outcomes in studying rare diseases.
4. Can you explain what breakthrough therapy designation is and how to achieve it?
The FDA is eager to support the development of treatments for RDs. Breakthrough Therapy is designed to expedite the development and review of drugs intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). A drug that receives Breakthrough Therapy designation is eligible for all Fast Track designation features, intensive guidance on an efficient drug development program, beginning as early as phase 1, and FDA commitment involving senior managers. Breakthrough Therapy designation request should be received by the FDA no later than the end-of-phase-2 meetings.
What about regulatory strategies when it comes to rare diseases?
Regulatory authorities are eager to work with sponsors who are developing therapies for RDs. Orphan Drug Designation for drugs for RDs or conditions provides tax credits for qualified clinical testing, waiver on the Prescription Drug User Fee, and the potential for seven years of market exclusivity after approval. Rare Pediatric Diseases may qualify for a Priority Review Voucher that is awarded by the FDA and can be redeemed to receive priority review of subsequent marketing application for a different product. Both Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) have programs for RDs, including CDER’s Accelerating Rare disease Cures (ARC) program which was developed to drive scientific and regulatory innovation and engagement to accelerate the availability of treatments for patients with RDs. All of these are designed to address the challenges in RD therapeutic development that include inherently small populations of patients, complex biology, and a lack of understanding of the natural history and heterogeneity of many RDs.
What are the unique challenges for designing and executing rare disease clinical trials?
RDs are very heterogeneous and detailed data of their natural history is often lacking. In addition, there is a variable expression within diseases and subtypes. Many RD clinical trials are multicenter and often multinational in order to achieve sufficient patient recruitment, even in phase I and II trials. This creates challenges in protocol harmonization, ethical review, clinical services, standards of care, and cultural diversity. In addition, there may be complex requirements of the trial itself (e.g., additional medications, and completing diaries) which add to the burden of patients and their families. Where existing treatment options for a RD are limited or nonexistent, patients would usually prefer access to an active intervention rather than the possibility of just placebo, making the gold standard of a placebo controlled trial extremely difficult to undertake. Regulators may require early trials to be conducted in adults first, before expanding to children because of potential safety concerns; however, some RDs may have significant mortality in childhood if not addressed in early years, necessitating clinical trials in children from the outset. Regulatory bodies are starting to acknowledge that endpoint selection may not be straightforward and that understanding the natural history of the RD is critical. The patient voice is also key in determining meaningful outcomes and, in this respect, patient groups and alliances are key in providing their input
What are optimal endpoints for rare disease trials?
The optimal endpoints are those that are clinically meaningful to patients/parents and can be measured in an objective way. If the pediatric endpoints need to be different from those used in adults for the same disease/condition, it is important to try to build the pediatric endpoints into the adult trials if possible so that there is a bridge with respect to the endpoints. It is critically important to work with patients/parents to understand what is clinically meaningful and then work with the regulatory agencies to discuss the endpoints that would be acceptable from a regulatory perspective. The CPath Rare Disease Clinical Outcome Assessment Consortium recently launched the Rare Disease COA Resource that provides information on published COAs that have the potential to be used to support efficacy endpoints in treatment trials for rare diseases.
For patients and families, the most important factors to consider are quality of life (QoL) or health outcomes and the socio-economic burden of the RD. Endpoints used in rare disease development research are meant to be valid and reliable measures of the clinical benefit as defined by a positive, clinically meaningful effect of an intervention (e.g., a positive effect on how an individual feels, functions, or survives).
How do you engage with patients, manage sites and in what ways can trial designs be improved?
Patients/parents in the RD space are extremely engaged in the clinical community. They are the best resource to identify approaches to decrease the burden of trials on patients and their families. The clinical trial simulation is one of the modes to obtain feedback from patients on how they planned to run their trial. One of the most talked-about approaches to improving patient engagement is through electronic patient-reported outcomes (ePRO). While it is not always possible to completely revamp the protocol, these insights can help determine how to better support patients in the trial. Children do not want to be seen as different from their peers. Opportunities for decentralized or hybrid trials have helped to reduce the interference with the daily life of these patients, including school and extra-curricular activities. Also, it is very helpful to digitize the patient database for updates and trial assignments and to pre-screen every patient to build site’s database of candidates across trials. It saves time during the enrollment period and prevents eligible patients from not being included. In addition, pre-screening for one trial can help find patients that may be eligible for another trial. Working with patient referral partners can help fill the recruitment funnel. Time taken to fully educate patients about the trial can support retention. Other methods, such as hybrid trial delivery, community-based sites, and digital engagement, will significantly facilitate trial completion. Another idea being proposed is the ability to professionalize remote or rural healthcare providers by providing them with training and equipment to deliver investigational treatments. All these methods will potentially improve trial enrollment throughout the industry.