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Strategies for de-risking rare disease programmes during research and development

The investment in and acquisition of rare disease drug development programmes have been encouraged by an advanced understanding of the molecular basis of rare disease, along with regulatory and economic incentives. However, merger and acquisition deals in the rare disease space frequently fail to lead to a marketed therapy, according to a 2023 Nature article1. The article suggests that challenges in research and development (R&D) play a key role in commercialisation failures, including difficulty validating scientific targets, and translating those targets into clinically relevant outcomes. 

Difficulties in R&D for rare disease therapeutics have been compounded by a historically challenging market for biotechs, even as projections for spending increase. A recent survey of more than 130 biotech executives, published by ICON, shows that 60% of respondents expected to increase R&D spending, whilst only 2% planned to reduce funding. Significantly, 32% of biotech executives cited clinical trials as one of the biggest challenges in bringing novel therapies to market, which suggests an opportunity for biotechs to consider how they can work more comprehensively with their clinical development partners. 

As development complexity and associated costs increase, optimising the efficiency and reach of secured funding becomes more crucial – especially in a highly competitive market for early-stage capital. The blog will highlight how biotechs developing rare disease therapeutics can maximise their funds and de-risk their asset development programmes through strategic trial design and engagement with regulators.

Optimising trial design

Many rare diseases are fatal and have a high degree of unmet clinical need. As a result, regulatory approvals for rare diseases follow a unique trajectory, compared to medicines for common illnesses, with more flexibility in regulatory pathways. This has created a favourable drug development landscape in which the clinical development of a rare disease therapy may require fewer patients, smaller trials, lower overall development costs, fewer external controls and higher chances of market authorisation compared to more common indications. For example, the United States Food and Drug Administration (FDA) may accept natural history data as a comparator for a new drug in the regulatory application for a rare disease drug, instead of data from randomised controlled trials.

However, taking advantage of the flexibility permitted in rare disease trials, compared to more common indications, requires specialised insight. Sponsors who wish to develop and execute a trial that is feasible and compliant must do so with input from various groups, such as experts in rare-disease drug development, patients, caregivers and regulators.

Of these groups, sponsors may be tempted to forgo engagement with patients and caregivers during initial protocol development. However, this is a mistake. In rare disease clinical trials, incorporating patient and caregiver input into clinical trial design and protocol design is critical to developing realistic and feasible studies. Incorporating patient input results in studies that enrol patients more quickly and have better patient retention, which ultimately accelerates time to market and reduces costs of developing new treatments.

One challenge sponsors may face during initial trial design for rare disease therapies is the selection of appropriate endpoints. Most rare diseases have never previously been treated, so clinical endpoints are often poorly defined, and it can be difficult to establish baselines against which to measure effectiveness. Rare disease sponsors should leverage diagnostic, pharmacy and procedural claims data to illustrate what a patient journey and baseline healthcare utilisation look like for a given rare disease. Additionally, natural history data should be used to select endpoints, eligibility criteria and expected levels of efficacy. 

Ultimately, rare disease companies should avoid responding to time-to-market pressures by moving too quickly during trial design. While meeting milestones on time is a priority, speed should not compromise the integrity of the trial at any level. In effect, the solution to a rapid development programme is getting it right the first time to avoid delays.

Strategically mapping failure points

Even when a trial is optimally designed, it may prove challenging to validate therapeutic targets for rare diseases and translate those targets into clinically relevant outcomes. The scientific validation of therapeutic targets for rare diseases may be far less robust than those for common diseases. And, because each rare disease may only have a handful of experts, independent due diligence is difficult to come by1. In some cases, substantial work is needed to establish that endpoints for use in pivotal trials are clinically meaningful and acceptable to regulators. In other cases, a therapeutic may be scientifically valid, but it may not be feasible to intervene early enough in the disease course.

To hedge against burning through cash stockpiles in scenarios in which the long-term goal is ultimately unachievable, developers of rare disease therapies should map strategic points to abort clinical development. Biotechs can identify these strategic points by exploring interim analyses and establishing rigorous go/no-go strategies, so that the ultimate success or failure can be determined at earlier points in the process and with clarity. Optimising this strategy requires careful consideration of what data would signal clear success or failure at key inflection points early in development, and then designing development plans to provide clear data readouts at each point to inform the viability of continuing further with the trial.

Engaging with regulators

According to the Tufts Center for the Study of Drug Development, the most common reason for implementing time-consuming, costly and burdensome protocol amendments to a clinical trial are requests from regulatory agencies2. Sponsors aiming to start a development programme quickly risk derailing their timelines if they have not properly prepared for regulatory compliance. Early and frequent communication with regulatory bodies can help to ensure more thorough preparedness and reduce protocol amendments, each of which can add months of delay.

For rare disease therapies, early engagement with regulators is of particular importance because there are several potential opportunities for fast-track development programmes that can optimise timelines. Regulatory bodies around the globe, including the FDA and the European Union’s European Medicines Agency, offer expedited programmes for therapies addressing unmet medical needs for serious or life-threatening conditions.

For example, the FDA has launched several programmes in recent years to advance rare disease treatments through the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER). These include the Support for clinical Trials Advancing Rare disease Therapeutic (START) pilot programme, the Accelerating Rare Cures (ARC) programme and the Rare Disease Endpoint Advancement (RDEA) pilot programme:

  • The START pilot programme, launched in October of 2023, is similar to Operation Warp Speed for COVID-19 vaccines, and allows participants to frequently meet with FDA staff to address development issues. The programme provides an alternative to the infrequent and formal meetings that are currently standard between product developers and the FDA during drug development, which can lead to development delays if important questions are not answered soon enough.
  • The ARC programme provides a way for stakeholders in rare disease drug development to share feedback with the FDA, and will be used to identify existing knowledge gaps. These insights will be used to develop publicly available resources informing regulatory considerations surrounding clinical trial design for rare disease drug developers. 
  • The RDEA pilot programme is a joint CDER/CBER initiative intended to support efficacy endpoint development for rare disease drugs through increased collaboration and engagement with the FDA.

Investments in expedited programmes for rare disease and orphan drugs by government regulators spell hope for the field, despite presently challenging economic conditions. Importantly, learnings from these pilot programmes may inform more successful drug development of rare disease going forward. An experienced partner can help guide biotechs through optimal clinical trial design and regulatory engagement to maximise their funds and accelerate time to market.

ICON experts can help you navigate the clinical development challenges in rare and orphan diseases. To speak with one of our experts, please contact us.

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