The design and execution of rare disease clinical trials pose distinct hurdles. These challenges stem from the limited number of participants, longer timelines, wide geographic spread, and the scarcity of treatment options.
Historically, rare disease clinical trials were designed around regulatory bodies’ potential reluctance to accept real-world data as valid proof of safety or efficacy. But times are changing, creating more possibilities to more efficiently design and manage rare disease studies while keeping participants engaged.
In this article, we explore:
- The shortcomings of randomized controlled trial designs
- Ethical concerns specific to rare disease research
- Modern clinical trial designs for rare disease studies
- The role of endpoints and biomarkers
- Managing and optimizing a lean supply chain
Randomized Controlled Trial Designs: The Shortcomings
Randomized controlled trials (RCTs) remain the gold standard within clinical research. However, conducting RCTs within rare disease research is not always possible because of:
- Small patient populations
- Ethical barriers
The time-consuming nature of these studies may also delay patient access to promising or life-saving therapies.
Perhaps most importantly, untreated control groups within RCTs could suffer lasting harm. Requiring participants, likely children, to remain on a placebo for an extended period to confirm clinical benefit in the treated group raises ethical concerns.
Addressing Ethical Concerns in Rare Disease Trials
Patients with rare diseases may be more motivated to participate in clinical research, sometimes at high costs.
It’s critical that researchers address ethical factors during study design, not only to protect research participants but to avoid delays. Ethical concerns can lead to regulatory setbacks – which, in turn, can impede access to potentially life-saving treatment.
Rare disease clinical trials can last a long time, sometimes decades. Long timelines mean some participants may take risks to join research without the chance of getting any benefits. In some cases, research participants may age beyond the point at which a newly approved treatment is deemed maximally efficacious. And those with life-threatening diseases may pass away before being able to access the treatment.
Once a regulatory agency approves a treatment, it can be incredibly expensive. This could prevent those who initially took the risk to participate in research from being able to access the treatment. And such treatments may be financially untenable in underprivileged health systems or geographies.
How to address ethical concerns
When creating trials for rare diseases, it’s important to consider the possible benefits and risks with extra care. For some participants, these trials represent their sole chance at potentially improving their condition. This aspect intensifies the concern surrounding receiving an active therapeutic intervention rather than a placebo.
To address this concern and ensure ethical integrity, proactive measures are essential. Collaboration with scientific and ethical review boards, as well as regulatory bodies, is paramount. Including these stakeholders in the study design process helps to avoid delays caused by ethical issues. Early engagement also leads to a more efficient and ethical trial design process.
Modern Clinical Trial Designs
Since the 21st Century Cures Act, the FDA has continued to evaluate new types of data and evidence during regulatory decisions. Using modified clinical trial designs and real-world data creates compelling possibilities for innovation.
For example, on April 10, 2020, the FDA approved the MEK inhibitor selumetinib for pediatric patients with symptomatic, inoperable plexiform neurofibromas. The FDA granted the approval based on a single-arm, multicenter trial of 50 pediatric patients. The trial used comparator arms from two previous trials to establish the natural history of the disease.
Some modern clinical trial designs to consider include:
- Synthetic control arms
- Umbrella studies
- Basket (or bucket) trials
- Platform studies
- Master Observational Trials (MOTs)
Synthetic Control Arms
Synthetic control arms are typically derived from real-world data from electronic health records, administrative claims data, natural history registries, and wearables. They can also be generated from previous clinical trial data.
Umbrella trials evaluate multiple targeted therapies for the same disease, separated into subgroups based on molecular alteration(s).
Basket (or bucket) trial
Basket trials evaluate a targeted therapy on multiple diseases with common molecular variations.
Platform studies are flexible, multi-arm, multistage study designs comparing multiple intervention groups with one common control group. Intervention arms can be added to an ongoing trial.
Master Observational Trial (MOT)
MOTs accept patients independent of biomarker signatures. They are well suited to collect prospective real-world data across multiple specialties.
In most disease trials, researchers have previously accepted endpoints and established quantitative measures. However, these markers often need to be identified in rare disease clinical trials.
Many rare disease trials involve ongoing disease discovery, including creating appropriate assessments. Researchers may define things as they move through the trial, possibly even developing new validated instruments, like quality-of-life assessments.
The Role of Biomarkers
Biomarkers may be the future of rare disease research. Rather than being a compromise, primary disease biomarkers provide accurate and precise measurements.
A recent STAT News article reported, “All drug approvals in rare genetic diseases (whether via accelerated or standard approval) that used primary disease biomarkers to measure the underlying disease are demonstrating clinical effectiveness through confirmatory studies or post-marketing requirements, and none have been withdrawn.”
HIV research has already demonstrated the effectiveness of primary disease biomarker-based approvals. The first drug approvals in 1992 used biomarkers rather than clinical outcomes. In fact, this approach quickly led to the development and approval of 29 drugs in 16 years.
The clinical research industry aims to achieve similar advancements in rare diseases. Therefore, it is crucial to consider the significance of primary or secondary biomarkers. Using biomarkers to measure efficacy may lead to faster regulatory approval than relying on patient outcomes.
Managing and Optimizing a Lean Supply Chain
To recruit enough participants, rare disease trials, even in early phases, may involve multiple sites across multiple continents. Participant recruitment may also ebb and flow. Therefore, allocating resources to the right site and delivering therapy to patients on time is a big challenge.
Rare disease trials benefit greatly from supply chain optimization to ensure efficient inventory use while safely minimizing waste.
Supporting a coordinated and patient-focused dispensing plan involves aligning:
- Demand-driven logistics
Supporting the supply chain and monitoring the chain of custody
Technologies like Randomization and Trial Supply Management (RTSM) solutions can help reduce the risk and burden of supplying sites in rare disease trials.
- Lean inventory requirements
- Efficient site fulfillment
- Agile response to incidents such as damage or quarantine events
- Optimized global site management with local resources
Tracking investigational products (IPs) is paramount to running a successful trial since treatments can be costly. RTSM offers control over the chain of custody from the depot to the patient and on to returns or destruction.
With sites sprawled over several countries or continents, RTSM supports the setup of either a single global depot or a parent-child system that incorporates local depots or local site networks. RTSM ensures IPs come from the closest source.
Supply chain strategies for rare disease research
To create an effective supply chain design for rare disease research, it’s important to take a holistic and optimized approach. The clinical dispensing plan and possible mid-trial modifications should drive manufacturing, packaging, labeling, and logistics planning.
Furthermore, implementing a centralized technology is important for streamlining the supply chain and reducing the burden of managing inventory during an unpredictable recruitment process.
Another critical aspect of strategic supply chain management is to proactively reduce risk. Automating incident responses for expiration, recalls, temperature issues, damage, loss, or mis-dispensation ensures a resilient and agile supply chain.
Navigating Rare Disease Trials
Navigating the complex landscape of rare disease clinical trials demands an adaptive approach.
Historically, these trials have faced unique challenges because of smaller participant pools, prolonged timelines, and limited treatment options. However, the evolving landscape offers new avenues for designing and managing rare disease studies with increased efficiency and participant engagement.
To learn more about these strategies and how to use them in rare disease research, check out our eBook. It provides detailed insights on implementing these methods and effectively involving rare disease participants.