patient recruitment in rare disease clinical trials

Patient recruitment in rare disease clinical trials presents several difficulties. These challenges include limited eligible patients, dispersed geographic distribution, low disease awareness, site and investigator identification difficulties, and ethical considerations. They hinder participant enrollment and cause trial completion delays.

Over the past few years, the rate of drug development in rare diseases has been increasing. This growth is particularly notable in countries where regulators are offering various incentives for drug development in rare diseases. Over the past five years, one-third of the approved drugs were to treat rare diseases. The huge leap of the pharma industry into the rare disease has led to the development of many life-turning treatments.

The major challenging issue in the clinical trial industry all over the world is finding patients for clinical trials. This challenge becomes particularly critical in rare disease clinical trials. Due to the limited population affected by rare diseases, finding patients, screening, and recruiting them can become a nightmare for many researchers.

Many experiences reveal that 50-70% of sites fail to even recruit one patient for study. This may result in increased timelines, and costs, and also lead to produce inefficient clinical trial data.

To overcome patient recruitment issues, developers are adopting new trends and patient-centric approaches that may improve patient recruitment and retention.

In this article, we will be discussing the key aspects to consider in patient recruitment in every stage of rare disease clinical trials.

Protocol design in rare disease clinical trials

Clinical trial designs with orphan drug approvals compared to non-orphan drugs differ in various aspects. Unlike traditional clinical trials, designing protocols for rare disease clinical trials is critical, and the focus shall be patient-centric. Here are some of the key factors to consider

  • Choosing alternative trial designs which can reduce patient burden and improve retention without compromising the quality of clinical data collected during a study. For example, applying a crossover trial design can give all patients access to investigational therapy,
  • The endpoints should be determined not only based on the efficacy of therapy but also on what would be most meaningful to the patients in terms of improving their quality of life.
  • Patient burdens such as travel, accommodations, special needs, comfort, fears, and concerns shall be taken into account. The best approach for this is to design very minimal visits, make travel a pleasure, provide comfort, Utilize site-less or virtual site approaches, video calling through Skype, etc.
  • If possible, consider in-home nurse visits for procedures like blood draws and infusions to prevent the travel burden on patients.
  • In many rare diseases, patients are often children, and their parents or caregivers are responsible for collecting primary and secondary endpoints in a clinical trial. This requires additional infrastructure to train on how to properly identify and objectively collect those endpoints.
  • Looking for clinical research centers that have previous experience in treating patients with the rare disease and conducting clinical trials
  • Establishing a dose-response relationship for dose selection in rare diseases is challenging for many reasons, particularly in pediatric populations. The patient populations are small, limiting the use of extensive dose-ranging phase 2 studies.
  • Patients are often in relatively poor physical condition, which may limit the number and type of procedures that may be performed.
  • While initiating a clinical trial, it is important to look at the available patient population rather than going for multiple trial sites and waiting for patients to recruit, which increases financial burdens and also trial failures.

Adaptive designs have been gaining efficiency in studying rare diseases. Adaptive designs use accumulating data from an ongoing trial to decide how to modify design aspects without undermining the validity and integrity of the trial.

Master protocols, such as basket trials, umbrella trials, and platform trials, are novel designs. They investigate multiple hypotheses through concurrent sub-studies. These trials may involve multiple treatments or populations and allow for adding or removing arms during the trial. Master protocols offer enhanced efficiency and a more ethical approach to trial evaluation.

Designs like repeated measures, crossover, Latin Square, and stepped wedge designs are anticipated to be applicable and more efficient compared to traditional parallel group designs.

Addressing costs in rare disease clinical trials

High costs of transit, lodging, and other miscellaneous expenses associated with getting the patient shall be considered while budgeting for rare disease clinical trials. The costs for all of the additional patient and family support activities can potentially double the individual patient costs,

It’s wise to include the additional time and allocated funds to allow extended or additional patient site visits or visits of nursing staff to patient’s homes to enhance support. This strategy also helps to retain patients.

Patients recruitment in rare diseases

To obtain quality data and successfully complete the trial, patient recruitment is a key factor. However, due to the challenges listed below, recruiting patients for rare disease clinical trials becomes a difficult task.

Some of the key challenges in patient recruitment for rare disease clinical trials are

  • Very few patient populations and scattered across the geography           
  • Rare disease patients are often very sick and can suffer from medical complications that can make it difficult for them to meet the study criteria.
  • Most of the patients, about ⅔, are pediatric or geriatric patients, where the patient site visits may not be flexible (for pediatrics scheduling site visits considering schools and for geriatric lack of flexibility in visits or transportation difficulties) 
  • Many diseases manifest heterogeneously and disease sub-types
  • Lack of trust or awareness in clinical trials in the patient population and often doubt about safety concerns in clinical trials 
  • Unpredictable trial durations or treatment periods that require a significant amount of commitment to the patient population
  • Lack of experts in rare disease clinical trials
  • Lack of accurate predefined endpoints as most of the rare diseases are studied for the first time
  • Traveling inconveniences and frequent site visits involved

With emerging technologies, various methods have been adopted to overcome patient recruitment challenges and find patients for clinical trials.

Before planning any rare disease clinical trial in a region, it is crucial to understand the patient population available for the study. Various approaches, such as utilizing the internet or social media, patient registries, and conducting clinical trial feasibility studies, prove to be quite helpful in identifying the patients available for recruitment in rare diseases.

Internet in the rare disease patient recruitment

Rare disease patients often feel isolated and actively search for various online resources to acquire more knowledge about their disease conditions.

Some organizations like

play an important role in creating a patient database.

Social media has also been playing a key role in bringing awareness and creating disease-specific patient communities and groups. One example where the activity of the patient community has had considerable influence is Hemophilia. The rise of social media has significantly changed recruitment strategies for rare disease clinical trials.

Patient registries

Patient registries are created through a collaboration between different nations like the U.S. (NORD), Europe (EURORDIS), and Canada (CORD). Rare disease-specific foundations, patient registries, databases, patient advocacy groups, and other support organizations serve as logical places to start patient outreach. This can be achieved through conventional marketing, communications, and social media efforts.

These provide potential demographic data, and some registries even provide the contact details of the patients.

  • These enable researchers to conduct epidemiological studies before choosing a region or location
  • Accelerate patient recruitment for rare diseases and prevent enrolment delays at sites
  • Enable better site planning before initiating a trial
  • Post-marketing surveillance studies, real-time data on orphan drugs, and also off-label drugs used on rare indications
  • Some of the regional and local registries provide contact information for patients 

Clinical trial feasibility studies in rare diseases

Conducting clinical trial feasibility is one of the first and crucial steps involved in rare disease clinical processes. Conducting clinical trial feasibility is one of the first and crucial steps in rare disease clinical processes. It helps assess the patient’s availability in a particular region, which is critical before initiating a rare disease clinical trial. Additionally, clinical trial feasibility examines investigators’ availability. It also assesses the country’s potential for conducting the trial and considers various other aspects involved in successfully executing a rare disease clinical trial.

By executing a sound clinical trial feasibility assessment, it’s possible to preempt the likely scenario in patient recruitment and make preparations to manage the challenges.

Learn about clinical trial feasibility and how it can help you.

Patient Retention in rare disease clinical trials

Patients drop out leads to a huge burden in terms of cost and trial timelines for clinical trial sites, as they can lead to trial extensions, or adding new sites. It’s very important that patients understand the risks, treatment levels, and outcomes associated with these clinical trials. Lack of this communication will always lead to misconceptions and patients dropping out.

  • Even though initially patients participate in clinical trials, long traveling distances and inconveniences often lead to patient dropout during the trial. In such situations, home-based approaches can be helpful, where physicians, nursing staff, or both reach the patient’s location to provide monitoring and support.
  • Here nurses or trained staff reach patients’ homes, administer infusions, and draw samples. These approaches are a lot useful in geriatric and pediatric patient populations.
  • Tracking systems and video illustrations of procedures also help in reducing traveling burdens for patients and improve the chances for patient retention. These approaches result in lesser site visits and reduce travel for the patients.

Here are some of the approaches trending in the clinical trial industry which help in retaining patients

Siteless or virtual sites

These new platforms remove obstacles in a long travel or frequent site visits. There are two approaches

  1. Using technology such as eHealth, mHealth where volunteers are engaged through various technological ways like video communication (skype, Facebook, etc)
  2. Using tracking systems such as smartwatches, devices that measure parameters of various health conditions. These are particularly helpful in neurological disorders like Alzheimer’s and Parkinson’s diseases.

These approaches really help in tracking the health scenarios but have some limitations such as, they are not suitable for all trials, or they cannot be applied for all age groups. (tracking approach is more relevant to the younger patient group and digitally naive patients)

Home-based approach

In this process, nursing staff visits patients’ homes, rather than patients visiting clinical trial sites. This process is more applicable in the case of geriatric and pediatric patients.

These approaches help researchers in patients binding to the clinical trial until completion. The cost incurred for such an approach is similar to the traditional methods, as patient accommodation in hospitals is also the same.

Concierge approach

This is another approach that removes the financial and logistic burden on volunteers and their families. This approach involves a contracted expert team, which may include a physician. The team is responsible for managing the complete patient care, including tasks such as addressing patient anxiety, collecting samples, assisting with relocation, arranging visas for cross-border trials, and making accommodation arrangements.

Regulatory agencies support patient recruitment in rare disease clinical trials

In 2017, FDA published draft guidance with an aim to remove logistic barriers which include the use of adaptive clinical trial designs, and mobile technology tools to substitute site visits. This guidance was prepared based on the feedback of patients and industry people and in collaboration with EMA.

Using the Gaucher disease model describes statistical models and simulations that can eliminate the use of traditional clinical trials and develop multi-arm and multicenter clinical trials which can reduce the number of patients to recruit for clinical trials.

In 2018 an additional guidance was published for adaptive approaches and trials with the title “Adaptive Design Clinical Trials for Drugs and Biologics Guidance for Industry

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