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Clinical trials for rare diseases

In this interview, Mindy Leffler, Managing Director of Qualitative Research and Psychometrics at Emmes Endpoint Solutions, discusses the nuances of designing clinical trials for rare diseases including specific challenges related to traditional endpoints.

boy in wheelchair being assessed by doctor in clinical trialsboy in wheelchair being assessed by doctor in clinical trials

Measuring treatment effect in rare disease populations presents many methodological challenges due to small sample sizes and heterogeneity of the study population. Additionally, negative or ambiguous results from clinical trials may leave regulators and clinical trial participants wondering whether the failure was due to the drug’s lack of efficacy or to methodological flaws. As participants and families devote years of their lives to clinical trial participation, it is crucial that any changes in function that patients experience are sensitively detected during a clinical trial.

Heterogeneous populations exist in both rare and common diseases, but the impact of that heterogeneity is far more difficult to overcome with smaller sample sizes

In March, Emmes Endpoint Solutions submitted its Duchenne Video Assessment (DVA) qualification plan to the US Food and Drug Administration (FDA)’s Center for Drug Evaluation and Research (CDER) for review.

The DVA assesses the progression and severity of Duchenne muscular dystrophy using video assessments as a primary endpoint. These videos are recorded at prescribed timepoints and are scored by certified central raters using pre-specified scorecards, allowing blinding to both treatment arm and assessment timepoint. Evaluating patients at home, in their real-world environments, is conducive to decentralising clinical trials and can help remove some of the biases inherent to the way trials are currently conducted.

FDA is expected to provide initial feedback on the data submitted by July 2024, with further data to be collected and analysed over the next two years. 

If successful, not only will sponsors be able to use the DVA in clinical trials, but it could have broader implications for the application of home-based video assessments as primary endpoints in other rare disease trials. Here, we speak to Mindy Leffler about the significance of this technology.

What are the key trends in clinical outcome assessments in clinical trials and what are the differences between those for common diseases and rare diseases?

I would not say that there are key trends in outcome measures, rather there is a growing recognition of the issues with existing outcomes that different groups are attempting to address in different ways. These issues include questions about existing outcomes’ ability to detect incremental change that is clinically meaningful to the population being assessed over the duration of the clinical trial. Additional issues include the equity of trial participation opportunities and a disconnect between home-based and clinic-based performances of study subjects. We are trying to solve those issues with our approach that centres on developing outcomes that quantify daily function as captured on home-based video.

Decentralised clinical trials: paving the way for modernisation

These issues are not entirely unique to rare diseases but are exacerbated by small population sizes. For example, the trial sites for clinical trials in common diseases tend to be more geographically dispersed to accommodate the larger populations, requiring less travel for participation. Heterogeneous populations exist in both rare and common diseases, but the impact of that heterogeneity is far more difficult to overcome with smaller sample sizes. There are some challenges that tend to be more unique to rare disease, such as their often multisystemic nature, which presents challenges to outcome measure selection and lack of availability of disease-specific measures.

What are two major challenges in establishing traditional endpoints in clinical trials for rare diseases?

I think the most significant challenges include the frequent disconnect that we see between the concept of interest being measured and what is meaningful to affected families. Additionally, the attempt to borrow outcome measures from other diseases, which can lead to a lack of sensitivity in the measure.

What is the main reason submission of the DVA qualification to FDA is significant for future clinical trials?

Submission of the qualification plan opens discourse with regulatory about the potential for video-based outcomes to serve as a primary or secondary outcome in clinical trials, as opposed to how video is frequently used anecdotally as a tool for applying pressure to regulators. The discourse will enable us to differentiate what we have developed from these anecdotal methods, with its end-to-end audit trail, video quality control, rater training and certification programme, and validated quantification methodology.

How does the qualification package support more meaningful endpoints and rare disease research as a result?

Over the past decade, over 40 clinical trials in Duchenne have failed to achieve statistically significant positive results on their primary outcomes. Each of those studies represents a group of families that have given up their time, money, literal blood and flesh in pursuit of definitive answers they deserve for their efforts. If we acknowledge the issues with our existing outcomes and work towards ones with a sound foundation, we put fewer of these families in the position of having sacrificed their son’s childhood to obtain answers on drug efficacy that remain elusive.

Because the submission of the plan will open this dialogue, it will also socialise these issues with other rare disease populations and provide the opportunity to mitigate them in their own communities. Additionally, we’ve utilised the DVA’s approach to develop a similar outcome that can reliably quantify meaningful changes in communication ability in a paediatric minimally/non-verbal population, which we hope will also benefit other communities.

How could the clinical trial landscape for rare diseases evolve over the next five years?

Three thoughts:

  1. Clinical trials need to decentralise to preserve the quality of life of trial participants, improve the integrity of the collected data, and increase equity of trial participation opportunities for rare disease families.
  2. We need to transition the outcomes we use from performative function to real-world function in the home environment to capture the true impact of potential treatments on patients and families.
  3. We need to start thinking of early-stage studies as more than mere safety studies, rather as an opportunity to vet the appropriateness, sensitivity and meaningfulness of proposed outcomes from the patient perspective to mitigate the potential for Type 2 errors in later stage studies. This can be done in a rigorous and pre-specified way that allows us to draw empirical conclusions.

About the interviewee

Mindy Leffler clinical trials for rare diseases author

Mindy Leffler clinical trials for rare diseases authorMindy Leffler is Managing Director of Qualitative Research and Psychometrics at Emmes Endpoint Solutions.

Mindy’s background in project management, software development and information architecture came in handy when designing a PRO programme for her son, Aidan, a 14-year-old with Duchenne Muscular Dystrophy. That PRO programme then proved instrumental in the approval of EXONDYS51, the first FDA-approved treatment for Duchenne. When Aidan’s insurance company denied coverage for EXONDYS, the data she captured overturned the denial in 24 hours without engaging in the appeal process. At Casimir, a company that she co–founded, she led a team that turned caregiver and patient anecdotes into data with rigour and validity. Currently Mindy is instrumental in validation studies of the DVA tool.