Innovator Spotlight

Q: Friedreich's Ataxia Research Alliance (FARA) very early on launched a natural history study of the disease. Can you describe the scope and purpose of it?

FARA and clinical researchers established the Collaborative Clinical Research Network (CCRN) in Friedreich's ataxia in about 2004, with the initial goal of developing clinical endpoints for Friedreich’s ataxia (FA). At that point, no industry-sponsored clinical trials had been carried out in FA, and FARA recognized that the community would need established clinical endpoints and clinical research infrastructure in order to be able to advance therapeutic development. These early studies to evaluate clinical outcome measures and disease-specific rating scales became the basis for an ongoing natural history study that has collected data on over 850 patients. Today the goals of the CCRN include:

  • Provide quantitative serial clinical and natural history data on patients;
  • Design improved clinical measures for use in trials;
  • Build a clinical database in parallel with a DNA and RNA repository for use in translational research, including modifier gene studies and biomarker studies;
  • Create a mechanism for sharing data and resources;
  • Facilitate the implementation and delivery of clinical trials;
  • Define best practices for FA and provide the highest level of clinical care for patients.

The natural history for more than 450 patients goes back more than 5 years with 100 patients going back 10 years. These data are available on request for data mining to answer questions on clinical protocol design, endpoints, biomarkers, etc. It is possible to use these natural history data to expand the interpretation of data collected in clinical trials.

Q: What need was the study intended to address?

Early from 2004 to 2006, the perceived need was validation of clinical rating scales and measures that would allow us to objectively measure the progression of the disease in individuals at various stages of disease and eventually use these measures in clinical trials. Over time these needs remain important, but we have added additional goals that are being achieved by the network, such as creating infrastructure and training staff so that we are trial ready, and novel research and development of other resources for drug development, such as biomarkers. In terms of education, the CCRN has been instrumental in training clinicians and other professionals at the sites in techniques needed for clinical trials in FA, familiarizing them with the endpoints and teaching them to overcome administrative hurdles. We invested into the use of an electronic data entry system early, similar to those used in clinical trials, both to ensure that the study data are as rigorous as possible and to familiarize staff with the systems and standards. In terms of additional research, the network has worked collaboratively with the research community to develop biobanks of cells and blood samples that are available, in conjunction with clinical data, for various research purposes. The CCRN has been engaged in both investigator-initiated trials and nearly all of the industry-sponsored clinical trials for FA with the outcome measures validated in the early years utilized as the primary and secondary endpoints in the trials.

Q: What have been the biggest challenges in planning, launching and sustaining this effort? What lessons have you learned?

The biggest challenges, as with any large collaborative project for a rare disease, are resources, both financial and human.

The CCRN was launched with collaborative funding from FARA and the Muscular Dystrophy Association and then after the third year supported only by FARA. Despite many attempts, government funding was not attainable. The initial investigators who saw the need for this effort have remained engaged, but expansion has been a challenge.

On average, an individual is traveling more than 650 kilometers [400 miles] to reach a study site. We still have large areas of the country that do not have a site close, so we miss engaging patients in the natural history study.

Given our limited resources, it is difficult to support new sites so that their staff time is protected for training and engaging in FA-specific clinical research activities. However, the sites that are currently engaged are very dedicated to FA research, see a lot of patients and can be supported to a reasonable degree by FARA.

We have learned that our patients are willing to travel long distances to go to the sites of the CCRN, where they see disease experts and can engage in research. We have also found that if we can provide modest travel support to ease the burden for patient families, this helps to improve retention for longitudinal evaluations.

Now that we are more than 10 years into this natural history study and have concurrent clinical trials running at our CCRN sites, there are new challenges related to managing time, effort and keeping people engaged (both the investigators and the patients) in the study.

Your natural history study is never done or sufficient, and there is always a need for improved clinical outcome measures to further optimize approaches to trials.

Q: Are there successes you can point to?

Today the CCRN is international with 10 sites (eight in the US, one in Canada and one in Australia). We have a continuously enrolling natural history study with more than 850 individuals enrolled, with about a 65 to 70 percent retain rate – this is certainly a significant success.

The clinical rating scales and outcome measures validated by the CCRN have been used in nearly all clinical trials. The clinical infrastructure has allowed us to launch several clinical trials simultaneously, with efficient and effective enrollment and execution of trials. The dataset that we have from this cohort of patients has informed clinical trial planning and design. We have worked with the National Institutes of Health and the international clinical research community to establish and publish common data elements and clinical care guidelines for FA.

The investment in the clinical research infrastructure, natural history study, biorepository and clinical outcome measures and biomarkers has been significant and is not complete; however, we are seeing returns in terms of our ability to gain greater interest and engagement from biopharma and the investment industry. We have been given very specific and direct feedback from companies looking to engage and invest in rare disease indications that we have made FA an attractive target. Both small and large pharma companies have selected FA as a disease of interest and initiated new programs or partnered to advance existing science. Our industry partners have expressed satisfaction with working with the sites, and have been very happy to have access to the data to plan trials, as well as to utilize the expertise of network experts for this purpose. Almost all trials to date have used endpoints that have been developed through the CCRN, and new trials are using these as well as newer outcome measures and biomarkers in development.

Q: What advice would you give other foundations that might be interested in undertaking a similar effort?
  • Building clinical research infrastructure and natural history studies requires a long-term commitment for all stakeholders, and are critical for drug development in any disease area.
  • A committed, collaborative and dedicated team of clinical researchers, physicians, study coordinators, statisticians, data managers, etc. are the engine. Without these individuals it is impossible to start or to maintain progress.
  • Patient engagement is essential. Educating the patient community on the importance of not only clinical trials but also non-interventional studies, like natural history studies, is required both to recruit and maintain enrollment over many years. Listen to patient feedback on how to make study participation easier and more meaningful. Communicate results and learnings. 
  • It is okay to start small and grow over time. 
  • Until successful trials have been completed, it is impossible to know if the right endpoints for trials have been identified, so continued research into new endpoints and biomarkers is very valuable, and can easily and efficiently be incorporated into natural history studies. 
  • Although board members and donors may not understand the immediate value, the long-term benefits are enormous, in terms of the interest that drug companies will have in investing in the disease space.