Rethinking Clinical Trials in Rare Diseases

Drug development in rare diseases is currently in a very exciting time. While much of the focus is on the scientific advances,  access to rare disease patients and well-designed clinical trials are also essential to evaluating new therapeutics.

In this article, PJ Brooks, Program Director at the Office of Rare Diseases Research of the National Institute of Health (NIH) in the US and his two colleagues — Tiina Urv and Anne Pariser — highlight the Rare Diseases Clinical Research Network (RDCRN) as a platform for carrying out clinical trials in multiple rare diseases concurrently, rather than the traditional one-disease-at-a-time model.

Drug development in rare diseases is currently in a very exciting time. While much of the focus is on the scientific advances,  access to rare disease patients and well-designed clinical trials are also essential to evaluating new therapeutics.

In this article, PJ Brooks, Program Director at the Office of Rare Diseases Research of the National Institute of Health (NIH) in the US and his two colleagues — Tiina Urv and Anne Pariser — highlight the Rare Diseases Clinical Research Network (RDCRN) as a platform for carrying out clinical trials in multiple rare diseases concurrently, rather than the traditional one-disease-at-a-time model.

Written on 13.03.2019

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The impetus of the RDCRN was the Rare Diseases Act of 2002 (Public Law 107-280) which included language specifically directing the NIH to establish centres of excellence for the study of rare diseases. The first iteration of the RDCRN was initiated in 2003. The program is supported through partnerships with multiple NIH Institutes and Centers and is coordinated through the Office of Rare Diseases Research at NCATS.

The RDCRN consists of individual consortia that study at least three different rare diseases.  Each consortium consists of researchers, clinicians, patient advocacy groups (PAGs), patient representatives, and NIH scientists working as partners.  The broad focus of the Network is to advance the diagnosis, management, and treatment of rare diseases through highly collaborative, multi-site, patient-centric, translational and clinical research with a narrower focus on addressing unmet clinical trial readiness needs. The consortia are also connected through a common Data Management and Coordination Center, tasked with data collections, data standards, and other support such as protocol assistance and oversight.

For an adequate and well-controlled clinical trial, valid clinical outcomes measures are essential, and the best outcomes measures are those derived from careful evaluation and understanding of disease natural history obtained through good quality natural history studies.

The current cohort is currently completing its third funding cycle. As of Sept 2018, the RDCRN consists of 21 research consortia, studying approximately 200 rare diseases.  The consortia are diverse and include those centred around a particular organ, an organelle (e.g., mitochondria, lysosomes), phenotypes, and other unifying concepts. Collectively, there are 128 accruing NIH-approved protocols in 278 Institutions throughout the world.  For some rare diseases, this international coverage is crucial to access sufficient numbers of patients for clinical studies.

Through the structure provided through the RDCRN uniform data, collection protocols have been made possible and the RDCRN has been able to establish meaningful, large-scale clinical studies in rare diseases.  In addition, the RDCRN trains new investigators in clinical rare disease research, which is quite different than working in more common diseases. For example, training in innovative study designs and the de novo development of clinical trial elements, such as outcome measures, are usually needed for rare disease research.

Throughout its existence, two key features of the RDCRN have been the engagement with PAGs and requirement for longitudinal natural history studies in rare diseases. The requirement for participation of PAGs reflects the reality that for rare diseases, strong working relationships with PAGs are essential for initiating and carrying out and completing effective clinical trials.

The second key feature of the RDCRN is the requirement for longitudinal natural history studies in rare diseases. For an adequate and well-controlled clinical trial, valid clinical outcomes measures are essential, and the best outcomes measures are those derived from careful evaluation and understanding of disease natural history obtained through good quality natural history studies.  Despite this, there are real challenges in funding natural history studies in rare diseases, due in part to the fact that proposals are open-ended, typically require long-term funding, and often evolve over the time-period of their conduct (such as design changes). These studies often do not do well in standard NIH review panels, in part due to the uncertainty in outcomes, and are often not viewed as innovative.  To address these challenges, the requirement for at least one longitudinal natural history study in every Award has been a requirement since the inception of the RDCRN.

The value of natural history studies supported by the RDCRN can be seen in recent clinical trials of genome editing in Hunter syndrome and Hurler syndrome.  Both syndromes are rare lysosomal storage diseases that have been under study by the Lysosomal Diseases Network (LDN). Clinical investigators from the LDN researchers worked with the company to develop the current clinical trial and recruit participants, and some of the centers involved in the trial are part of the LDN.  As part of these trials, investigators will be able to assess the safety of the gene editing technique in patients and will evaluate effectiveness by using LDN-developed clinical tools, including brain imaging.

In summary, for the reasons highlighted above, we envision the RDCRN as a unique rare disease clinical trials platform. As we look forward to starting the next round of the RDCRN, we encourage those looking to evaluate novel therapeutics for the rare diseases we have under study to contact Dr Tiina Urv (urvtiin@mail.nih.gov) or one of the RDCRN principal investigators about the potential for collaborative efforts.

Authors

Philip John (P.J.) Brooks
Philip John (P.J.) Brooks

Program Director at the Office of Rare Diseases Research of the National Institute of Health (NIH) in the US

Tiina K. Urv
Tiina K. Urv

Program director for the Rare Diseases Clinical Research Network (RDCRN)

Anne R. Pariser, M.D.
Anne R. Pariser, M.D.

Deputy director of the Office of Rare Diseases Research (ORDR), NCATS

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