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Designing clinical trials for rare diseases: unique challenges and opportunities

Orphan drug development is a rapidly expanding field. Nevertheless, clinical trials for rare diseases can present inherent challenges. Optimal study design and partnerships between academia and industry are therefore required for the successful development, delivery and clinical approval of effective therapies in this group of disorders.

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  1. Nguengang Wakap, S. et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur. J. Hum. Genet. 28, 165–173 (2020).

    Article  Google Scholar 

  2. Rosales, X. Q. et al. The North American mitochondrial disease registry. J. Transl Genet. Genom. 4, 81–90 (2020).

    Google Scholar 

  3. Reid Thompson, W. et al. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genet. Med. 23, 471–478 (2021).

    Article  Google Scholar 

  4. Germain, D. P. et al. Treatment of Fabry’s disease with the pharmacologic chaperone migalastat. N. Engl. J. Med. 375, 545–555 (2016).

    Article  Google Scholar 

  5. Tandon, P. K. & Kakkis, E. D. The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases. Orphanet J. Rare Dis. 16, 183 (2021).

    Article  Google Scholar 

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C.P. is supported by a Clore Duffield Foundation grant. R.D.S.P. is supported by a Medical Research Council (UK) Clinician Scientist Fellowship (MR/S002065/1). R.D.S.P. and M.G.H. are funded by a Medical Research Council (UK) strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) (MR/S005021/1).

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Correspondence to Robert D. S. Pitceathly.

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Pizzamiglio, C., Vernon, H.J., Hanna, M.G. et al. Designing clinical trials for rare diseases: unique challenges and opportunities. Nat Rev Methods Primers 2, 13 (2022).

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