Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy


Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

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Fig. 1
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Between-individual variability


Body mass index


Between-study variability


Clinical data interchange standards consortium


Committee for medicinal products for human use


Cooperative international neuromuscular research group


Duchenne muscular dystrophy


Duchenne regulatory science consortium


European Medicines Authority


Food and Drug Administration




Letter of intent


Model-informed drug discovery and development


Qualification of novel methodologies


Residual variability


Scientific advice working party


Therapeutic area user guide


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We would like to thank the members of the D-RSC consortium who have funded and participated in this project. We would also like to thank those who have contributed data to the project and made these analyses possible, in particular the CINRG Investigators for the CINRG DNHS study, and the Imaging-DMD consortium. KRA is partially supported as a UK National Institute for Health Research (NIHR) Senior Investigator Emeritus (NI-SI-0512-10159). MH received funding from Project HERCULES, which is funded by Duchenne UK. KRA and MC were partially supported by Project HERCULES. Critical Path Institute is supported in part by Grant No. 5U18FD005320 from the Food and Drug Administration.

Cooperative International Neuromuscular Research Group (CINRG) Investigators

V Vishwanathan, S. Chidambaranathan (Sundaram Medical Foundation and Apollo Children’s Hospital, Chennai, India); W. Douglas Biggar, Laura C. McAdam (Holland Bloorview Kids Rehab Hospital, Toronto, Ontario, Canada);Jean K. Mah (Alberta Children’s Hospital, Calgary, Alberta, Canada); Mar Tulinius (Queen Silvia Children’s Hospital, Göteborg, Sweden); Avital Cnaan, Lauren P. Morgenroth, Robert Leshner, Carolina Tesi-Rocha, Mathula Thangarajh, Tina Duong (Children’s National Medical Center, Washington DC, USA); Andrew Kornberg, Monique Ryan (Royal Children’s Hospital, Melbourne, Victoria, Australia); Yoram Nevo (Hadassah Hebrew University Hospital, Jerusalem, Israel); Alberto Dubrovsky (Instituto de Neurosciencias Fundacion Favaloro, Buenos Aires, Argentina); Paula R. Clemens, Hoda Abdel-Hamid (University of Pittsburgh and Department of Veterans Affairs, Pittsburgh, Pennsylvania, USA); Anne M. Connolly, Alan Pestronk (Washington University in St Louis, St Louis, Missouri, USA); Jean Teasley (Children’s Hospital of Virginia, Richmond, Virginia, USA); Tulio E. Bertorini (University of Tennessee, Memphis, Tennessee, USA); Richard Webster (Children’s Hospital at Westmead, Sydney, New South Wales, Australia); Hanna Kolski, (University of Alberta, Edmonton, Alberta, Canada); Nancy Kuntz, Sherilyn Driscoll, John B. Bodensteiner (Mayo Clinic, Rochester, Minnesota, USA); Jose Carlo (University of Puerto Rico, San Juan, Puerto, Rico), Ksenija Gorni (University of Pavia and Niguarda Ca’ Granda Hospital, Milan, Italy); Timothy Lotze (Texas Children’s Hospital, Houston, Texas, USA); John W. Day, Peter Karachunski (University of Minnesota, Minneapolis, Minnesota, USA); Erik K. Henricson, Richard T. Abresch, Nanette C. Joyce, and Craig M. McDonald (University of California, Davis, Sacramento, California, USA).

The Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS) was funded by the U.S. Department of Education/NIDRR (#H133B031118, #H133B090001); U.S. Department of Defense (#W81XWH-12-1-0417); National Institutes of Health/NIAMS (#R01AR061875); Parent Project Muscular Dystrophy. The authors thank the dedicated CINRG DNHS researchers. Additional CINRG DNHS network sites and researchers who contributed to this project include: University of California, Davis—Michelle Cregan, Erica Goude, Alina Nicorici, Merete Glick, Linda Johnson, Jay Han; Holland Bloorview Kids Rehabilitation—Laila Eliasoph, Elizabeth Hosaki, Angela Gonzales, Vivienne Harris; Alberta Children’s Hospital—Angela Chiu, Karla Sanchez, Natalia Rincon, Tiffany Haig; Queen Silvia Children’s Hospital—Anne-Christine Alhander, Lisa Wahlgren, Anne-Berit Ekstrom, Anna-Karin Kroksmark, Ulrika Sterky; Children’s National Medical Center—Marissa Birkmeier, Sarah Kaminski, Allyn Toles; Royal Children’s Hospital—Kate Carroll, Katy DeValle, Rachel Kennedy, Andrew Kornberg, Dani Villano; Hadassah Hebrew University Hospital—Adina Bar Leve, Elana Wisband, Debbie Yaffe; Instituto de Neurosciencias Fundacion Favaloro—Luz Andreone, Jose Corderi, Lilia Mesa, Lorena Levi; Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh–Hoda Abdel-Hamid, Christopher Bise, Ann Craig, Casey Nguyen, Andrea Smith, Jason Weimer; Washington University, St. Louis—M. Al-Lozi, Julaine Florence, Betsy Malkus, Renee Renna, Jeanine Schierbacker, Catherine Seiner, Charlie Wulf; Children’s Hospital of Virginia–Susan Blair, Barbara Grillo, Karen Jones, Eugenio Monasterio; University of Tennessee, Memphis—Meegan Barrett-Adair, Judy Clift, Cassandra Feliciano, Rachel Young; Children’s Hospital of Westmead—Kristy Rose, Richard Webster, Stephanie Wicks; University of Alberta—Lucia Chen, Cameron Kennedy; the CINRG DNHS Coordinating Center—Adrienne Arrieta, Tanisha Brown-Caines, Avital Cnaan, Tina Duong, Fengming Hu, Lauren Morgenroth, Wenze Tang.

ACT DMD Study Group

McDonald CM, Campbell C, Torricelli RE, Finkel RS, Flanigan KM, Goemans N, Heydemann P, Kaminska A, Kirschner J, Muntoni F, Osorio AN, Schara U, Sejersen T, Shieh PB, Sweeney HL, Topaloglu H, Tulinius M, Vilchez JJ, Voit T, Wong B, Alfano LN, Eagle M, James MK, Lowes L, Mayhew A, Mazzone ES, Nelson L, Rose KJ, Abdel-Hamid HZ, Apkon SD, Barohn RJ, Bertini E, Bloetzer C, de Vaud LC, Butterfield RJ, Chabrol B, Chae JH, Jongno-Gu DR, Comi GP, Darras BT, Dastgir J, Desguerre I, Escobar RG, Finanger E, Guglieri M, Hughes I, Iannaccone ST, Jones KJ, Karachunski P, Kudr M, Lotze T, Mah JK, Mathews K, Nevo Y, Parsons J, Péréon Y, de Queiroz Campos Araujo AP, Renfroe JB, de Resende MBD, Ryan M, Selby K, Tennekoon G, Vita G.

Tadalafil DMD Study Group

Abdel-Hamid H, Apkon S, Barohn R, Belousova E, Bertini E, Brandsema J, Bruno C, Burnette W, Butterfield R, Byrne B, Campbell C, Carlo J, Chae JH, Chandratre S, Comi G, Connolly A, De Groot I, Deconinck N, Dooley J, Dubrovsky A, Durigneux J, Finanger E, Finkel R, Frank LM, Goemans N, Harper A, Hattori A, Herguner O, Iannaccone S, Janas J, Jong YJ, Kirschner J, Komaki H, Kuntz N, Lee WT, Leung E, Mah J, Mathews K, McDonald CM, Mercuri E, McMillan H, Mueller-Felber W, Lopez de Munain A, Nakamura A, Niks E, Ogata K, Pascual S, Pegoraro E, Pereon Y, Renfroe B, Sanka RB, Schallner J, Schara U, Selby K, Sendra II, Servais L, Smith E, Sparks S, Topaloglu H, Victor R, Vilchez JJ, Wicklund M, Wilichoswki E, Wong B.

UC Davis (DMD-1000) and UC Davis 2 (DMD-1000A)

Richard T. Abresch, Gergory T. Carter, Erik Henricson, and Craig M. McDonald.

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DJC, AB, JL, JB and KR wrote this manuscript. DJC, AB, KR, KRA, MH, MC, SK and SS contributed directly to the analysis. All authors contributed to the analysis plan and concept development and reviewed the manuscript.

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Correspondence to Daniela J. Conrado.

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Conflict of interest

The D-RSC Consortium includes Biophytis, Catabasis Pharmaceuticals, Mallinckrodt, Pfizer, Santhera Pharmaceuticals, Sarepta Therapeutics and Wave Life Sciences. The ImagingDMD Network is funded through NIH Grant RO1AR056973. KRA has served as a paid consultant, providing methodological advice, to; Abbvie, Amaris, Allergan, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Creativ-Ceutical, GSK, ICON/Oxford Outcomes, Ipsen, Janssen, Eli Lilly, Merck, NICE, Novartis, NovoNordisk, Pfizer, PRMA, Roche and Takeda, and has received research funding from Association of the British Pharmaceutical Industry (ABPI), European Federation of Pharmaceutical Industries & Associations (EFPIA), Pfizer and Sanofi. He is a Partner and Director of Visible Analytics Limited, a healthcare consultancy company. CMM has served as a consultant for clinical trials for PTC Therapeutics, and outside the submitted work as a consultant for Biomarin, Sarepta, Eli Lilly, Pfizer, Santhera Pharmaceuticals, Cardero Therapeutics, Inc., Catabasis, Capricor Therapeutics, Astellas and FibroGen; serves on external advisory boards related to Duchenne muscular dystrophy for PTC Therapeutics, Eli Lilly, Sarepta Therapeutics, Santhera Pharmaceuticals, and Capricor; and reports grants from US Dept. of Education/NIDRR, NIDILRR, US NIH/NIAMS, US Dept. of Defense, and Parent Project Muscular Dystrophy US, during the conduct of the study. Project HERCULES, which supported MH, KRA and MC, is funded by Duchenne UK, Pfizer, PTC Therapeutics, Roche, Summit Therapeutics PLC, Sarepta Therapeutics Inc, Wave Life Sciences USA Inc, Solid Biosciences, Santhera Pharmaceuticals and Catabasis Pharmaceuticals.” MC has served as a paid consultant, providing methodological advice, to ICON/Oxford Outcomes and Roche. DChapman, LH and CV are employees and shareholders of Pfizer.

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Conrado, D.J., Larkindale, J., Berg, A. et al. Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy. J Pharmacokinet Pharmacodyn 46, 441–455 (2019).

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  • Rare diseases
  • Duchenne muscular dystrophy consortium (D-RSC)
  • Model-informed drug development
  • Drug development tools
  • Regulatory endorsement