A checklist for clinical trials in rare disease: Obstacles and anticipatory actions-lessons learned from the FOR-DMD trial

被引：33

作者：

Crow R.A. ^{[1
]}

Hart K.A. ^{[2
]}

McDermott M.P. ^{[2
]}

Tawil R. ^{[2
]}

Martens W.B. ^{[2
]}

Herr B.E. ^{[2
]}

McColl E. ^{[3
]}

Wilkinson J. ^{[3
]}

Kirschner J. ^{[4
]}

King W.M. ^{[2
]}

Eagle M. ^{[1
]}

Brown M.W. ^{[2
]}

Hirtz D. ^{[5
]}

Lochmuller H. ^{[1
]}

Straub V. ^{[1
]}

Ciafaloni E. ^{[2
]}

Shieh P.B. ^{[6
]}

Spinty S. ^{[7
]}

Childs A.-M. ^{[8
]}

Manzur A.Y. ^{[9
]}

Morandi L. ^{[10
]}

Butterfield R.J. ^{[11
]}

Horrocks I. ^{[12
]}

Roper H. ^{[13
]}

Flanigan K.M. ^{[14
]}

Kuntz N.L. ^{[15
]}

Mah J.K. ^{[16
]}

Morrison L. ^{[17
]}

Darras B.T. ^{[18
]}

von der Hagen M. ^{[19
]}

Schara U. ^{[20
]}

Wilichowski E. ^{[21
]}

Mongini T. ^{[22
]}

McDonald C.M. ^{[23
]}

Vita G. ^{[24
]}

Barohn R.J. ^{[25
]}

Finkel R.S. ^{[26
]}

Wicklund M. ^{[27
]}

McMillan H.J. ^{[28
]}

Hughes I. ^{[29
]}

Pegoraro E. ^{[30
]}

Bryan Burnette W. ^{[31
]}

Howard J.F. ^{[32
]}

Thangarajh M. ^{[33
]}

Campbell C. ^{[34
]}

Griggs R.C. ^{[2
]}

Bushby K. ^{[1
]}

Guglieri M. ^{[1
]}

机构：

[1] Newcastle University, John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle upon Tyne

[2] University of Rochester Medical Center, Rochester, NY

[3] Newcastle University, Newcastle upon Tyne

[4] University Medical Center, Freiburg

[5] National Institutes of Health, Bethesda, MD

[6] UCLA, Los Angeles, CA

[7] Alder Hey Children's Hospital, Liverpool

[8] Leeds Teaching Hospitals, Leeds

[9] GOSH, UCL, London

[10] Neurological Institute Carlo Besta, Milan

[11] University of Utah, Salt Lake City, UT

[12] Greater Glasgow and Clyde NHS Yorkhill Hospital, Glasgow

[13] Birmingham Heartlands Hospital, Birmingham

[14] Nationwide Children's Hospital, Columbus, OH

[15] Ann and Robert H. Lurie Children's Hospital, Chicago, IL

[16] University of Calgary, Calgary

[17] University of New Mexico, Albuquerque, NM

[18] Boston Children's Hospital, Boston, MA

[19] Technical University Dresden, Children's Hospital, Dresden

[20] University of Essen, Essen

[21] Children's University Hospital, Göttingen, Göttingen

[22] University of Torino, Turin

[23] UC Davis Medical Center, Sacramento, CA

[24] University of Messina AOU Policlinico Gaetano Martino, Messina

[25] University of Kansas Medical Center, Kansas City, KS

[26] Nemours Children's Hospital, Orlando, FL

[27] Penn State College of Medicine, Hershey, PA

[28] Children's Hospital of Eastern Ontario, Ottawa

[29] Royal Manchester Children's Hospital, Manchester

[30] University of Padova, Padua

[31] Vanderbilt Children's Hospital, Nashville, TN

[32] University of North Carolina School of Medicine, Chapel Hill, NC

[33] Children's National Medical Center, Washington, DC

[34] Children's Hospital London Health Sciences Centre, London

来源：

Trials | / 19卷 / 1期

基金：

美国国家卫生研究院;

关键词：

Academic-led clinical trial; Clinical trial; Clinical trial regulations; Duchenne muscular dystrophy; Rare disease;

D O I：

10.1186/s13063-018-2645-0

中图分类号：

学科分类号：

摘要：

Background: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. Method: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Results: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Conclusion: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate. © 2018 The Author(s).

引用

共 34 条

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