TY - JOUR
T1 - A checklist for clinical trials in rare disease
T2 - Obstacles and anticipatory actions-lessons learned from the FOR-DMD trial
AU - Crow, Rebecca A.
AU - Hart, Kimberly A.
AU - McDermott, Michael P.
AU - Tawil, Rabi
AU - Martens, William B.
AU - Herr, Barbara E.
AU - McColl, Elaine
AU - Wilkinson, Jennifer
AU - Kirschner, Janbernd
AU - King, Wendy M.
AU - Eagle, Michele
AU - Brown, Mary W.
AU - Hirtz, Deborah
AU - Lochmuller, Hanns
AU - Straub, Volker
AU - Ciafaloni, Emma
AU - Shieh, Perry B.
AU - Spinty, Stefan
AU - Childs, Anne Marie
AU - Manzur, Adnan Y.
AU - Morandi, Lucia
AU - Butterfield, Russell J.
AU - Horrocks, Iain
AU - Roper, Helen
AU - Flanigan, Kevin M.
AU - Kuntz, Nancy L.
AU - Mah, Jean K.
AU - Morrison, Leslie
AU - Darras, Basil T.
AU - von der Hagen, Maja
AU - Schara, Ulrike
AU - Wilichowski, Ekkehard
AU - Mongini, Tiziana
AU - McDonald, Craig M.
AU - Vita, Giuseppe
AU - Barohn, Richard J.
AU - Finkel, Richard S.
AU - Wicklund, Matthew
AU - McMillan, Hugh J.
AU - Hughes, Imelda
AU - Pegoraro, Elena
AU - Bryan Burnette, W.
AU - Howard, James F.
AU - Thangarajh, Mathula
AU - Campbell, Craig
AU - Griggs, Robert C.
AU - Bushby, Kate
AU - Guglieri, Michela
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/5/10
Y1 - 2018/5/10
N2 - 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.
AB - 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.
KW - Academic-led clinical trial
KW - Clinical trial
KW - Clinical trial regulations
KW - Duchenne muscular dystrophy
KW - Rare disease
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U2 - 10.1186/s13063-018-2645-0
DO - 10.1186/s13063-018-2645-0
M3 - Review article
C2 - 29793540
AN - SCOPUS:85047553551
SN - 1745-6215
VL - 19
JO - Trials
JF - Trials
IS - 1
M1 - 291
ER -