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

Rebecca A. Crow, Kimberly A. Hart, Michael P. McDermott, Rabi Tawil, William B. Martens, Barbara E. Herr, Elaine McColl, Jennifer Wilkinson, Janbernd Kirschner, Wendy M. King, Michele Eagle, Mary W. Brown, Deborah Hirtz, Hanns Lochmuller, Volker Straub, Emma Ciafaloni, Perry B. Shieh, Stefan Spinty, Anne Marie Childs, Adnan Y. Manzur & 28 others Lucia Morandi, Russell J. Butterfield, Iain Horrocks, Helen Roper, Kevin M. Flanigan, Nancy L. Kuntz, Jean K. Mah, Leslie Morrison, Basil T. Darras, Maja von der Hagen, Ulrike Schara, Ekkehard Wilichowski, Tiziana Mongini, Craig M McDonald, Giuseppe Vita, Richard J. Barohn, Richard S. Finkel, Matthew Wicklund, Hugh J. McMillan, Imelda Hughes, Elena Pegoraro, W. Bryan Burnette, James F. Howard, Mathula Thangarajh, Craig Campbell, Robert C. Griggs, Kate Bushby, Michela Guglieri

Research output: Contribution to journalReview article

Abstract

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.

LanguageEnglish (US)
Article number291
JournalTrials
Volume19
Issue number1
DOIs
StatePublished - May 10 2018

Fingerprint

Duchenne Muscular Dystrophy
Rare Diseases
Checklist
Steroids
Clinical Trials
National Institutes of Health (U.S.)
Pharmaceutical Preparations
Organizations
Contracts
Insurance
Italy
Canada
Germany
Fruit
Language
Research

Keywords

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

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology (medical)

Cite this

Crow, R. A., Hart, K. A., McDermott, M. P., Tawil, R., Martens, W. B., Herr, B. E., ... Guglieri, M. (2018). A checklist for clinical trials in rare disease: Obstacles and anticipatory actions-lessons learned from the FOR-DMD trial. Trials, 19(1), [291]. https://doi.org/10.1186/s13063-018-2645-0

A checklist for clinical trials in rare disease : Obstacles and anticipatory actions-lessons learned from the FOR-DMD trial. / Crow, Rebecca A.; Hart, Kimberly A.; McDermott, Michael P.; Tawil, Rabi; Martens, William B.; Herr, Barbara E.; McColl, Elaine; Wilkinson, Jennifer; Kirschner, Janbernd; King, Wendy M.; Eagle, Michele; Brown, Mary W.; Hirtz, Deborah; Lochmuller, Hanns; Straub, Volker; Ciafaloni, Emma; Shieh, Perry B.; Spinty, Stefan; Childs, Anne Marie; Manzur, Adnan Y.; Morandi, Lucia; Butterfield, Russell J.; Horrocks, Iain; Roper, Helen; Flanigan, Kevin M.; Kuntz, Nancy L.; Mah, Jean K.; Morrison, Leslie; Darras, Basil T.; von der Hagen, Maja; Schara, Ulrike; Wilichowski, Ekkehard; Mongini, Tiziana; McDonald, Craig M; Vita, Giuseppe; Barohn, Richard J.; Finkel, Richard S.; Wicklund, Matthew; McMillan, Hugh J.; Hughes, Imelda; Pegoraro, Elena; Bryan Burnette, W.; Howard, James F.; Thangarajh, Mathula; Campbell, Craig; Griggs, Robert C.; Bushby, Kate; Guglieri, Michela.

In: Trials, Vol. 19, No. 1, 291, 10.05.2018.

Research output: Contribution to journalReview article

Crow, RA, Hart, KA, McDermott, MP, Tawil, R, Martens, WB, Herr, BE, McColl, E, Wilkinson, J, Kirschner, J, King, WM, Eagle, M, Brown, MW, Hirtz, D, Lochmuller, H, Straub, V, Ciafaloni, E, Shieh, PB, Spinty, S, Childs, AM, Manzur, AY, Morandi, L, Butterfield, RJ, Horrocks, I, Roper, H, Flanigan, KM, Kuntz, NL, Mah, JK, Morrison, L, Darras, BT, von der Hagen, M, Schara, U, Wilichowski, E, Mongini, T, McDonald, CM, Vita, G, Barohn, RJ, Finkel, RS, Wicklund, M, McMillan, HJ, Hughes, I, Pegoraro, E, Bryan Burnette, W, Howard, JF, Thangarajh, M, Campbell, C, Griggs, RC, Bushby, K & Guglieri, M 2018, 'A checklist for clinical trials in rare disease: Obstacles and anticipatory actions-lessons learned from the FOR-DMD trial' Trials, vol. 19, no. 1, 291. https://doi.org/10.1186/s13063-018-2645-0
Crow, Rebecca A. ; Hart, Kimberly A. ; McDermott, Michael P. ; Tawil, Rabi ; Martens, William B. ; Herr, Barbara E. ; McColl, Elaine ; Wilkinson, Jennifer ; Kirschner, Janbernd ; King, Wendy M. ; Eagle, Michele ; Brown, Mary W. ; Hirtz, Deborah ; Lochmuller, Hanns ; Straub, Volker ; Ciafaloni, Emma ; Shieh, Perry B. ; Spinty, Stefan ; Childs, Anne Marie ; Manzur, Adnan Y. ; Morandi, Lucia ; Butterfield, Russell J. ; Horrocks, Iain ; Roper, Helen ; Flanigan, Kevin M. ; Kuntz, Nancy L. ; Mah, Jean K. ; Morrison, Leslie ; Darras, Basil T. ; von der Hagen, Maja ; Schara, Ulrike ; Wilichowski, Ekkehard ; Mongini, Tiziana ; McDonald, Craig M ; Vita, Giuseppe ; Barohn, Richard J. ; Finkel, Richard S. ; Wicklund, Matthew ; McMillan, Hugh J. ; Hughes, Imelda ; Pegoraro, Elena ; Bryan Burnette, W. ; Howard, James F. ; Thangarajh, Mathula ; Campbell, Craig ; Griggs, Robert C. ; Bushby, Kate ; Guglieri, Michela. / A checklist for clinical trials in rare disease : Obstacles and anticipatory actions-lessons learned from the FOR-DMD trial. In: Trials. 2018 ; Vol. 19, No. 1.
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abstract = "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.",
keywords = "Academic-led clinical trial, Clinical trial, Clinical trial regulations, Duchenne muscular dystrophy, Rare disease",
author = "Crow, {Rebecca A.} and Hart, {Kimberly A.} and McDermott, {Michael P.} and Rabi Tawil and Martens, {William B.} and Herr, {Barbara E.} and Elaine McColl and Jennifer Wilkinson and Janbernd Kirschner and King, {Wendy M.} and Michele Eagle and Brown, {Mary W.} and Deborah Hirtz and Hanns Lochmuller and Volker Straub and Emma Ciafaloni and Shieh, {Perry B.} and Stefan Spinty and Childs, {Anne Marie} and Manzur, {Adnan Y.} and Lucia Morandi and Butterfield, {Russell J.} and Iain Horrocks and Helen Roper and Flanigan, {Kevin M.} and Kuntz, {Nancy L.} and Mah, {Jean K.} and Leslie Morrison and Darras, {Basil T.} and {von der Hagen}, Maja and Ulrike Schara and Ekkehard Wilichowski and Tiziana Mongini and McDonald, {Craig M} and Giuseppe Vita and Barohn, {Richard J.} and Finkel, {Richard S.} and Matthew Wicklund and McMillan, {Hugh J.} and Imelda Hughes and Elena Pegoraro and {Bryan Burnette}, W. and Howard, {James F.} and Mathula Thangarajh and Craig Campbell and Griggs, {Robert C.} and Kate Bushby and Michela Guglieri",
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publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - A checklist for clinical trials in rare disease

T2 - Trials

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

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

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