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Case‐Study: Protocol Operationalization and Site Engagement Strategies for Cooperative International Neuromuscular Research Group Studies
Erik Henricson, MPH
Associate Director for Clinical Research
UC Davis Department of Physical Medicine and Rehabilitation
Formerly Operations Director for the
Cooperative International Neuromuscular Research Group
(or)
How to Start Your Own Academic CRO / MicroPharma Group with 7 Researchers, an Idea,
a Little Experience, and a Chrysler Minivan
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Disclosures
– CINRG Executive Committee
– Consulting for Genzyme, PTC Therapeutics, Prosensa
Inc.
– Research and Meeting Travel Funding from Parent Project Muscular Dystrophy (USA, Italy), Levine Family Foundation, U.S. Dept of Education, NIH/NIAMS, U.S. Dept of Defense, U.S. Centers for Disease Control, Stichting Porticus Foundation (NL), Glaxo SmithKline, PTC Therapeutics, Prosensa Inc., Sarepta Inc., Ely Lilly Inc., Genzyme Inc.
Overview
3500 Years of DMD
Why we started the CINRG network
Developing the Infrastructure
Logistical Issues & Funding
Site Selection
Study Protocols
Site Support & Communication
Challenges (A few fun examples)
Leveraging Your Data for Clinical Trials
Lessons Learned
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Duchenne Muscular Dystrophy
• Neuromuscular
– Affects proximal muscles more severely
• Progressive
– Loss of ambulation by early teens
• Most common NMD of childhood
– 30 per 100,000 liveborn males
• Treatment: glucocorticoids
• X‐linked
• Due to changes in the dystrophin gene and complete
loss of the dystrophin protein.
Descriptions of DMD:
• Illustrations in temple of Beni
Hasan, Egypt (2500BC) (according to Emery…)
• Case descriptions by Charles Bell (1830) and Gaetano Conti (1836), WJ Little (1847)
• Edward Meryon first to systematically describe “Granular degeneration of voluntary muscles” AKA Meryon’s Disease (1851) in 4 families.
A E Emery and M L Emery. Edward Meryon (1809‐1880) and muscular dystrophy. J Med Genet. Jun 1993; 30(6): 506–511.
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Duchenne (1862)
Duchenne, G. B. A. (1862). Album de photographes pathologiques. Paris: Balliere
100 years pass…
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Brooke MH1, Fenichel GM, Griggs RC, Mendell JR, Moxley R, Florence J, King WM, Pandya S, Robison J, Schierbecker J, et al. Duchenne muscular dystrophy: patterns of clinical progression and effects of supportive therapy. Neurology. 1989 Apr;39(4):475‐81.
Brooke MH, Fenichel GM, Griggs RC, Mendell JR, Moxley R, Miller JP, Province MA. Clinical investigation in Duchenne
dystrophy: 2. Determination of the "power" of therapeutic trials based on the natural history. Muscle Nerve. 1983 Feb;6(2):91‐103.
Mendell JR1, Moxley RT, Griggs RC, Brooke MH, Fenichel GM, Miller JP, King W, Signore L, Pandya S, Florence J, et al.Randomized, double‐blind six‐month trial of prednisone in Duchenne's
muscular dystrophy. N Engl J Med. 1989 Jun 15;320(24):1592‐7.
Sets the stage for steroids to alter the natural history of DMD.
The Dystrophin Gene/Protein (Discovered 1989)
Davies, K. E., & Nowak, K. J. (2006). Molecular mechanisms of muscular dystrophies: old and new players. Nat Rev Mol Cell Biol, 7(10), 762‐773.
Muntoni, F., Torelli, S., & Ferlini, A. (2003). Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol, 2(12), 731‐740. 5
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Multiple Tissue‐Specific Isoforms
Slide 11
The Problem
Lots of patients ~15,000 in U.S. alone
No significant clinical trials since the 1980s
Lack of clinical trials infrastructure
Lack of funding
No pharmaceutical interest or research in muscle diseases.
– Funding mostly via advocacy organizations – MDA ~$2M nationwide in research funding in 2000, all basic research
– Federal Funding $17M/year, no NIH‐funded multicenter clinical trials (about $.01 for every NIH $1 spent in oncology, and >90% to basic work)
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The Idea (1999)
Build a collaborative multidisciplinary international network to advance the clinical study of new interventions for children with neuromuscular diseases
The Resources
– Small lab (7 people) and Institutional Support for a Muscle Genetics Lab (2 Neurologists, 4 Geneticist and a Public Health Specialist)
– New Advances in Genetics and Technologies – Lots of new toys
– Growing Body of Basic Science Data on Potential Interventions from Established Collaborating Labs
– Multiple drug candidates with identified pathways
– Many interested expert clinicians around the world with established pediatric neuromuscular clinics
– GCRC (for biostatistics, pharmacy)
– Outreach partners and advocacy groups
– Patient Advocacy Groups with Seed Funding and High Profile “Connections”
– Chrysler Minivan (with Evita C.D.)
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The German Response
Association Francaise Contre les Myopathies (AFM)
Nice, France, 2000
Developing the Necessary Organizational Structure (2000‐
2005)
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And you wanted to be a scientist…..
If you are running a multicenter network, doing the
hands‐on research is 10% of the work
– If you’re thinking of running a one‐off multicenter clinical trial, ask yourself whether it’s worth it!
– (The answer might be yes)
– Infrastructure and “coordinating center” activities for 1 study vs. multiple studies are nearly the same, so think about the long‐
term.
– Are you going to 1) be an administrator; or 2) hire one?
– You will also need to 1) be a Study Designer, Study Coordinator, Personnel Coordinator, Regulatory Affairs Coordinator, Legislative Affairs Coordinator, Grant Writer, Finance Coordinator, Contract Coordinator, Data Manager, Web Developer, Outcome Measure Developer, Publication Author, Meeting Planner, Travel Coordinator, Cab Driver, Caterer; or 2) hire them. – So ‐ Make sure you have TIME to do those jobs, or FUNDING to hire the people.
No resources? No problem! (Well, maybe a problem).
Partnering with Advocacy Groups
(The Flaming Phone Call and Decimal Dust)
– The magazine interview that went wrong and how it created a longstanding partnership with advocacy groups (MDA, PPMD, FED).
– Frustrations with Family Involvement
– Frustrations with Funding Agencies
– How our partnership helped lead to the MD‐CARE Act
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The MD CARE Act: A Game‐Changer
– Legislative Advocacy – 2000 Muscular Dystrophy Community Assistance, Research and Education (MD CARE) Act
– Congressionally‐mandated NIH Muscular Dystrophy Coordinating Committee established goals
– MD CARE Act authorized every year since 2001, today $75M annually in federal grants, over $300M since 2000
– Now funding multiple cooperative groups (CINRG, Muscle Study Group, TreatNMD, etc.), pharma
industry projects.
CINRG: Where We Are Today
• CINRG with 25 sites worldwide
• Multiple investigator‐
initiated CINRG clinical trials and mechanistic/obser
vational studies completed and published
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Choosing Sites:
Just because everyone wants to join the network today,
does not necessarily mean it’s a good idea!
– If you build it, they will come. Often without invitation.
– Big networks look awesome on paper. Don’t let your eyes get bigger than your stomach (or staff).
• Once you have X sites on board, you have to support them. Do you want 30 (variable) sites, or 15 high‐quality ones?
• Be very selective and set a high bar for entry: Less productive sites provide the smallest fraction of scientific data (the whole point), but take the most time to supervise and support.
• Starting a site is a LOT of work and can be expensive, you don’t want it to be wasted.
– Carefully evaluate each investigator and evaluate their resources.
– If you lack funding, say so up front. Sites and investigators who are willing to invest in an effort make great partners.
– Use a formal site application to set expectations and ensure standardized resources.
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Writing Your Study Protocol:
Know who will read it (and where they are!)
– Pre‐plan, investigate what regulatory framework you’re working in – FDA? NIH? EMEA? IRBs? Ethics Boards? Foreign Governments Agencies?
– Review all of the regulatory guidance
– Fit your study protocol format to meet all of the requirements (See example TOC)
– Get some local peer review ahead of time from sites to identify weak areas
– Organize your central and site files and make sure they are complete (See example Key Document Checklist)
Site Support: Annual Meetings as a Forum for Science, Education and Testing
– Annual meetings include:
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All investigators, coordinators, evaluators
Coordinating Center leadership and staff
Outside committee and advisory group members
Advocacy organizations
Pharma Industry Collaborators
– Public day – Scientific Forum
– Private day – Training and Reliability Testing
– Dinner Party for All (Hosted/Catered by Scientific Director)!
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Site Support Activities
– Regular “Leadership Team”/study chair teleconferences (Monthly or greater)
– Regular investigator/site staff teleconferences (Quarterly)
– Regular (and active) site regulatory and data monitoring – Coordinator “Hotline”
– IRB Preparation Assistance
• Assistance with IRB package and consent preparation (Incl. translations)
• Review of final documents prior to submission
• Central tracking for “future use of data” provisions
– Enrollment Assistance • ClinicalTrials.gov
• Advocacy Foundations
– Enrollment Tracking
• Setting enrollment goals
• Regular communication of actual vs. planned enrollment
• Working with PIs and coordinators to craft site‐specific enrollment assistance plans if lagging behind
Other Ideas for Site Support Materials
– Group or Study Specific Website
– Example Study Document CD
– Standardized Fax Coversheets for Coordinating Center (and any other required regular contacts)
– Central Contact Information Sheet
– Visit Calculators
– Study Materials Checklists and Order Form
– Central Pharmacy Medication Request Form
– Sample Prescriptions
– Sample Outside Consult Requests (if used)
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Challenge ‐ New Toy on the Block: Partnering with Big Pharma to Invent, Build, Validate and Distribute
Pediatric Strength Testing Equipment
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Ask investigators to find local funding assistance
Source materials locally where possible.
Plan and budget for import taxes
Know the customs regulations for host nations
Sometimes small‐
batch electronics look like bombs –
you will answer lots of questions
Challenge: DNA is everywhere but you can’t
always get it (directly, that is)
• Case of India:
– lack of molecular diagnostics
– can’t get DNA out of the country
• DNA can’t transport. Data can!
Dr. B.R. Lakshmi
Sundaram Medical Foundation
Chennai, India
– Training a new fellow with the Stichting‐
Porticus Foundation
– Setting up a new MLPA lab (First in India)
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Leveraging Our Data for Clinical Trials
• 15 trial, biomarker and natural history publications
• Advisory board and data sharing with multiple novel drug development programs
• 1 EU marketing approval (U.S. pending)
• 3 “spinoff” startup pharma companies
Lessons Learned
• This is very expensive. Coordinating Center ~$1.5M/year on a “shoestring” budget. Leverage all the resources you can (CTSC, etc .)
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Data management / Biostatistics
Project managers / CRAs / Monitors
Annual meetings (~$75‐100K) and face to face ++ important.
Evaluator training (ongoing and necessary)
• Specific funding required for C.C. “infrastructure”. This is NOT feasible on a project‐by‐project basis.
• There is always a site that needs staff trained. Reliability needs to be checked regularly. Plan your finances accordingly.
• Investment is worth it, with enough sites.
– 5 sites? Probably not.
– 15‐25 sites? Yes, some sites more prolific than others, some will drop out. A small central staff will be very busy, select sites carefully.
– >25 sites? Bigger infrastructure grant.
• Streamline administrative processes early to avoid becoming the stereotypic bureaucracy.
• You will be a great resource for Pharma, they can contribute $
• BUT, no matter how good your infrastructure is, Pharma will build and run their own trials ‐ don’t count on being a CRO.
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Funding
U.S. Department of Education/NIDRR (#H133B031118, #H133B090001)
U.S. Department of Defense (#W81XWH-09-1-0592)
National Institutes of Health (#UL1RR031988, U54HD053177, #UL1RR024992, #U54RR026139, #2U54HD053177, #G12RR003051)
Parent Project Muscular Dystrophy
Collaborating Authors:
Sundaram Medical Foundation and Apollo Children’s Hospital – V. Vishwanathan, PhD, S. Chidambaranathan, MD, Holland Bloorview Kids Rehabilitation Hospital – Doug Biggar,
MD, Alberta Children’s Hospital – Jean K. Mah, MD, Queen Sylvia Children’s Hospital – Mar Tulinius, MD, Children’s National Medical Center – Eric Hoffman, PhD, Yetrib Hathout,
PhD, Heather Dressman, PhD, Chris Spurney, MD, Robert Leshner, MD, Carolina Tesi-Rocha, MD, Royal Children’s Hospital – Andrew Kornberg, MD, Monique Ryan, MD,
Hadassah Hebrew University Hospital – Yoram Nevo, MD, Instituto de Neurosciencias Fundacion Favaloro – Alberto Dubrovsky, MD, Mayo Clinic – Nancy Kuntz, MD, Sherilyn
Driscoll, MD, Washington University, St. Louis – Anne Connolly, MD, Alan Pestronk, MD, Children’s Hospital of Virginia –Jean Teasley, MD, University of Tennessee, Memphis –
Tulio Bertorini, MD, Children’s Hospital of Westmead – Kathryn North, MD, University of Alberta – Hanna Kolski, MD, University of Puerto Rico – Jose Carlo, MD, University of Pavia
and Niguarda Ca’ Granda Hospital – Ksenija Gorni, MD, Texas Children’s Hospital – Timothy Lotze, MD, University of Minnesota – John Day, MD
The CINRG Group:
University of California, Davis –Michelle Cregan, Erica Goude, Merete Glick, Jay Han, Linda Johnson, Nanette Joyce, David Kilmer, Nicoole Mans, Alina Nicorici, Divya Reddy,
Andrew Skalsky, Amanda Witt, Medical Foundation and Apollo Children’s Hospital, Chennai –Suresh Kumar, Holland Bloorview Kids Rehabilitation Hospital – Laila Eliasoph,
Elizabeth Hosaki, Angela Gonzales, Vivienne Harris, Alberta Children’s Hospital – Angela Chiu, Edit Goia, Jennifer Thannhauser, Lori Walker, Caitlin Wright, Mehrnaz Yousefi, Queen
Sylvia Children’s Hospital – Ann-Christine Alhander, Lisa Berglund, Ann-Berit Ekstrom, Anna-Karin Kroksmark, Ulrika Sterky, Children’s National Medical Center – Marissa Birkmeier,
Sarah Kaminski, Royal Children’s Hospital – Kate Carroll, Katy DeValle, Rachel Kennedy, Dani Villano, Hadassah Hebrew University Hospital – Adina Bar Leve, Itai Shurr, Elana
Wisband, Debbie Yaffe, Instituto de Neurosciencias Fundacion Favaloro – Luz Andreone, Jose Corderi, Lilia Mesa, Lorena Levi, Mayo Clinic – Krista Coleman-Wood, Ann Hoffman,
Wendy Korn-Petersen, Duygu Selcen, University of Pittsburgh – Hoda Abdel-Hamid, Christopher Bise, Ann Craig, Casey Nguyen, Jason Weimer, Washington University, St. Louis –
M. Al-Lozi, Paul Golumbak, Glenn Lopate, Justin Malane, Betsy Malkus, Kenkicki Nozaki, 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 –Judy Clift, Cassandra Feliciano, Masanori Igarashi, Rachel Young,
Children’s Hospital of Westmead – Kristy Rose, Richard Webster, Stephanie Wicks, University of Alberta – Lucia Chen, Cameron Kennedy, University of Puerto Rico –Brenda Deliz,
Sheila Espada, Pura Fuste, Carlos Luciano, University of Pavia - Luca Capone, Niguarda Ca’ Granda Hospital – Maria Beneggi, Valentina Morettini, Texas Children’s Hospital – Anjali
Gupta, Robert McNeil, University of Minnesota –Amy Erickson, Marcia Margolis, Cameron Naughton, Gareth Parry, David Walk, The CINRG Coordinating Center –Naomi Bartley,
Paola Canelos, Robert Casper, Lauren Hache, Mohammad Ahmed, Angela Zimmerman
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