How To Set Up A Successful Clinical Trials Network

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1 How To Set Up A Successful Clinical Trials Network Bonnie Ramsey, MD CF Endowed Professor of Pediatrics and Vice Chair of Research, UWSOM April 4, 2017 Director, Center for Clinical and Translational Research, Seattle Children s Research Institute Co-PI, UW Institute of Translational Health Science

2 Faculty Disclosure In my former capacity as Director of the Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, I have received grants or contracts from the following companies in the past 3 years: Novartis Pharmaceuticals N30 Pharmaceuticals Aptalis Pharma, Inc. Insmed Inc. Pharmaxix Ltd. Celtaxsys KaloBios Kamada 12 th Man Technologies Vertex Pharmaceuticals Nordmark Corbus Pharmaceuticals Parion Sciences Flatley Discovery Lab LLV Savara Pharmaceuticals Mpex Pharmaceuticals, Inc Aridis Pharmaceuticals LLC National Institutes of Health CURx Pharmaceuticals Inc PulmoFlow Gilead Sciences Inc Pulmatrix Pharmagenesis (Cornerstone 281) Breathe Easy Ltd ProQR Therapeutics BV Eli Lilly Achaogen Genentech Respira Therapeutics Inc Bristo-Myers Squibb INC Research Cornerstone Therapeutics GlycoMimetics Inc Catabasis Grifols Therapeutics Cystic Fibrosis Foundation *Companies mentioned in this presentation

3 Advantages of Collaborative Multicenter Studies (Kraemer et al, Arch Gen Psychiatry 1990;47:1163) Large participant pool permitting more generalizable cohorts Critical need among orphan disease populations Enhancement of training and expertise at the sites Broad expertise of multiple investigators contributing to the scientific questions and process Standardized processes to enhance data quality and reduce variability

4 What is the Cystic Fibrosis Therapeutics Development Network (CF-TDN)? A non-profit clinical trials network, established in 1998 to facilitate development and conduct of all phases of clinical trials and identify appropriate outcomes for future studies TDN is a program supported and managed by Cystic Fibrosis Foundation Therapeutics Inc (CFFT) TDN Coordinating Center is located at Seattle Children s Research Institute Funding history Infrastructure: Grant support from Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) and NIH ( ) Study specific: CFFT, industry, NIH

5 Why did the CFF choose to start the CF TDN in 1998? (1) CF community had a long history of negative, underpowered single site clinical studies Pattishall, Pediatrics 1990;85: Cheng, Peds Pulmonology, 2000;29:1-7 CF Foundation had been involved in two successful development programs (Pulmozyme, 1993 and TOBI, 1998) but wanted to take a more active role in catalyzing and derisking therapeutic development for industry Scientific breakthroughs emerging in 1990s provided a window of opportunity for novel drug development

Understanding the Molecular Pathophysiology of

the cystic fibrosis transmembrane conductance

gene encodes a protein (CFTR channel) that

and other ions to pass through the membrane of

6 Understanding the Molecular Pathophysiology of CF in the 1990s CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; discovered in 1989 CFTR gene encodes a protein (CFTR channel) that functions as a regulated channel for chloride and other ions to pass through the membrane of epithelia in multiple organs CFTR gene CFTR Protein Channel

Emerging Allele-Specific Therapies Three approaches will include > 90% of genotypes F508del CFTR Processing Corrector (F508del, possibly others)

7 Emerging Allele-Specific Therapies Three approaches will include > 90% of genotypes F508del CFTR Processing Corrector (F508del, possibly others) CFTR Potentiators (G551D, R117H, R1070W ) Translational Readthrough (G542X, W1282X, R1162X, ) Adapted from New Engl J Med 352(19): , 2005

CFF Therapeutics Development Program Initiated in 1998 DISCOVERY Basic Research CFTR Corrector

Genzyme Pfizer Proteostasis Vertex Therapeutics Development Awards IND Preclinical Safety Testing

A L Bring Existing Drugs for CF Indication The CF Foundation has really paved the way for other

8 CFF Therapeutics Development Program Initiated in 1998 DISCOVERY Basic Research CFTR Corrector Consortium CFTR Structural Consortium Mucociliary Clearance Consortium High-throughput Screening Genzyme Pfizer Proteostasis Vertex Therapeutics Development Awards IND Preclinical Safety Testing Development TDN NDA Clinical Dosage and Efficacy FDA P Distribution Available to CF Patients P R O V A L Bring Existing Drugs for CF Indication The CF Foundation has really paved the way for other small disease nonprofits to take drug discovery into their own hands. -Harvard Business School Professor Robert Higgins

9 What was unique about the CF TDN network? Integral part of an audacious translational program to develop novel therapies to change the lives of patients with CF Partnership of a Foundation and NIH (NCATS) Partnership of a Foundation and Industry Spanned pediatric and adult patients Created a significant infrastructure to ensure longterm sustainability Well-supported sites Large coordinating center Robust data systems Specialized national resource centers

10 Therapeutics Development Centers # TDC Sites: 89# # of NRC Sites: 7

11 CFTDN Goals Conduct efficient, successful studies Protect the safety and rights of study participants and provide equitable access to CF clinical studies Perform innovative ancillary studies Develop novel biomarkers and outcome measures Promote the continued advancement of junior faculty Make efficient use of limited resources by utilizing archived data and specimens

12 CFTDN Governance Structure * NRC Working Group * National Resource Centers

13 Therapeutics Development Centers

14 2017 CF Therapeutics Development Network # TDC: 89 Sites #NRC: 7 Sites

15 Therapeutics Development Centers Selected from CFF-accredited Adult and Pediatric Care Centers Chosen through a competitive process by CFFT CFFT infrastructure grants support: Small portion of Adult and Pediatric PI salary Adult and pediatric research staff Site equipment Robust staff training and mentoring program Sites reviewed annually through performance tracking process; performance considered in competitive renewal every 2 years

16 CFTDN Coordinating Center

TDNCC Overview of Responsibilities Maintains central tracking database

capture (RAVE ) and management of all CFF studies Supports statistical

Liaison Clinical Coordinating Center Study design and implementation Site

17 TDNCC Overview of Responsibilities Maintains central tracking database Supports governance structure Network Oversight Supports electronic data capture (RAVE ) and management of all CFF studies Supports statistical design, analyses and manuscript preparation Data Coordinating Center Industry Liaison Clinical Coordinating Center Study design and implementation Site training and monitoring Study closeout Consultation Assistance with site communication and selection

18 CFTDN Impact Met Mission Statement: Facilitated clinical studies of new and existing therapies to cure and control CF

19 # of Studies TDN Study Activities by Cycle

20 Highlights of CFTDN Studies ( ) Since inception, network has primarily supported industry-based therapeutic development (70-75% of all studies) Initial studies were early Phase (1 and 2) Transition to larger Phase 3 trials First CFFT Phase Industry moved to predominantly Phase 3 by 2009 PI initiated studies have focused on outcome measure development (~ 25% of studies)

21 Roles of Partners in CF Drug Development CFF* Industry* Academic(TDN)* De-risked program with initial funding through Therapeutics Development Awards Pre-clinical development Drug Screening Formulation Animal Toxicology Manufacturing Defined patient population (phenotype:genotype studies) Formed development committee Regulatory FDA documents Developed biomarkers and clinical endpoints Found experts and developed teams Funding and conduct of clinical trials Assisted in clinical development plan and individual study design Supported the Therapeutic Development Network Conducted studies at sites *Joint Development Committee oversaw program

22 CF Therapeutic Program Goals Orally bioavailable drugs Two key CFTR targets: Class III mutations Potentiators: Increase opening (gating) of CFTR channels G551D * VX-770 Class II mutations Correctors: Increase number and function of CFTR channels at the cell surface (also requires a potentiator) F508del ** VX-809 * = IVACAFTOR (KALYDECO ** = LUMACAFTOR

23 Absolute Change from Baseline in FEV 1 : % Predicted Ramsey et al. New Engl J Med Nov 3;365(18):

24 FDA Approval of Kalydeco January 2012 and Orkambi July 2015 Kalydeco Orkambi

25 Key Therapeutic Trials Developed Through the TDN Therapy Publication AAV gene therapy Moss R, Human Gene Rx 2007;18:726 *Pancreatic enzymes Borowitz D, J Pediatrics 2006;149:658 Topical Gentamicin for premature stop mutations Clancy JP, AJR Cell Mol Biol 2007;37:57 *Inhaled aztreonam McCoy K, AJRCCM 2008;178:921 Retsch-Bogart G, Chest 2009;135:1223 *Azithromycin Saiman L, JAMA 2003;290: 1749 Saiman L, JAMA 2010;303:1707 *Early eradication of Pa (TOBI) Gibson R, AJRCCM 2003;167:841 Treggiari M, Archives Ped Adol Med 2011;165:847 *Ivacaftor Accurso F, NEJM 2010;363:1991 Ramsey B, NEJM 2011; 365:1663 *Lumacaftor/ivacaftor Boyle M, Lancet Respir Med 2014 Jul;2(7): Wainwright C, NEJM 2015 *Hypertonic saline in infants Rosenfeld M, JAMA 2012;307:2269 *Inhaled Mannitol Aitken M, AJRCCM 2012;185:645 Inhaled Levofloxacin Geller D, AJRCCM 2011;183:1510 *Available to patients

26 Scientific Impact Clinical Endpoints and Biomarkers Measure Publication PFT reference values Kulich M, AJRCCM 2005;172:885 Induced sputum Aitken M, Chest 2003;123:792 Ordonez CL, AJRCCM 2003;168:1471 Inflammatory markers Mayer-Hamblett N, AJRCCM 2007;175:822 Sagel S, J Pediatrics 2009;154:183 Quality of Life measure Quittner A, Chest 2009;135:1610 Infant Outcomes: PFTs and Growth Davis S, AJRCCM 2010;182:1387 Heltshe S, JCF 2014; (in press) Biofilm susceptibility testing Moskowitz S, Peds Pulm 2011;48:184 Pa phenotypes and CF infection stages and clinical outcomes Mayer-Hamblett N, AJRCCM 2014;190(3): CFTR Rowe S, AJRCCM 2013;190(2): Heltshe S, Chest 2013; 144(4):1418

27 Lessons Learned for Successful Drug Development in an Orphan Disease Establish partnerships across industry, foundations, academics, federal agencies and patient/families Develop laboratory and clinical infrastructure in parallel and far in advance of first patient enrolled. Focus on deliverables and a common goal Biology and mechanisms of action are secondary gains Use the new drugs to further the science, e.g. GOAL study (S. Rowe, AJRCCM 2014)

28 Ongoing Challenges of a CTN in an Academic Setting Ensuring recognition and success of junior faculty Solutions: Encourage ancillary studies utilizing data and specimen repositories Academic promotion letters written by CTN leader Overcoming bureaucratic barriers (e.g. contract negotiations) Solution: Work closely with CTSAs and institutional officers

29 Ongoing Challenges of a CTN in an Academic Setting Managing burn-out and turn-on of faculty and staff Solutions: Robust training programs Anticipating workload Sustained infrastructure funding Solutions: Find partners in non-profit sector Have a clear vision

30 Thank you! Contact Information:

On behalf of the Cystic Fibrosis Foundation (CFF) and the 30,000 people with cystic

Robert J. Beall, Ph.D. President and Chief Executive Officer Cystic Fibrosis Foundation On behalf of the Cystic Fibrosis Foundation (CFF) and the 30,000 people with cystic fibrosis (CF) in the United States,