A Mini-Sentinel Assessment of FDA Regulatory Policies for Long Acting Beta 2 Agonists Melissa Butler, PharmD, MPH, PhD Center for Health Research – Southeast Kaiser Permanente Georgia KP Center for Effectiveness and Safety Research On behalf of the Mini-Sentinel LABA Workgroup January 31, 2013 1
Mini-Sentinel LABA Workgroup Name Affiliation Role Esther Zhou CDER/FDA Co-Lead Melissa Butler Kaiser Permanente Co-Lead Fang Zhang Harvard Pilgrim Health Care Institute Member Meghan Baker Harvard Pilgrim Health Care Institute Member Ann Wu Harvard Pilgrim Health Care Institute Member Mark Levenson CDER/FDA Member Solomon Iyasu CDER/FDA Member Yu-te Wu CDER/FDA Member Darren Toh Harvard Pilgrim Health Care Institute Member Pinsheng Wu Vanderbilt Member Marsha Reichman CDER/FDA Member Monika Houston CDER/FDA Member Sally Seymour CDER/FDA Member 2
Mini-Sentinel Partner Organizations Institute for Health, Health Care Policy & Aging Research 3
Mini-Sentinel Key Feature Assessment of the impact of FDA actions on utilization of medical products 4
Long Acting Beta 2 Agonists Mechanism of Action and Use • LABA are bronchodilators that relax the smooth muscle of the airways of the lungs • The onset of action tends to take longer and the duration of action is longer than short-acting beta 2 agonists • LABA are approved for treating both asthma and COPD • LABA may be steroid-spearing Safety concerns in asthma began in the 1990s 5
LABA Regulation and Safety 2006 2008 • Salmeterol / fluticasone HFA FDA review Timeline approval stressed need • Formoterol / budesonide for more approval pediatric data • SMART Study results 1994 2000 2002 2004 published Salmeterol Salmeterol / Formoterol Additional • Public Health Advisory on aerosol fluticasone phase IV salmeterol new labeling approval diskus trial label changes approval initiated 2010 1996 2003 2005 2007 • Label • Salmeterol diskus • SMART Study FDA reviews • Label approval ended early changes risk and changes • Reports of serious • Salmeterol decides • Safety • Information exacerbations and labeling changes removal of information to healthcare deaths reported with to incorporate salmeterol released to use of salmeterol preliminary professionals not • SMART Study initiated results of SMART consumers warranted released and • Med Guides 1993 healthcare requested for Salmeterol 2001 professionals LABA Nationwide Formoterol • Formoterol / containing Surveillance fumerate mometasone Study (UK) approval agents approval published 6
Overarching Goals of the Project To assess the impact of the FDA 2010 regulatory action on LABA drug utilization patterns • Population based prevalent use of asthma medications • Population based initiation of LABA products • Characteristics of LABA initiation and course of therapy – Uptake of use of combination LABA products – Appropriateness of LABA initiation – Length of therapy – Concomitant controller medication use • Characteristics of LABA discontinuation – Use of controller medications after discontinuation 7
Timeline Draft final report Final proposal report 1 st workplan sent Analysis complete Kick-off meeting Nov 11 July 12 Feb 13 Apr 13 Mar 12 8
Quasi-Experimental Designs for Policy Analysis Pooled analyses Vs. Difference-in-difference Interrupted time series Extended Cox regression 9
Interrupted Time Series (ITS) One of the most rigorous quasi-experimental designs Multiple policies can be modeled over time ITS shows the immediate effect of a policy as well as trends over time The rolling cohort design allows individuals to enter and exit the study base 10
Mini-Sentinel Distributed Analysis Mini-Sentinel Operations Center 1 Workgroup creates and submits work plan (a 6 1 computer program) Mini-Sentinel Secure Network Portal 2 Data partners retrieve Data Partner 1 the work plan Review & Review & Return Run work Results plan 3 Data partners review 5 3 2 and run work plan against 4 Enrollment Demographics their local data Utilization Pharmacy Etc 4 Data partners review results Data Partner N 5 Data partners return Review & Review & Return results via secure Run work Results plan network 3 4 Enrollment Demographics 6 Results are aggregated Utilization and returned Pharmacy Etc 11
Making Distributed Analyses Efficient Use of multiple definitions • Number of outpatient visits for asthma • Position of diagnosis codes for hospitalizations • Discontinuation Identifying subgroups a priori Programming model alternatives for model diagnostics • Poisson and negative binomial Pooling individual site data • Additive process for ITS • Meta-analysis methods for other regression methods 12
Cohort Creation – Pooled Results Total population in Mini-sentinel ~90,000,000 LABA – Long-acting beta 2 agonists ICS – Inhaled corticosteroids LM – Leukotriene modifiers Applying eligibility criteria OCM – Other controller medications (age, medical history, etc) OCS – Oral corticosteroids SABA – Short-acting beta 2 agonists Pooled number of patients with asthma 1,545,077 LABA LM Other Bronchodilators OCS Pre: 35,095 Pre: 275,287 Pre: 69,543 Pre: 340,600 Post: 6,387 Post: 113,137 Post: 22,837 Post: 139,974 SABA No Medication ICS-LABA ICS OCM Pre: 678,770 Pre: 339,517 Pre: 232,439 Pre: 589,176 Pre: 20,432 Post: 307,936 Post: 206,675 Post: 98,559 Post: 274,160 Post: 3,589 13
Summary of Overarching Goals to Date Changes in asthma medication use were not unique to LABA during the pre and post policy periods • Confirms the difficulty of selecting a control group Changes in LABA use started prior to the 2010 regulations 14
Re-Use of the LABA Framework To assess the impact new technology on utilization of medical products To assess changes in delivery systems on utilization of medical products To assess differences in state regulations on utilization of medical products • Allows for the possibility to include a comparison group in the ITS 15
Proposal Details Can be Found Here www.mini-sentinel.org/work_products/Assessments/Mini-Sentinel_Impact-FDA-Regulatory-Policies-LABAs-Protocol.pdf 16
Thank You 17
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