/ABTRACT Ever since the introduction of a generic version in 2006, the antidepressant bupropion XL (300mg extended release) has been plagued with reports of therapeutic inefficacy and increased adverse events. The only formal bioequivalence testing of a 300mg generic bupropion XL (Budeprion XL) with branded Wellbutrin XL (in healthy volunteers) resulted in Budeprion being found non-bioequivalent. Budeprion was thus withdrawn in 2012. This raised significant new concerns: 1) Are other 300mg bupropion XL generics bioequivalent to Wellbutrin XL, and to each other? 2) Are there clinically significant differences between 300mg XL products in antidepressant effectiveness or adverse outcomes (side effects or relapse)? These concerns are pressing, as no other 300mg XL generic has undergone bioequivalence or clinical equivalence testing. No 300mg XL product at all has undergone such testing in patients with major depression. FDA recognized this urgent un- met need, and issued RFA-FD-13-021, "Bioequivalence of generic bupropion". We propose a definitive study, responsive to these concerns and the RFA, to (1) evaluate steady-state bioequivalence between branded and all three currently marketed generic 300mg XL bupropion products in patients with major depressive disorder, (2) determine if patients perceive differences in release patterns, clinical effectiveness, and adverse events between drug products, and (3) determine patients'clinical response using validated objective measures of depression.
The Specific Aims are to (1) Determine bioequivalence between branded and generic bupropion 300mg XL products (and between generic products) at steady state in patients with major depressive disorder; (2) Compare patients'self-reported clinical differences (release patterns, antidepressant effectiveness, adverse events) between all bupropion 300mg XL products (brand vs generics, and between generics), using innovative methods for assessing patient perspectives;(3) Compare objective evaluation of patients'clinical response to each bupropion 300mg XL product, using standard, well-validated measures of depression response and side effects;and (4) Compare population-based pharmacometric/pharmaceutical outcomes between bupropion XL products, and to bupropion disposition. A unique investigative team, comprised of a clinical pharmacologist, depression clinical trialist, biostatistician, and national pharmacy benefit manager, brings the data, expertise, and experience to assure timely and unbiased success, and dissemination of results. The results will resolve patient and regulatory agency concerns about quality, bioequivalence, and therapeutic equivalence of bupropion XL generics, and thereby improve the clinical effectiveness and safety of bupropion, and the psychiatric care for the >1 million Americans taking bupropion for the treatment of major depressive disorder. This research also promises to develop a new paradigm for drug safety, using pharmacy benefit manager data on a massive scale for active surveillance monitoring, with the potential for signal detection and intervention much earlier than currently possible by conventional voluntary reporting.

Public Health Relevance

Results of this research will improve the clinical effectiveness and safety of the antidepressant drug bupropion, and enhance the psychiatric care for the more than 1 million Americans taking bupropion for major depressive disorder. Results will resolve patient and regulatory agency concerns about quality, bioequivalence, and therapeutic equivalence of bupropion XL 300mg generic products. Research also promises to develop a new paradigm for drug safety, using pharmacy benefit manager data on a massive scale for active surveillance and monitoring, with the potential for signal detection and intervention much earlier than is currently possible using conventional voluntary reporting.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01FD004899-01
Application #
8669663
Study Section
Special Emphasis Panel (ZFD1-SRC (99))
Project Start
2013-09-15
Project End
2016-08-31
Budget Start
2013-09-15
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130