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  1. Generic Drug User Fee Amendments

FY2015 Regulatory Science Research Report: Nanotechnology: Postmarket: Patient Substitution Studies


Over 80% of all prescription drugs in the U.S. are filled by generic drugs. The FDA is entrusted to ensure that all medications entering the U.S. market are safe and effective; consequently, FDA needs a range of tools to monitor that all marketed generic drugs have the same safety and efficacy profile as their RLD. Postmarket research on generic drugs has focused on developing surveillance methods, understanding patient perceptions of generic drug quality and effectiveness, and verifying therapeutic equivalence via brand-to-generic switching studies in patients.


Some physicians are not fully convinced that BE established in healthy subjects can correlate to BE in the patient population. Since 2010, based upon public comments and research opportunities identified within FDA, OGD has funded a series of brand-to-generic drug switching studies in corresponding patient populations; this includes studies on anti-epileptic drugs, immunosuppressant drugs, anti-depressant drugs, attention deficit hyperactivity disorder drugs, and cardiovascular drugs.

To date, all completed patient investigations (lamotrigine and tacrolimus) have confirmed the BE conclusions of studies submitted in ANDAs using healthy subjects. These studies provide additional data in therapeutic areas where concern has been expressed about the substitutability of generic drugs. The resulting positive outcomes will help to assure the public about the safety and efficacy of generic drugs approved based upon the current generic drug requirements.

Figure 27. Timeline and progress of comparative pharmacokinetic studies of brand and generic products in patients
Figure 3. Timeline and progress of comparative pharmacokinetic studies of brand and generic products in patientsFigure 28. Plasma concentration profile of generic and brand lamotrigine products

Figure 4. Plasma concentration profile of generic and brand lamotrigine products

ORS staff facilitating research in this area

  • Wenlei Jiang, Sarah Dutcher, Nan Zheng, Hyewon Kim, Andrew Babiskin, Lanyan Fang, Oluwamurewa Oguntimein, Larissa Lapteva, Kimberly Witzmann and other ORS staff members

Projects and Collaborators

  • Pharmacokinetic studies of anti-epileptic drugs (I)
    • Site PI: Jim Polli and Tricia Ting
    • Contract #: HHSF223201010244A
  • Pharmacokinetic studies of anti-epileptic drugs (II)
    • Site PI: Michael Privetera and Michel Berg
    • Contract #: HHSF223201110112A
  • Characterization of epilepsy patients at-risk for adverse outcomes related to switching antiepileptic drug products
    • Site PI: Tricia Ting
    • Contract #: HHSF223201400188C
  • Pharmacokinetic studies of tacrolimus in transplant patients
    • Site PI: Rita Alloway
    • Grant #: 1U01FD004573-01
  • Evaluation of clinical and safety outcomes associated with conversion from brand-name to generic tacrolimus products in high risk transplant recipients
    • Site PI: Rita Alloway
    • Contract #: HHSF223201310224C
  • Retrospective analysis on the impact of generic immunosuppressants on acute rejection and long term graft survivals
    • Site PI: Alan Leichtmann, Arbor Research Collaborative for Health
    • Grant #: 1 U01FD005274-1
  • Prospective study comparing brand and generic immunosuppression on transplant outcomes, adherence, and immune response
    • Site PI: Suphamai Bunnapradist
    • Grant #: 1U01FD005271-01
  • Open-labeled pharmacokinetic and pharmacodynamic (PK-PD) studies of Metoprolol ER
    • Site PI: Larisa Cavallari
    • Grant #: 1U01FD005235-01
  • Bioequivalence and clinical effects of generic and brand Bupropion
    • Site PI: Evan Kharasch
    • Grant #: 1U01FD004899-01
  • A pharmacokinetic/pharmacodynamic study of methylphenidate formulations in pediatric attention-deficit/hyperactivity disorder (ADHD) patients in a laboratory classroom
    • Site PI: Thomas Spencer
    • Grant #: 1U01FD005240-01

Publications and Presentations

  • Wong J, Jones J, Jiang W, Polli J, Kane M. Quantification of lamotrigine in patient plasma utilizing a fast liquid chromatography-tandem mass spectrometry method with backflush technology. Ther Drug Monit (2014)
  • Shokati T, Bodenberger N, Vinks A, Jiang W, Alloway R, Christians U. Therapeutic drug monitoring of the immunosuppressant tacrolimus on dried blood spots using LC-MS/MS. J Vis Exp (accepted)
  • Peipert, J. Assessing the Association of Four Measurements of Adherence to Tacrolimus for Organ Transplant Recipients, presentation at  The 2015 Pittsburgh Conference on the Science of Medication Adherence (June 2-3, 2015)
  • Ting, T. Y., Jiang, W., Lionberger, R., Wong, J., Jones, J. W., Kane, M. A., Krumholz, A., Temple, R. and Polli, J. E. (2015), Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard. Epilepsia, 56: 1415–1424. doi: 10.1111/epi.13095
  • Privitera MD, Welty TE, Gidal BE, Diaz FJ, Krebill R, Szaflarski JP, Dworetzky BA, Pollard JR, Elder EJ Jr, Jiang W, Jiang X, Berg M. Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial.Lancet Neurol. 2016 Apr;15(4):365-72


  • Research projects in progress



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