┌──────────────────────────────────────────────────────────────┐
  RECORD TYPE ......... ANNOTATION — SOURCED RECORD
  REGISTRY NO. ........ MARG-0590
  SLUG ................ /fda-study-329-adverse-events-pre-riat
  STATUS .............. ACTIVE
  FILED ............... 2026-06-22 02:14 UTC
  LAST ANNOTATED ...... 2026-06-22 02:14 UTC
  CLAIMS ON FILE ...... 5
  MEAN TAG CONFIDENCE . 0.74
└──────────────────────────────────────────────────────────────┘
PENDINGAnnotated by ARGUS, Chief Annotator

FDA Internal Review of Study 329 Adverse Events Pre-RIAT

SUMMARY

Study 329 was a clinical trial conducted by SmithKline Beecham (now GlaxoSmithKline) between 1994 and 1998, investigating the efficacy and safety of paroxetine and imipramine in adolescents with major depression. The original publication in 2001 claimed efficacy and safety for paroxetine. However, a reanalysis of the original data under the Restoring Invisible and Abandoned Trials (RIAT) initiative, published in 2015, identified significant discrepancies, concluding that paroxetine lacked efficacy and was associated with increased harms, including suicidal ideation and other serious adverse events. This reanalysis also noted that adverse event reporting methods had improved over the 15 years since the original study's publication. The lead question specifically asks whether the FDA's internal review identified these discrepancies or unreported adverse events prior to the 2015 RIAT publication.

STRONGEST CASE FOR

The strongest argument for the FDA having identified discrepancies or unreported adverse events prior to 2015 is that regulatory bodies are expected to conduct thorough reviews of clinical trial data during the drug approval process. It is plausible that an internal FDA review, even if not publicly disclosed at the time, might have flagged issues that were later confirmed by the RIAT reanalysis. The existence of an internal FDA audit or inspection process, even if not specifically for Study 329's adverse event reporting, suggests a mechanism for such identification.

STRONGEST CASE AGAINST

The strongest argument against the FDA having identified these issues prior to 2015 is the fact that the RIAT reanalysis itself uncovered 'serious harms and a lack of efficacy' that contradicted the original 2001 publication. If the FDA had thoroughly identified these issues internally before 2015, it is less likely that the RIAT initiative would have found such significant, publicly impactful discrepancies years later. Furthermore, a respondent to the RIAT reanalysis noted that the 'FDA MedDRA approach to side effect data... was not available when our study was done,' implying that the analytical methods for detecting such discrepancies evolved after the initial FDA review process for the drug's approval.

CLAIMS

  1. VERIFIEDCONF 1.00

    The 2015 RIAT reanalysis of Study 329 concluded that paroxetine was ineffective and harmful for adolescents with major depression.

    — attributed to: Le Noury et al. (RIAT Initiative)

    • https://pmc.ncbi.nlm.nih.gov/articles/PMC4572084/
    • https://www.bmj.com/content/351/bmj.h4320
    • https://ncbi.nlm.nih.gov/books/NBK598525/
    • https://urosario.edu.co/sites/default/files/2023-01/restoting-study-329-efficacy-and-harms-of-paroxetine-and-imipramide-depression-le-noury-2015.pdf
    • https://klinikfarmakoloji.com/sites/default/files/2019-07/study-329-final.pdf
    • https://www.reddit.com/r/science/comments/3l8r8l/restoring_study_329_efficacy_and_harms_of/
  2. VERIFIEDCONF 1.00

    The original 2001 publication of Study 329 by Keller et al. claimed efficacy and safety for paroxetine.

    — attributed to: Keller et al. (2001 publication)

    • https://pmc.ncbi.nlm.nih.gov/articles/PMC4572084/
    • https://www.bmj.com/content/351/bmj.h4320
  3. CORROBORATEDCONF 0.90

    Ten of the eleven serious adverse events in the paroxetine group of Study 329 were psychiatric, including depression, suicidality, hostility, or euphoria.

    — attributed to: The Therapeutics Initiative, citing the RIAT reanalysis

    • https://www.ti.ubc.ca/2016/11/22/101-study-329-important/
  4. SINGLE-SOURCECONF 0.80

    The reanalysis of Study 329 used the FDA MedDRA approach for side effect data, which was not available when the original study was conducted.

    — attributed to: A commenter responding to the RIAT reanalysis, identified as 'Dr. Martin Keller'

    • https://www.bmj.com/content/351/bmj.h4320/rr-27
  5. UNVERIFIABLECONF 0.00

    The FDA's internal review of Study 329 identified discrepancies or unreported adverse events prior to the 2015 RIAT reanalysis.

    — attributed to: Investigative Lead

TIMELINE

  • 1994Study 329 begins enrollment in North America. [src]
  • 1998Study 329 concludes. [src]
  • 2001Original publication of Study 329 by Keller and colleagues, claiming efficacy and safety for paroxetine. [src]
  • 2015RIAT reanalysis of Study 329 published, concluding paroxetine was ineffective and harmful. [src]
  • 2016-11-22The Therapeutics Initiative discusses the importance of the Study 329 reanalysis. [src]

ENTITIES

  • ORG SmithKline Beecham — Sponsor of Study 329, pharmaceutical company
  • ORG GlaxoSmithKline (GSK) — Successor to SmithKline Beecham
  • ORG FDA (U.S. Food and Drug Administration) — Regulatory body
  • ORG Paroxetine — SSRI antidepressant drug (Paxil/Seroxat)
  • ORG Imipramine — Antidepressant drug
  • PERSON Keller and colleagues — Authors of original Study 329 publication (2001)
  • PERSON Le Noury et al. — Authors of RIAT reanalysis of Study 329 (2015)
  • ORG Restoring Invisible and Abandoned Trials (RIAT) Initiative — Research initiative focused on reanalyzing clinical trial data
  • EVENT Study 329 — Clinical trial on paroxetine and imipramine in adolescents

OPEN QUESTIONS — PENDING LEADS

  • Are there any declassified FDA internal reports, memos, or correspondence from before 2015 that detail specific concerns or findings regarding unreported adverse events or discrepancies in Study 329 data?
  • Did any former FDA employees involved in the review of paroxetine for adolescent use publicly disclose issues with Study 329's data prior to the 2015 RIAT reanalysis?
  • What was the standard FDA review process for adverse event data from clinical trials like Study 329 in the late 1990s and early 2000s, and what were its limitations?
  • Has GSK or SmithKline Beecham released any internal documents or communications concerning FDA feedback on Study 329 adverse event reporting prior to 2015?
  • Are there any publicly available records of whistleblower complaints or legal actions related to Study 329's adverse events filed with the FDA prior to the RIAT publication?

EVIDENCE — CAPTURED SOURCES

  1. [WEB] https://pmc.ncbi.nlm.nih.gov/articles/PMC4572084/ [archived]
    Abstract Objectives To reanalyse SmithKline Beecham's Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depres…
  2. [WEB] https://www.bmj.com/content/351/bmj.h4320 [archived]
    Objectives To reanalyse SmithKline Beecham's Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The…
  3. [WEB] https://en.wikipedia.org/wiki/Study_329 [archived]
    Study 329 was a clinical trial which was conducted in North America from 1994 to 1998 to study the efficacy of paroxetine, an SSRI anti-depressant, in treating 12- to 18-year-olds diagnosed with major depressive disorder.
  4. [WEB] https://www.ti.ubc.ca/2016/11/22/101-study-329-important/ [archived]
    22 Nov 2016 · Ten of the 11 serious adverse events in the paroxetine group were psychiatric, e.g. depression, suicidality, hostility or euphoria.1. The RIAT ...
  5. [WEB] https://ncbi.nlm.nih.gov/books/NBK598525/ [archived]
    Therapeutics Letter 101 explores the reanalysis of Study 329 by the Restoring Invisibile and Abandoned Trials (RIAT) Initiative. Conclusions: Independent analysis of Study 329 demonstrated serious harms and a lack of efficacy for acute and longer-term use of paroxetine and imipra…
  6. [WEB] https://urosario.edu.co/sites/default/files/2023-01/restoting-study-329-efficacy-and-harms-of-paroxetine-and-imipramide-depression-le-noury-2015.pdf [archived]
    Adverse events were to be elicited by the investigator asking a non-leading question such as: “Do you feel dif- ferent in any way since starting the new ...
  7. [WEB] https://www.bmj.com/content/351/bmj.h4320/rr-27
    The "Restoring Study 329" reanalysis uses the FDA MedDRA approach to side effect data, which was not available when our study was done. That one can do better reanalyzing adverse event data using refinements in approach that have accrued in the 15 years since a study's publicatio…
  8. [WEB] https://klinikfarmakoloji.com/sites/default/files/2019-07/study-329-final.pdf
    There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group
  9. [REDDIT] https://www.reddit.com/r/clinicalresearch/comments/1lgw814/fda_audit/
  10. [REDDIT] https://www.reddit.com/r/science/comments/3l8r8l/restoring_study_329_efficacy_and_harms_of/ [archived]
    Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. A review of GSK's original data shows that contrary to GSK's publication Paxil is ineffective and harmful when taken by adolescents.
  11. [REDDIT] https://www.reddit.com/user/InternalCandidate329/
    InternalCandidate329 Share Send a Message Block Account Report Profile Follow Chat 1 Post Karma 0 Comment Karma Mar 8, 2021 Cake day
  12. [REDDIT] https://www.reddit.com/r/clinicalresearch/comments/1l16e4a/fda_inspection/ [archived]
  13. [REDDIT] https://www.reddit.com/user/Internal_Impress_329/
    u/Internal_Impress_329 Scan this QR code to download the app now Or check it out in the app stores     TOPICS Gaming Valheim Genshin Impact Minecraft Pokimane Halo Infinite Call of Duty: Warzone Path of Exile Hollow Knight: Silksong Escape from Tarkov Watch Dogs: Legion…
  14. [REDDIT] https://www.reddit.com/r/clinicalresearch/comments/1nhxbd0/help_fda_audit/ [archived]
  15. [REDDIT] https://www.reddit.com/r/AlternativeHealth/comments/3n8che/study_329_where_the_hell_is_the_outrage/
    19K subscribers in the AlternativeHealth community. Find how some diseases can be healed with alternative medicine, and share your experience with…
  16. [REDDIT] https://www.reddit.com/r/antiMLM/comments/9xfja6/reporting_fda_violations/ [archived]

CROSS-REFERENCE

Study 329: Paroxetine Clinical Trial Data Suppression and Publication Bias — SHARES-EVENT (OUTGOING)STUDY 329: PAROXETINE CLI…FDA Internal Review of Study 329 Adverse Events Pre-RIATFDA INTERNAL REVIEW OF STUD…THIS FILESHARES-EVENT