1 / 18

Psychiatric Conditions Attempts to Confirm Signal John McLane, Ph.D. Roche Medical Science and Safety

Psychiatric Conditions Attempts to Confirm Signal John McLane, Ph.D. Roche Medical Science and Safety. 9/5/00. Clinical Overview Pharmaco-epidemiological Assessment Clinical Analysis of Spontaneous Reports Additional Assessments Biological plausibility Risk Management.

duncan
Download Presentation

Psychiatric Conditions Attempts to Confirm Signal John McLane, Ph.D. Roche Medical Science and Safety

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Psychiatric ConditionsAttempts to Confirm SignalJohn McLane, Ph.D.Roche Medical Science and Safety 9/5/00

  2. Clinical Overview Pharmaco-epidemiological Assessment Clinical Analysis of Spontaneous Reports Additional Assessments Biological plausibility Risk Management

  3. Assessment Strategy to Confirm Signal • Post-approval analysis • Retrospective analysis • Prospective analysis 9/5/00

  4. Retrospective Epidemiological Analysis Relative Risk - Accutane versus Antibiotic Objective • Relative risk for psychiatric disorders Methods • Population-based epidemiological study • Retrospective matched-control cohort • Analysis of prevalence rates for a variety of psychiatric disorders and suicide/suicide attempts 9/5/00

  5. Retrospective AnalysisEpidemiological Data Source • Two Validated Healthcare Databases • Canadian Saskatchewan Health Database (SASK) • Accutane users (n = 7,195) • antibiotic drug therapy (n = 13,700) • UK General Practice Research Database (GPRD) • Accutane users (n = 340) • antibiotic drug therapy (n = 676) 7/11/00

  6. Relative Risk for Disorders SASK Database • Current Accutane use: RR= 1.0 (95% CI 0.9-1.3) • Recent Accutane use: RR= 0.9 (95% CI 0.6-1.4) • Current antibiotics use: RR= 1.3 (95% CI 1.0-1.5) • Recent antibiotics use: RR= 0.9 (95% CI 0.7-1.1) • Prior psychiatric history emerged as the only predictor for the above outcome 9/5/00

  7. Accutane and Antidepressant Prescriptions:Symmetry Analysis of Prescription Sequence • Accutane did not show effect on prescriptions for antidepressants in symmetry analysis • Prescription Sequence ratio = A/B, where A = # pts. prescribed Accutane before antidepressants B = # pts. prescribed Accutane after antidepressants. • Ratio near unity indicates no effect *Hallas J. Epidemiology 1996; 7:478-484

  8. Accutane and Antidepressant Prescribing*Prescription Sequence Symmetry Analysis Antidepressant Drugs Accutane PrescribedBefore/After (A/B) Adjusted Rate Ratio*(95% CI) All Amine SSRI “Other” 1,382 / 1,439 174 / 200 874 / 861 334 / 378 0.97 (0.92-1.02) 0.90 (0.78-1.04) 0.99 (0.93-1.02) 0.95 (0.85-1.05) Adjusted rate ratio was less than one within each class and for all antidepressants *Synergy Pharmacy Claims Database, June 1999 - March 2000 adjusted for changes in prescribing trends during analysis period

  9. Minocycline and Antidepressant Prescribing* Prescription Sequence Symmetry Analysis Antidepressant Drugs Minocycline Prescribed Before/After (A/B) Adjusted Rate Ratio(95% CI) All Amine SSRI “Other” 3,609 / 3,751 494 / 569 2,277 / 2,170 838 / 1,012 0.98 (0.95-1.02) 1.01 (0.93-1.10) 1.00 (0.96-1.04) 0.94 (0.88-1.00) *Synergy Pharmacy Claims Database, June 1999 - March 2000 adjusted for changes in trends during analysis period

  10. Prospective Analysis of Signal • Evaluate in clinical trial using 2 tools • Mood assessment questionnaire • Beck Depression Inventory (BDI-II) • Evaluate 600 patients treated with one of 2 formulations of isotretinoin • Obtain baseline values and end of treatment values • At monthly visits: Mood assessment questionnaire

  11. Distribution of Change in Grade on BDI-II Treatment Group Accutane NF Accutane Change in Grade N N -2 4 1 -1 7 10 0 283 283 +1 3 5 +2 2 1 BDI-II Grades Minimal 0-13 (– indicates decrease grade / + increase) Mild 14-19 Moderate 20-29 Severe 30-63 (table 10 ISS)

  12. Change in BDI-II ScoresBaseline to Week 20 Accutane NF Accutane N = 263 N =255 BDI Score Baseline Week 20 Baseline Week 20 Mean  SD 3.5  4.6 1.7  3.1 3.6  4.5 1.9  3.7 Range 0 - 24 0 - 21 0 - 29 0 - 28 PSY 207, (1492), 9/5/00

  13. Clinical Overview Pharmaco-epidemiological Assessment Clinical Analysis of Spontaneous Reports Additional Assessments Biological Plausibility Risk Management

  14. CNS Relationships With RetinoidsRats and Mice • Specific dopamine enriched brain regions have retinoid receptors (cortex, hippocampus, caudate/putamen, nucleus accumbens, olfactory tubercle) • Localization of proteins differs from localization by mRNA • Dopamine 2 receptor genes have retinoid response elements • Isotretinoin can be found in the brain after injections Zetterstrom et al 1999, Krezel, 1999, Le Doze et al. 2000

  15. Biological Summary • Although some of the component factors are in place, retinoids have not been shown to activate genes to induce behavioral/psychiatric changes • In mice lacking retinoid receptor genes no behavioral effects other than long term memory (Long Term Potentiation/Depression) • Lack of evidence demonstrating functionality of retinoid signaling pathways in the mature CNS

  16. Conclusion • All available evidence does not confirm signal • Biological plausibility is not established • Background disease rate in population warrants attention to signs and symptoms of psychosocial disturbance by Dermatologists

  17. Clinical Overview Pharmaco-epidemiological Assessment Clinical Analysis of Spontaneous Reports Additional Analysis Biological Feasibility Risk Management

  18. End

More Related