How to access and process FDA drug approval packages for use in research

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FDA reviews on new drugs can be used to learn the results of unpublished studies. Unfortunately, the FDA website (Drugs@FDA) is not user-friendly, nor are these review documents. These slides explain how to navigate Drugs@FDA, and they provide tips on how to make documents easier to use. These slides are based on, and expand upon, an article in the BMJ, available at http://www.bmj.com/content/347/bmj.f5992 .

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  • 1. How to access and process FDA drugapproval packages for use in researchBased on: Turner, E. H. (2013). BMJ (Clinical Research Ed),347(oct14), f5992f5992. doi:10.1136/bmj.f5992Video: http://www.bmj.com/content/347/bmj.f5992#F1Erick Turner, M.D.Former FDA Medical Officer / reviewerStaff Psychiatrist, Portland VA Medical CenterAssociate Professor, Oregon Health & Science University

2. Background on FDA workingsBefore the study1. Sponsor decides to pursue marketing approval for anew drug-indication combination goals: Get drug onto US market (1st indication) Advertise new indication (print ads, TV)2. Sponsor submits IND registers trial with FDA Registering trials with FDA has been required for decades IND is for a specific indication3. FDA reviews protocol learns of trials......existence sponsor cant later pretend it never happened...methodological details avoids post hoc torturing of the data until it eventually confesses 3. After the study (NDA stage) FDA receives clinical study reports (CSRs) All studies Summary statistics Raw data FDA conducts review Return to IND orig. protocol planned methods Raw data + prespecified methods re-analyze ? same results as sponsor? Results of review written up FDA decision on drug-indication combination Not approved trade secret results not made public Approved review documents Drug Approval Package Drug Approval Packages posted on website Drugs@FDATurner, E. H. (2004). A taxpayer-funded clinical trials registry and results database.PLoS Medicine, 1(3), e60. doi:10.1371/journal.pmed.0010060 4. Limitations of Drugs@FDA-1 Dates: 1997 to present Electronic Freedom of Information Act (eFOIA) of 1996 Approval 1996 can be FOIAd Pre-marketing, not postmarketing No off-label uses Sponsor might have sought approval but failed First approved indication reliably available, less sofor 2nd, 3rd, etc. 5. Limitations-2 Completeness (no patient-level data) Reviews / summaries of CSRs, not CSRs themselves Just summary statistics (like journal articles) May omit SDs, SEs (but can calculate ES from P values) User-unfriendly Formatting issues Redaction of confidential info / trade secrets Searchability Newer drugs = searchable PDFs Older drugs = image files = not searchable (but you can apply OCR) Website cumbersome to navigate... 6. www.fda.gov 7. Before you dive in,avoid wasting time on blind alleys Are you sure the indication is FDA-approved and not off-label?Counter-examples: Fluvoxamine (an SSRI, but not approved for depression) Gabapentin Used for many types of pain Approved only for postherpetic neuraligia (and szr d/o) Was this the first FDA-approved indication? Yes job is easy oldest item in approval history No find approval date, then look in approval history Tip: often more efficient to use brand, not generic, name Generics reviewed only for bioequivalence to innovator No data on efficacy or safety 8. Example using generic name... 9. Generic name extraneous hitsGeneric of Pristiq bioequivalence only, no efficacy or safetyBrand generic, same as Pristiq, approved 2013. Bioequivalence only, no efficacy.Metabolite of venlafaxine, but considered an NME. Approved in 2008 avail. onlineGeneric version. Not a new molecule or new formulation. Reviewed only for bioequivalence to brand.No (re)review of or data on efficacy or safety 10. If you use the brand name instead... 11. Brand name just 2 hitsNew molecular entity (NME) approved in 1994, before eFOIA (so NOT available online)New formulation of existing molecular entity (EME). Approved in 1997 available... 12. Approval history pageScroll downtoearliestactiondate. 13. Earliest action date = original approval 14. Medical review: efficacy + safetyStatistical review: efficacy only 15. Inside thereviewTheRegistryTable ofStudies,page 1 publishedUse FDA results to verify results in published literature 16. Table ofStudies,page 2Not published 17. Study 367(unpublished)Results onprimaryoutcomeNSx2 doses 18. What if the indication is not the 1st one approved?(Warning: Less likely to find this online)1- Be sure the indication was indeed approvedby the FDA (not off-label use) Product label2- Find out when it was approved Google3- Find that date in approval history and see iftheres a Review link 19. Example Drug = aripiprazole (Abilify) Indication Original FDA-approved indication = schizophrenia Indication of interest = autistic disorder Question: Is aripiprazole approved for autistic d/o? Problem: Can any drug truly treat a developmentaldisorder? Indication needs to be more specific 20. Free online product label DailyMedhttp://dailymed.nlm.nih.gov Collaboration between FDA and NLM 21. Indications & Usage section 22. Label List of FDA-approved indications 23. Locate date in the approval history see if there is an assocd review 24. The review document 25. Review not online? Consider FOIA requesthttp://www.accessdata.fda.gov/scripts/foi/FOIRequest/requestinfo.cfm 26. FOIA request, contd Avoid complex queue. Make your request......small (1 drug, 1 indication)...specific (see FDAs approval letter to sponsor) drug name, approval date, NDA #, supplement # Can take 1 month to May be a bridge too far given time constraints If you get the data, consider sharing publicly forfuture research Supplemental data accompanying publication