FDA reviews on new drugs can be used to learn the results of unpublished studies.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 .

1. How to access and process FDA drug
approval packages for use in research
Based on: Turner, E. H. (2013). BMJ (Clinical Research Ed),
347(oct14), f5992–f5992. doi:10.1136/bmj.f5992
Video: http://www.bmj.com/content/347/bmj.f5992#F1
Erick Turner, M.D.
Former FDA Medical Officer / reviewer
Staff Psychiatrist, Portland VA Medical Center
Associate Professor, Oregon Health & Science University

2. Background on FDA workings
Before the study
1. Sponsor decides to pursue marketing approval for a
new 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 indication
3. FDA reviews protocol  learns of trial’s...
...existence
• sponsor can’t 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@FDA”
Turner, 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 “FOIA’d”
• Pre-marketing, not postmarketing
• No off-label uses
– Sponsor might have sought approval but failed
• First approved indication reliably available, less so
for 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

9. 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

10. Example using generic name...

11. Generic name  extraneous hits
Generic of Pristiq  bioequivalence only, no efficacy or safety
“Brand generic”, same as Pristiq, approved 2013. Bioequivalence only, no efficacy.
Metabolite of venlafaxine, but considered an NME. Approved in 2008  avail. online
Generic version. Not a new molecule or new formulation. Reviewed only for bioequivalence to brand.
No (re)review of or data on efficacy or safety

12. If you use the brand name instead...

13. Brand name  just 2 hits
New molecular entity (NME) approved in 1994, before eFOIA (so NOT available online)
New formulation of existing molecular entity (EME). Approved in 1997  available...

15. Approval history page
Scroll down
to
earliest
action
date.

16. Earliest action date = original approval

17. Medical review: efficacy + safety
Statistical review: efficacy only

18. Inside the
review
“The
Registry”
Table of
Studies,
page 1 published
Use FDA results to verify results in published literature

19. Table of
Studies,
page 2
Not published

20. Study 367
(unpublished)
Results on
primary
outcome
NS
x
2 doses

21. What if the indication is not the 1st one approved?
(Warning: Less likely to find this online)
1- Be sure the indication was indeed approved
by the FDA (not off-label use)
• Product label
2- Find out when it was approved
• Google
3- Find that date in approval history and see if
there’s a “Review” link

22. 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 developmental
disorder?
• Indication needs to be more specific

23. Free online product label  DailyMed
http://dailymed.nlm.nih.gov Collaboration between FDA and NLM

24. Indications & Usage section

25. Label  List of FDA-approved indications

27. Locate date in the approval history 
see if there is an assoc’d review

28. The review document

29. Review not online?  Consider FOIA request
http://www.accessdata.fda.gov/scripts/foi/FOIRequest/requestinfo.cfm

30. FOIA request, cont’d
• Avoid “complex queue”. Make your request...
...small (1 drug, 1 indication)
...specific (see FDA’s 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 for
future research
– Supplemental data accompanying publication