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 CenterAssociate Professor, Oregon Health & Science University

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”

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

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.

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...

www.fda.gov

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

Example using generic name...

Generic name extraneous hits

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

Metabolite of venlafaxine, but considered an NME. Approved in 2008 avail. online

“Brand generic”, same as Pristiq, approved 2013. Bioequivalence only, no efficacy.

Generic of Pristiq bioequivalence only, no efficacy or safety

If you use the brand name instead...

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...

Approval history page

Scroll down to

earliest action date.

Earliest action date = original approval

Medical review: efficacy + safety

Statistical review: efficacy only

Inside the review

“The Registry”

Table of Studies, page 1

published

Use FDA results to verify results in published literature

Table of Studies, page 2

Not published

Study 367(unpublished)

Results on primary

outcome

NS x

2 doses

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

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

Free online product label DailyMed

http://dailymed.nlm.nih.gov Collaboration between FDA and NLM

Indications & Usage section

Label List of FDA-approved indications

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

The review document

Review not online? Consider FOIA request

http://www.accessdata.fda.gov/scripts/foi/FOIRequest/requestinfo.cfm

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