Did You Catch That “New” Drug Product Addition to the Orange Book?

August 25, 2016

By Kurt R. Karst –      

Orange Book aficionados may have noticed an interesting entry that recently appeared as an addition to the Orange Book. It came out earlier this month with FDA’s publication of the July 2016 Orange Book Cumulative Supplement (page 1-2C), and also with an update to the electronic Orange Book.  Here it is on both formats:


Proprietary Name: LIBRAX
Dosage Form; Route of Administration: CAPSULE; ORAL
Strength: 5MG;2.5MG
Reference Listed Drug: Yes
TE Code: N/A
Application Number: N012750
Product Number: 001
Approval Date: Approved Prior to Jan. 1, 1982
Marketing Status:  Prescription

That’s right! LIBRAX, approved under NDA 012750, is now officially listed in the Orange Book.  Of course, LIBRAX has been identified by name in the Orange Book for quite some time – since the 14th edition (1994) – but only in the second line of the Orange Book Preface: “Drugs on the market approved only on the basis of safety (covered by the ongoing Drug Efficacy Study Implementation [DESI] review [e.g.,Donnatal® Tablets and Librax® Capsules] or pre-1938 drugs [e.g., Phenobarbital Tablets]) are not included in this publication.” And it was just a few months ago that FDA identified LIBRAX as a drug product subject to a pending DESI proceeding in correspondence to Congress.  But change has been afoot, as we intimated in a post a couple of months ago with a link to Docket No. FDA-1975-N-0336.

For decades now, FDA has treated LIBRAX as a “DESI drug.”  After all, NDA 012750 was approved prior to the enactment of the 1962 Kefauver-Harris Drug Amendments . . . right? “No,” according to FDA.  In a bit of revisionist history, FDA now believes that the LIBRAX NDA 012750 was approved on September 1, 1966, instead of pre-1962.

By way of background, FDA initially failed to include LIBRAX under the DESI program. In 1975, FDA became aware that LIBRAX had not been included in the DESI review and published a Federal Register notice (40 Fed. Reg. 52,644, 52,645-46 (Nov. 11, 1975)) requesting that the NDA holder provide substantial evidence of effectiveness for LIBRAX (DESI 10837).  FDA explained that:

On September 1, 1966, the [NDA] was reinstated after [the NDA holder] submitted new data including new test procedures to detect the amount of impurities.  However, since this reinstatement approval was not based upon a complete review of the entire application and did not constitute a determination that all claimed indications are supported by substantial evidence of effectiveness, exclusion of Librax from NAS-NRC review was in appropriate [sic].  The clinical data included in the [NDA] have now been reviewed by the [FDA] and it has been concluded that the data do not provide substantial evidence of effectiveness of the fixed combination . . . .  There is therefore no substantial evidence that the addition of chlordiazepoxide to clidinium bromide contributes to the effectiveness of the latter in the adjunctive therapy of peptic ulcer disease.

In January 1981, FDA issued a Notice of Opportunity for Hearing to withdraw approval of NDA 012750 on the basis that the data submitted to FDA were inadequate and did not provide substantial evidence that LIBRAX was effective for its intended uses.  FDA revoked the temporary exemption allowing LIBRAX to be marketed while the NDA was under review at FDA.  In July 1981, FDA, in response to a request from the NDA holder for a hearing on LIBRAX, stated that LIBRAX may continue to be marketed while the hearing request is under review at FDA pending a final ruling on that request.

On July 24, 2012, FDA published a notice in the Federal Register (77 Fed. Reg. 43,337) asking companies with outstanding hearing requests for pre-1962 DESI drugs to either affirm their hearing requests or withdraw them.  LIBRAX was one of the drugs discussed in the notice.  The NDA holder responded to the Federal Register notice on August 22, 2012 affirming its hearing request. 

And then things went quiet . . . . until May 23, 2016, when FDA posted a rather cryptic memorandum in Docket No. FDA-1975-N-0336 for the LIBRAX DESI proceeding (DESI 10837). According to the 1-page memo:

As set forth in the Stipulation for Dismissal in Hoffmann-La Roche, Inc. v. Richardson, et. al, Civil Action 11-73 (D.N.J. August 2, 1973), “[a] new drug application for Librax was approved by the Food and Drug Administration on September 1, 1966.  At that time, pursuant to the 1962 New Drug Amendments, the Food and Drug Administration determined that Librax was safe and effective for the indications set forth in its labeling.”  As such, Librax is not subject to review under DESI.

A few days later, our firm, on behalf of a client, sent a letter to FDA requesting that the Agency withdraw the May 23rd document and not take any action based on it. “The May 23 document is factually and legally wrong,” our firm explained in the letter.  But in an August 18, 2016 response to our firm’s May 27, 2016 letter, FDA doubles down on the Agency’s newfound position. 

At this juncture, FDA has determined that [the] Stipulation for Dismissal [in Hoffmann-La Roche, Inc. v. Richardson, et. al] is the controlling legal document on the question of whether Librax is subject to DESI review. In accordance with this Stipulation for Dismissal, FDA has concluded that Librax is not subject to review under DESI, as the drug was fully approved on the basis of safety and effectiveness in 1966. . . .

[W]e recognize that there were conflicting agency statements concerning the regulatory status of Librax. Nonetheless, FDA has concluded that it must look to the August 1973 Stipulation for Dismissal of the Roche lawsuit on the question of whether Librax is subject to review under DESI, as the Roche lawsuit was filed in January 1973 over this precise question. In our assessment, FDA is bound by the Stipulation for Dismissal, which was signed on behalf of, among others, the Commissioner of Food and Drugs, and which explicitly states that Librax was fully approved on the basis of safety and effectiveness in September 1966.

Right around the time the August 18, 2016 response from FDA was sent, the Orange Book was updated with the “NEWA” (“New drug product approval usually in the supplement month”) addition for LIBRAX. If FDA’s dubious determination stands, then that’s one less pending DESI review for the Agency to deal with.