By Kurt R. Karst –      

Nearly two years after Depomed, Inc. (“Depomed”) filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s denial of orphan drug exclusivity for GRALISE (gabapentin) Tablets, the court (Judge Ketanji Brown Jackson) has finally ruled in the case.  And it’s a bit of a shocker!  In an Order handed down last Friday, Judge Jackson denied FDA’s Motion to Dismiss/Motion for Summary Judgment and granted Depomed’s Motion for Summary Judgment (Reply and Opposition briefs available here and here).  In doing so, Judge Jackson ordered FDA to recognize orphan drug exclusivity for GRALISE “without requiring any proof of clinical superiority or imposing any additional conditions on Depomed.” 

Although we’d like to share with you a copy of the court’s Memorandum Opinion, we can’t.  We don’t have it because it was issued under temporary seal.  In an Order To Show Cause, Judge Jackson is giving Depomed and FDA the chance to show cause why his opinion should not be made public in its entirety given that portions of the 771-page administrative record in the case were filed under seal.  Hopefully the decision will be made public later this month.  Until then, we’ll be chomping at the bit to read it!  In the meantime, we can glean some things from the few lines in Judge Jackson’s Septemeber 5, 2014 Order.  But first, some background on the case and the issues involved. . . .

FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan-drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug” (emphasis added).  The term “orphan drug” is defined in FDA’s regulations to mean “a drug intended for use in a rare disease or condition as defined in section 526 of the act” (i.e., FDA considers a drug to be an orphan drug regardless of whether or not it has been designated as such).  A “clinically superior” drug is a drug shown to have greater efficacy, greater safety, or that provides a major contribution to patient care vis-à-vis the previously approved drug, and, by virtue of its clinical superiority, is not considered the “same drug” as the previously approved orphan drug.

In cases where orphan drug designation has been granted based on a plausible hypothesis of clinical superiority, FDA has determined that, in order to be granted a period of orphan drug exclusivity, clinical superiority must be demonstrated.  FDA explained that the standard for obtaining orphan drug designation is different from the standard for obtaining orphan drug exclusivity in the Agency’s proposed and final orphan drug regulations from 2011 and 2013, respectively (see our previous post here), as well as in an August 2012 Citizen Petition decision (see our previous post here) where FDA noted:

Though the sponsor of a subsequent orphan drug must set forth a plausible hypothesis of clinical superiority over the previously approved drug at the designation stage, such a sponsor faces a higher standard at the time of approval.  At approval, the sponsor of a drug which was designated on the basis of a plausible hypothesis of clinical superiority must demonstrate that its drug is clinically superior to the previously approved drug.  Should the sponsor fail to do so, then the subsequent drug will be considered to be the same drug as the previously approved drug, and will not be able to gain marketing approval if the previously approved drug’s orphan-drug exclusive approval period is still running.  Once this exclusivity has expired, the subsequent drug may be approved . . . , but it will not be eligible for orphan-drug exclusivity because the same drug has already been approved for the same orphan indication.

As we previously reported, FDA designated GRALISE as an orphan drug in November 2010 for the management of Postherpetic Neuralgia (“PHN”), and approved the drug product on January 28, 2011 under NDA No. 022544 for the orphan-designated indication.  The designation was based on FDA’s determination that Depomed provided a plausible hypothesis that GRALISE may be clinically superior to NEURONTIN (gabapentin) for the management of PHN.  FDA approved NEURONTIN for PHN many years ago, but the Agency never designated and approved NEURONTIN as an orphan drug.

Despite the orphan drug designation and approval of GRALISE, however, FDA did not grant orphan drug exclusivity.  FDA laid out the Agency’s rationale in a November 2012 Letter Decision sent to Depomed’s counsel after the lawsuit was filed.  According to FDA:

Section 527(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. § 360cc) generally grants orphan exclusivity to designated drugs upon approval, but does not address eligibility for exclusivity when the same drug has already been approved for the same orphan indication.  FDA interprets this statute to confer exclusivity only to drugs that are designated and not the same as an already approved drug.  By regulation, FDA requires sponsors of orphan-designated drugs to demonstrate the clinical superiority of their drug to the previously approved drug to show that their drug is not the same as the previously approved drug and is therefore eligible for exclusivity.

Gralise obtained orphan designation pursuant to section 526(a) (21 U.S.C. § 360bb) by offering a plausible hypothesis of clinical superiority over the previously approved drug, Neurontin.  But, at the time of approval, Depomed was unable to demonstrate actual clinical superiority.  Nor have any additional Depomed submissions demonstrated Gralise’s clinical superiority over Neurontin. Gralise is therefore the “same drug” as the previously approved drug, Neurontin, and is ineligible for orphan exclusivity.

Depomed’s September 2012 Complaint, seeking declaratory and injunctive relief, alleges that FDA is violating the Administrative Procedure Act by refusing to grant orphan drug exclusivity for GRALISE.  FDA “placed additional hurdles between Gralise and orphan-drug exclusivity by attempting to impose requirements that are found nowhere in the statute and that exist in regulation only for circumstances not present here,” alleges Depomed.  Elsewhere, Depomed lays out with particularity its beef with FDA:

FDA’s course of action with respect to Gralise is a paradigm of arbitrary and capricious decision-making.  From the beginning, FDA has maintained a singular focus on its preferred outcome in this case, and it violated its own regulations and the statute to get there.  The agency began by denying Gralise orphan designation because Depomed had not presented a plausible hypothesis of clinical superiority.  As the record makes clear, FDA did not have a lawful basis for requiring a hypothesis of clinical superiority over a drug that never had marketing exclusivity under the Orphan Drug Act.  No such requirement appears in 21 C.F.R. § 316.25, the regulation that provides the exclusive list of permissible reasons for denying designation requests, and indeed FDA never cited that regulation as a basis for its decisions.  Instead, the agency raised concerns about the uses of taxpayer money and cited an inapplicable regulatory provision on timing. Then, in its second letter, the agency claimed the clinical-superiority hypothesis was in fact required by virtue of still another regulation, although that rule, too, was irrelevant.  Thus, in denying Gralise orphan designation for failure to present a clinical-superiority hypothesis, FDA violated 21 C.F.R. § 316.24, the regulation stating that the agency “will grant” a request for designation if none of the exclusive bases in 21 C.F.R. § 316.25 applies.

FDA followed this unlawful course to its conclusion when it approved Gralise without granting it marketing exclusivity.  The reason FDA gave for this decision was that the data did not prove the clinical-superiority hypothesis the agency had unlawfully demanded in the first place.  This time, the agency’s action was doubly flawed: It violated both the Orphan Drug Act, which provides that marketing exclusivity automatically attaches to a drug designated and approved for its orphan indication, and it violated FDA regulations, which confirm that the agency will record and confirm marketing exclusivity upon approval.

For its part, FDA argued that the Orphan Drug Act is not intended

to reward the development of drugs that merely duplicate drugs already on the market and that offer no benefit to patients over the existing drugs.  Thus, FDA has long interpreted the Orphan Drug Act and its implementing regulations to deny orphan exclusivity to a later-approved “same” drug unless the sponsor demonstrates that its drug is clinically superior to the previously approved drug.  FDA’s interpretation and its past practice are consistent with the statute and its goal of encouraging the development of new treatments for orphan conditions or clinically significant improvements to existing drugs – not just minor modifications to existing drugs that offer no material benefit to patients.

Although we won’t know for sure until we see the Memorandum Opinion what Judge Jackson’s reasoning is for ruling against FDA, it seems that FDA’s all-encompassing definition of “orphan drug” and and the two-step process for first providing a plausible hypothesis of, and then demonstrating, clinical superiority may be in jeopardy.  However, we doubt FDA will take this decision on the chin and will probably appeal it to the D.C. Circuit.  If it stands, then we suspect that FDA’s Office of Orphan Products Development will need to do a lot of backpeddling on designation files where these issues were critical to determinations denying orphan drug designation or orphan drug exclusivity.

In conjunction with Virginia CLE, Hyman, Phelps & McNamara, P.C. Director Ricardo Carvajal and Senior Counsel Brian Donato are presenting a 2-hour CLE telephone seminar that will provide an overview of the Food Safety Modernization Act and its anticipated impact on food businesses.  The seminar is directed to attorneys who serve clients in the food industry, but whose practice does not focus on FDA regulatory matters.  The seminar is scheduled at noon on Tuesday, September 23, and again at noon on October 16.  Registration is available here.  Attorneys licensed in other states may be able to apply for CLE credit in those states (see here).

By Kurt R. Karst –      

It was just a few months ago that we posted on what might have been the first decision in a case involving a counterclaim seeking an order to correct or delete patent information from the Orange Book (and that does not concern a patent use code).  In that case, involving OFIRMEV (acetaminophen) Injection (NDA No. 022450), the U.S. District Court for the Southern District of California denied a Motion for Summary Judgment to remove a patent from the Orange Book.  That decision now appears to have been vacated as part of dismissal of the patent infringement litigation.  Ah, but no worries; there’s yet another patent delisting counterclaim decision to take its place.  But the new decision – this time out of the U.S. District Court for the District of Delaware and involving Avanir Pharmaceuticals’ (“Avanir”) NUEDEXTA (dextromethorphan hydrobromide and quinidine sulfate) Capsules (NDA No. 021879; approved on October 29, 2010) – is not a denial of an ANDA sponsor’s attempt to seek Orange Book patent delisting.  Instead, it is an Order to delist a patent.  The net effect of the Order, however, is probably zero, and has left us wondering why one of the ANDA sponsors in the case, Par Pharmaceutical, Inc. (“Par”), in particular, pursued the patent delisting with such vigor. 

By way of background, the 2003 Medicare Modernization Act (“MMA”) added provisions to the FDC Act to give ANDA (and 505(b)(2)) applicants the ability to challenge the listing of a patent in the Orange Book for a brand-name reference listed drug.  Prior to the enactment of the MMA, courts had ruled that there was no private right of action to seek Orange Book delisting of an allegedly improperly listed patent. 

The patent delisting counterclaim provisions at FDC Act § 505(j)(5)(C)(ii)(I) applicable to ANDAs state:

If an owner of the patent or the holder of the approved application under [FDC Act § 505(b)] for the drug that is claimed by the patent or a use of which is claimed by the patent brings a patent infringement action against the applicant, the applicant may assert a counterclaim seeking an order requiring the holder to correct or delete the patent information submitted by the holder under FDC Act § 505(b) or (c)] on the ground that the patent does not claim either – (aa) the drug for which the application was approved; or (bb) an approved method of using the drug.

The MMA also added the same counterclaim provisions at FDC Act § 505(c)(3)(D)(ii)(I) applicable to 505(b)(2) applications.

Outside of the statute’s patent delisting counterclaim provisions, an NDA sponsor may, on its own initiative, request that FDA remove patent information from the Orange Book.  In response, FDA may or may not remove the patent information.  In some instances, FDA continues to list the patent information, but includes a “Patent Delist Request Flag,” which is described by FDA in an Orange Book data file as follows:

Sponsor has requested patent be delisted.  This patent has remained listed because, under Section 505(j)(5)(D)(i) of the Act, a first applicant may retain eligibility for 180-day exclusivity based on a paragraph IV certification to this patent for a certain period.  Applicants under Section 505(b)(2) are not required to certify to patents where this flag is set to Y.  Format is Y or null.

NUEDEXTA is listed in the Orange Book with three patents: (1) U. S. Patent No. 7,659,282 (“the ‘282 patent”) (expiring on August 13, 2026); (2) U.S. Patent No. 8,227,484 (“the ‘484 patent”) (expiring on July 17, 2023); and (3) U.S. Patent No. RE 38,115 (“the ‘115 patent”) (expiring on January 26, 2016).  Only the ‘282 and ‘115 patents were listed in the Orange Book when the first ANDA was submitted to FDA on March 7, 2011 containing a Paragraph IV certification.  Par and Impax Laboratories, Inc. (“Impax”) both certified Paragraph IV to the ‘282 and ‘115 patents (and later to the ‘484 patent as well) and were sued for infringement (here and here).  Par is believed to be the first applicant eligible for 180-day exclusivity. 

Earlier this year, the Delaware District Court ruled in Avanir’s favor, upholding the validity of all three patents, and holding that the proposed ANDA drug products infringe the claims of the ‘282 and ‘484 patents.  At the same time, the court, in response to an earlier counterclaim filed by Par and Impax to “enter an order requiring Plaintiffs to delete the ‘115 patent information that they submitted to the FDA,” said that it had insufficient information to decide on the delisting counterclaim and ordered supplemental briefing on the issue.  Within weeks of that decision, Avanir voluntarily asked FDA to delete the ‘115 patent information from the Orange Book . . . which FDA did by adding a “Patent Delist Request Flag” in relation to the patent information.  Avanir then filed a brief with the court saying that the Par/Impax delisting counterclaims are moot and should be dismissed for lack of subject matter jurisdiction. 

So that was the end of the matter . . . right?  Wrong!

Par and Impax pressed their delisting counterclaims with the court, saying in a brief that the unilateral delisting of the ‘115 patent information was an empty gesture and that an Order from the court is necessary to prevent relisting:

Without a court order, Defendants believe Avanir will not be able to delist the '115 patent.  The FDA will likely decline Avanir’s unilateral request because there is no statutory provision regarding delisting Orange Book patents without a counterclaim. . . .  Without the order provided in the statute and requested by Defendants, Plaintiffs have no barrier against relisting the '115 patent if they can successfully delist it.  Defendants cannot accept Plaintiffs' offer to moot their delisting counterclaims with a letter to the FDA that has not  yet—and may never be—approved.  Even if the FDA accepts the delisting request, nothing bars Plaintiffs from relisting the '115 patent at some point n the future.  

Perplexed that its voluntary patent delisting request did not satisy Par, Avanir shot back in a response brief, saying:

Here, Plaintiffs are at a loss to understand why Par seeks delisting of the ’115 patent, when its continued listing would be intended to protect Par’s own interest in regulatory exclusivity against other generics.  [And, in any case,] Defendants are enjoined from launching their product until 2026 – ten years after the expiration of the ’115 patent.

In any event, what the FDA does or does not do with Plaintiffs’ request is irrelevant to Defendants’ counterclaims.  The statutory remedy is limited to requiring the patent holder—i.e., Plaintiffs—to correct or delete patent information . . . .  The statute does not mandate that the FDA delist the ’115 patent.  Since Plaintiffs have already done what is called for by the statute, Defendants’ counterclaims are moot. . . .  Defendants apparently seek an order requiring Plaintiffs to send another letter to the FDA again requesting delisting of the ’115 patent.  Such an order would be futile.  The FDA has received Plaintiffs initial request and will either delist the patent or not.  A second letter will not change anything.  Indeed, neither Defendants nor Plaintiffs have identified any case where a patent was actually removed from the Orange Book as a result of a delisting counterclaim.  [(Emphasis in oroginal)]

Perhaps not understanding what all the fuss was about given Avanir’s notification to FDA to delist the ‘115 patent information from the Orange Book, the Delaware District Court issued an Order in June 2014 directing the parties in the litigation to “make reasonable efforts to inform [FDA] of the pending request for delisting and of this Court’s request that the FDA provide its views relating to that pending request.” 

Finally, after submitting a joint status report to the Court in which each side sparred with the other and pressed for a dismissal (Avanir) or a delisting Order (Par), the Court issued a delisting Order pursuant to FDC Act § 505(j)(5)(C)(ii)(I)(aa).  In it, the Court recognizes that Par is entitled to such a delisting Order under the statute, but the Court also seems to acknowledge that Avanir can only do so much to “delete” patent information from the Orange Book:

WHEREAS the Court appreciates that Plaintiffs have tried to delete the ‘115 patent from the Orange Book and have failed to do so, yet the law entitles Defendants to an order directing Plaintiffs to try to do so (in this case, to try again to do so); [(Which Avanir did in an August 21, 2014 letter to FDA.)]

IT IS HEREBY ORDERED that Plaintiffs are directed by mandatory injunction under 21 U.S.C. § 355(j)(5)(C)(ii)(I)(aa) to correct within twenty (20) days from the date of this Order and Judgment its improper listing of the '115 patent by submitting to FDA a request enclosing this Order and Injunction to delete the '115 patent from the Orange Book entry for Nuedexta®. . . .  [(Emphasis in oroginal)]

Putting aside for a moment the issue of what it means to delist a patent from the Orange Book, the vigor with which the delisting Order was pursued has perplexed us.  (Though, we note that other strategies pursued by one of the defendants in the case have also perplexed us – see here.)  After all, the ‘115 patent expires more than a decade before the other 180-day exclusivity-bearing patent (i.e., the ‘282 patent) expires on August 13, 2026.  But perhaps an answer lies in a decision by the U.S. Court of Appeals for the Federal Circuit in which that Court ruled that Par’s appeal of the Delaware District Court’s patent infringement decision was premature for lack of a decision on the then-pending patent delisting counterclaim. 

An article set to be published in the Albany Law Review in Spring 2015, titled “Drug Diversion Administrative Revocation and Application Hearings for Medical and Pharmacy Practitioners: A Primer for Navigating Murky, Drug-Infested Waters,” explores the increasingly complex and nuanced practice of administrative law before the Drug Enforcement Administration (“DEA”), and provides a “how to” manual of sorts for counsel undertaking the litigation of a DEA administrative enforcement. 

The article is coauthored by DEA Chief Administrative Law Judge John J. Mulrooney, II, and the latest addition to the ranks of Hyman, Phelps & McNamara, P.C., Andrew J. Hull, who previously served as a judicial law clerk to Chief Judge Mulrooney.  As the authors explain in their article:

One inexorable result of federal efforts to react reasonably to an immense growth in prescription medication dependence is an increasingly complex and nuanced practice of administrative law before the [DEA].  The practice has morphed into a more contested and complicated dynamic that now requires litigation and academic skills that far exceed those previously demanded.  Without an established manual or research resource currently available for this practice, even seasoned administrative practitioners can find themselves overwhelmed by well-trained and seasoned agency trial counsel, experts, and regulators.  Hardened litigators unprepared for the technical nuances of this sophisticated regulatory scheme can unwittingly blunder their clients into irreparable and draconian results.  This is a practice that now requires both skillful litigation and thoughtful study into the statutes, regulations, and precedents from both the agency and the courts of appeal that circumscribe the exercise of powerful discretionary authority that can wreak career-ending consequences on the members of the regulated community.

Chief Judge Mulrooney and Mr. Hull not only provide in their article a general overview of the proceedings and the body of law pertinent to administrative proceedings against medical and pharmacy practitioners, but they also discuss the various bases for revocation or suspension of a DEA license and examine the bases for denial of an application for a DEA license.  They don’t stop there, however.  The article also provides a helpful summary of the process surrounding immediate suspension cases (followed by a discussion of the burdens on the parties and the DEA’s exercise of discretion in sanctioning a party), and an examination of various pre-hearing, hearing, and post-hearing procedures. 

By Kurt R. Karst –      

With the recent litigation surrounding FDA’s approval of ANDAs for generic versions of PRECEDEX (dexmedetomidine HCl) Injection – which litigation has now moved on to Motions for Summary Judgment (see our updates here for the latest briefs) – we’ve had renewed interest in (and requests to update) our popular Generic Drug Labeling Carve-Out Scorecard (a.k.a. the Labeling Carve-Out Citizen Petition Scorecard).  We last updated that scorecard more than two years ago (see here), and we promised to make it a static feature of the FDA Law Blog home page last September when we introduced our Biosimilars State Legislation Scorecard (which also needs to be updated).  So much to do; so little time. . . .  But we found a few minutes to finally draft this post and make a permanent home for the Generic Drug Labeling Carve-Out Scorecard.

This version of the scorecard adds several new FDA decisions (either as a response to a citizen petition, or from an FDA letter decision outside of the petitioning process) and some new (and still pending) citizen petitions. 

Enjoy the scorecard!  And if you're aware of anything you think we missed, then please let us know and we'll take a look and decide whether or not to update the scorecard accordingly.  We note that sometimes determining whether or not a citizen petition submitted to FDA is really about a labeling carve-out issue can be difficult to discern.  Take, for example, a recent citizen petition concerning ProAir HFA (albuterol sulfate) Inhalation Aerosol (Docket No. FDA-2014-P-0404), which FDA responded to late last week.  While the petition does raise, among other things, the issue of 3-year exclusivity eligibility and the effects on generics, that petition is more about the scope of 3-year exclusivity than ANDA labeling carve-outs.  Thus, we would not include a petition like that on our scorecard.

FDA Citizen Petition Responses & Letter Decisions Permitting a Labeling Carve-Out

• FDA Response, Docket Nos. 2001P-0495, 2002P-0191, FDA-2002-P-0003 (June 11, 2002) – ULTRAM (tramadol HCl)
• FDA Response, Docket Nos. 2001P-0495/PRC, 2002P-0191/PRC, FDA-2002-P-0003/PRC (Mar. 31, 2003) – ULTRAM (tramadol HCl)
• FDA Response, Docket No. FDA-2003-P-0074 (Apr. 6, 2004) – REBETOL (ribavirin)
• FDA Letter Decision (Mar 1, 2004) - SKELAXIN (metaxalone) Tablets
• FDA Response, Docket No. FDA-2005-P-0368 (Dec. 1, 2006) – OXANDRIN (oxandrolone)
• FDA Response, Docket No. FDA-2006-P-0274 (Mar. 13, 2008) – ETHYOL (amifostine)
• FDA Response, Docket No. FDA-2007-P-0169 (Apr. 25, 2008) – MARINOL (dronabinol)
• FDA Response, Docket No. FDA-2008-P-0304 (June 18, 2008) – ALTACE (ramipril)
• FDA Response, Docket No. FDA-2008-P-0069 (July 28, 2008) – CAMPTOSAR (irinotecan HCl)
• FDA Response, Docket No. FDA-2006-P-0073 (Nov. 18, 2008) – PULMICORT Respules (budesonide inhalation suspension)
• FDA Response, Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411 (Dec. 4, 2008) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2008-P-0343/PRC and PSA & FDA-2008-P-0411 (June 16, 2009) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2009-P-0411 – ACTOS (pioglitazone HCl) & ACTOPLUS MET (March 15, 2010) (pioglitazone HCl; metformin HCl)
• FDA Response, Docket No. FDA-2009-P-0601 (June 17, 2010) – NAROPIN (ropivacaine HCl monohydrate)
• FDA Response, Docket No. FDA-2010-P-0087 (July 30, 2010) – LYRICA (pregabalin) 
• FDA Response, Docket No. FDA-2010-P-0545 (Feb. 24, 2011) – XYZAL (levocetirizine dihydrochloride)
• FDA Response, Docket No. FDA-2011-P-0128 (May 11, 2011) – XIBROM/BROMDAY (bromfenac)
• FDA Response, Docket No. FDA-2011-P-0702 (Feb. 8, 2012) – DORYX (doxycycline hyclate)
• FDA Letter Decision, Related to Docket Nos. FDA-2011-P-0662 & FDA-2011-P-0663 (Mar. 27, 2012) – SEROQUEL (quetiapine fumarate)
• FDA Response, Docket No. FDA-2006-P-0007 (Apr. 9, 2012) – VANCOCIN (Vancomycin HCl) Capsules
• FDA Response, Docket No. FDA-2012-P-1018 (Feb. 15, 2013) – COLCRYS (colchicine) Tablets
• FDA Response, Docket No. FDA-2013-P-0247 (Aug. 1, 2013) – RECLAST (zoledronic acid) Injection
• FDA Response, Docket No. FDA-2013-P-1293 (Mar. 10, 2014) – REMODULIN (treprostinil) Injection
• FDA Letter Decision, Docket No. FDA-2014-N-0087 (Aug. 18, 2014) – PRECEDEX (dexmedetomidine HCl) Injection

FDA Citizen Petition Responses Not Permitting a Labeling Carve-Out

• FDA Response, Docket No. FDA-2003-P-0002 (Sept. 20, 2004) – RAPAMUNE (sirolimus)
• FDA Response, Docket No. FDA-2010-P-0614 (May 25, 2011) – COLCRYS (colchicine) Tablets

Pending Labeling Carve-Out Citizen Petitions

• Docket No. FDA-2007-P-0294 – ACTOS (pioglitazone)
• Docket No. FDA-2009-P-0581 – BAYTRIL (enrofloxacin) (Animal Drug)
• Docket No. FDA-2009-P-0597 – Fluticasone Propionate and/or Salmeterol Xinafoate Products
• Docket No. FDA-2011-P-0482 – VAGIFEM (estradiol) Tablets 
• Docket No. FDA-2012-P-0632 – COLCRYS (colchicine) Tablets  
• Docket No. FDA-2014-P-1649 – FUSILEV (levoleucovorin) for Injection

Non-Response Denials of Labeling Carve-Out Citizen Petitions

• FDA Response, Docket No. FDA-2011-P-0662 (Mar. 7, 2012) – SEROQUEL (quetiapine fumarate)
• FDA Response, Docket No. FDA-2011-P-0663 (Mar. 7, 2012) – SEROQUEL XR (quetiapine fumarate) 
• FDA Response, Docket No. FDA-2011-P-0823 (May 11, 2012) – CRESTOR (rosuvastatin calcium)

BPCA Section 11 Pediatric Labeling Citizen Petitions

• FDA Response, Docket No. FDA-2001-P-0053 (January 24, 2002) – BPCA Implementation
• FDA Response, Docket No. FDA-2002-P-0289 (May 21, 2003) – ALPHAGAN (brimonidine)
• FDA Response, Docket No. FDA-2010-P-0545 (February 24, 2011) – XYZAL (levocetirizine dihydrochloride) 

FDC Act § 505(j)(10) Citizen Petitions and Approval Precedents

• FDA Response, Docket No. FDA-2011-P-0702 (Feb. 8, 2012) – DORYX (doxycycline hyclate) Delayed-Release Tablets
• ANDA No. 076786, Donepezil Hydrochloride Tablets, 5 mg and 10 mg
• ANDA No. 078388, Donepezil Hydrochloride Orally-Disintegrating Tablets, 5 mg, and 10 mg
• ANDA No. 077431, Exemestane Tablets, 25 mg
• ANDA No. 076361, Levofloxacin Tablets, 250 mg, 500 mg, and 750 mg
• ANDA No. 077179, Amlodipine besylate and Benazepril HCl Capsules, 5 mg (base)/40 mg and 10 mg (base)/40 mg

Moot/Withdrawn/“Dead” Labeling Carve-Out Citizen Petitions

• Docket Nos. FDA-2004-P-0426, FDA-2003-P-0081, & 2001P-0481 - SKELAXIN (metaxalone) Tablets; FDA Letter Decision – SKELAXIN (metaxalone) Tablets (see our previous post here)
• Docket No. FDA-2001-P-0445 – NEURONTIN (gabapentin) Capsules
• Docket No. FDA-2005-P-0368 (Petition for Reconsideration; Dec. 5, 2006) – OXANDRIN (oxandrolone)
• Docket No. FDA-1997-P-0034 (Legacy FDA Docket No. 1997P-0178) – TORADOL (ketorolac tromethamine)
• Docket No. FDA-2007-P-0113 – THALOMID (thalidomide); FDA Response (Sept. 30, 2014)
• Docket No. FDA-2010-P-0403 – VAGIFEM (estradiol) Tablets

By Kurt R. Karst –      

The hope is that years from now (but hopefully not too many years), once the review and performance metrics FDA agreed to as part of the Generic Drug User Fee Amendments are in full effect and 10-month ANDA reviews (resulting in timely tentative and final approvals) are the norm, we’ll look back at posts like this one just to refresh our recollection as to how FDA, in the “dark ages,” went about determining that a sponsor forfeited eligibility for a period of 180-day exclusivity under FDC Act § 505(j)(5)(D)(i)(IV).  We’re already in a period of relative calm when it comes to forfeiture, with only a dozen or so FDA decisions so far this year.  But that calm is probably a bit misleading, as forfeiture decisions that would have come up at 30 months after ANDA submission have been delayed to 40 months as a result of the enactment of Section 1133 of the 2012 FDA Safety and Innovation Act (“FDASIA”) (see our previous post here).  

It’s been a while since we last posted on an FDA forfeiture decision.  But that’s the topic of today’s post . . . a recent and interesting case concerning generic ACTONEL (risedronate sodium) Tablets approved under NDA No. 020835.  And the case serves as a gentle reminder of FDA’s “our failure is your failure position” when it comes to the failure-to-obtain-timely-approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV).  First things first, however . . . a little statutory background.

Under FDC Act § 505(j)(5)(D)(i)(IV), 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final Agency action on the petition (inclusive of such beginning and ending dates) . . . .” FDC Act § 505(q)(1)(G).  Forfeiture decisions involving this provision have been invariably linked to a change in or review of decision under FDC Act § 505(j)(5)(D)(i)(IV).  FDA has yet to make a stand-alone decision under FDC Act § 505(q), adding a specific number of days to the 30-month forfeiture date. 

FDASIA made further changes with respect to the application of FDC Act § 505(j)(5)(D)(i)(IV) to certain ANDAs.  In particular (though not relevant to the case at hand), for an ANDA submitted to FDA between January 9, 2010 and July 9, 2012 initially containing a Paragraph IV certification (or that is amended during that time to first contain a Paragraph IV certification), the time to obtain timely tentative approval (or final approval if tentative approval is not warranted) is 40 months during the period of July 9, 2012 and September 30, 2015, and not 30 months.

FDA’s application of the exception (i.e., the “unless”) provision at FDC Act § 505(j)(5)(D)(i)(IV) was, at first, very narrow and draconian (and it still is to some extent).  For example, FDA explained in an October 2008 Letter Decision that “[t]his express description of the circumstances in which exclusivity will not be forfeited for failure to obtain tentative approval makes it clear that, under other circumstances in which an applicant has failed to obtain tentative approval, regardless of what party might be responsible for that failure, the first applicant will forfeit exclusivity” (emphasis added).  Although FDA still sticks to a “our failure is your failure position,” as we explained in a post back in June 2013, the Agency has shown some willingness to allow a little wiggle room under FDC Act § 505(j)(5)(D)(i)(IV).  In particular, FDA has rejected as too draconian “but for” causation in its application of the statutory forfeiture provision.  As we explained back then:

FDA has determined that even if one of the causes of failure to get tentative approval by the 30-month forfeiture date was a change in or a review of the requirements for approval imposed after the application was submitted, a first applicant will not forfeit eligibility notwithstanding that there may have been other causes for failure to obtain tentative approval by the 30-month forfeiture date that were not caused by a change in or review of the requirements for approval.  That is, to avoid forfeiture, an applicant need only show that acceptability of one aspect of its ANDA (e.g., chemistry, labeling, or bioequivalence) was delayed due, at least in part, to a change in or review of the requirements for approval, irrespective of what other elements may also have been outstanding at the 30-month date.  In other words, “but-for” causation is not required in order to qualify for the exception under FDC Act § 505(j)(5)(D)(i)(IV).  FDA has apparently determined that this interpretation best effectuates the policy embodied in the exception, insofar as it does not penalize first applicants for reviews of or changes in approval requirements imposed after their ANDAs are submitted that cause the failure to obtain approvals or tentative approvals within 30 months, and continues to incentivize applicants to challenge patents by preserving (in many instances) the opportunity to obtain 180-day exclusivity.

In the case of forfeiture of 180-day exclusivity eligibility for generic ACTONEL Tablets, 150 mg, FDA builds on to and hammers home the Agency’s “our failure is your failure position.” 

Teva Pharmaceuticals USA (“Teva”) submitted the first ANDA to FDA – ANDA No. 079215 – containing a Paragraph IV certification for two strengths of generic ACTONEL Tablets: 75 mg and 150 mg.  The first Paragraph IV for the 75 mg strength was submitted on September 10, 2007 as part of the company’s original ANDA submission, and a second Paragraph IV for the 150 mg strength was submitted on August 12, 2008 as part of an amendment to ANDA No. 079215.  Teva’s eligibility for 180-day exclusivity for the 75 mg strength was forfeited pursuant to FDC Act § 505(j)(5)(D)(i)(II) when the company withdrew the strength from ANDA No. 079215 on December 98, 2009, but Teva continued to pursue approval of the remaining 150 mg tablet strength. 

Years passed, and it was not until August 17, 2011 that FDA finally tentatively approved ANDA No. 079215.  This is, of course, more than six months past the date that is 30 months from the August 12, 2008 submission of the 150 mg strength amendment to the ANDA (i.e., February 12, 2011).  (Final ANDA approval was granted on June 13, 2014.) 

Although FDA has not yet posted on the Agency’s Drugs@FDA website a copy of the approval letter for ANDA No. 079215, we were able to get our hands on a copy of FDA’s internal 180-Day Exclusivity Forfeiture Memorandum.  In that memorandum, FDA’s Office of Generic Drugs (“OGD”) details the basis for the Office’s conclusion that Teva forfeited 180-day exclusivity eligibility pursuant to FDC Act § 505(j)(5)(D)(i)(IV), even though as of February 11, 2011, one day prior to the 30-month forfeiture date, all OGD review disciplines had completed review of the ANDA:

We note that although no individual disciplines were outstanding at the 30-month forfeiture date, FDA had not completed its final review of the ANDA by that date.  The decision to approve (or tentatively approve) an ANDA involves not only the disciplines’ evaluations of their respective portions of the ANDA, but final review by [OGD] management.  That final step did not take place by the 30-month forfeiture date, and was complete on August 17, 2011.  We also note that any claim that a company should not forfeit because of the possibility that FDA’s delays caused the company’s failure to obtain tentative approval by the 30-month forfeiture date is unavailing.  Under section 505(j)(D)(1)(IV) of the FD&C Act, exclusivity is forfeited “unless” there is a review of or change in the requirements that has delayed approval or tentative approval of the ANDA.  The statute does not permit, let alone require, either FDA or an ANDA applicant to comb through the ANDA review records and decide whether, had the review been conducted more quickly, the application could have received tentative approval before the 30-month forfeiture date.  Notably, section 1133 of FDASIA . . . , which, among other things, extended the 30-month forfeiture period to 40 months for certain ANDAs, reflects Congress’s understanding both that the length of time that it takes FDA to review an ANDA might contribute to a sponsor’s failure to obtain tentative approval by the 30-month forfeiture date, and that in such instances forfeiture nonetheless may occur.

We’ve always found FDA’s “our failure is your failure position” problematic from a fairness standpoint; however, no company has yet taken FDA to task in a lawsuit challenging the Agency’s interpretation and application of this position.  That’s probably because finding the perfect case is very difficult.  After all, what ANDA file is clean enough from a response timeframe to make such a challenge? 

By Ricardo Carvajal & Diane B. McColl –

The Grocery Manufacturers Association ("GMA") announced an initiative designed to “improve the process and increase transparency for making Generally Recognized As Safe ("GRAS") determinations of ingredients added to food.”  The initiative includes the following five elements:

1. Development by independent technical experts of a publicly available standard to provide guidance on the conduct of ingredient safety assessments.  The standard is intended to be “suitable for accreditation using an independent official accreditation body.”
2. Establishment of a database listing information on GRAS assessments conducted pursuant to the aforementioned standard.  Information in the database will be made available to FDA and other stakeholders.
3. Expansion of GMA’s curriculum of GRAS education and training programs, both with respect to regulatory requirements and the scientific procedures used in safety assessments.  The expertise of the recently established Center for Research and Ingredient Safety (CRIS) will be made available to stakeholders.
4. Adoption of a Code of Practice that addresses the conduct of assessments, maintenance of the GRAS assessment database, and training of employees on GRAS procedures.
5. Outreach to inform stakeholders and consumers of the above-described measures.

The initiative implicitly recognizes that, at least when it comes to food ingredient safety, we live in a “show me” era.  The increased flow of information on safety assessments to FDA and others, coupled with greater clarity about the conduct of such assessments, should help address the principal concerns that have been raised about the current system.

Of course, we also live in a “my way” (or the highway) era.  As we’ve noted in prior postings (here and here), some critics of the current system have pursued a no-holds-barred approach to seeking change, and would prefer nothing less than mandatory premarket approval – a solution that is both unworkable and unattainable.  The GMA initiative effectively calls their bluff.

By Alan M. Kirschenbaum –

We have reported previously (here and here) on PhRMA’s lawsuit challenging a HRSA regulation implementing the orphan drug exclusion that applies to certain types of covered entities under the 340B Drug Discount Program. To recap briefly, the rule had provided that the orphan drug exclusion is applicable only to orphan drugs when used for the rare condition or disease for which that orphan drug was designated, so that covered entities are entitled to 340B discounts when a drug designated as an orphan drug for one indication is used for a different, non-orphan indication. In May, the D.C. District Court vacated the rule on the ground that HRSA did not have statutory authority to promulgate a legislative rule on this subject. Last month, HRSA responded by issuing a substantially identical rule, but characterizing it as an interpretive rule. PhRMA then asked the Court to either order additional briefing on whether the now-interpretive rule is valid, or to vacate the rule.

Today, the Court denied PhRMA’s request, ruling that the new interpretive rule is not the subject of PhRMA’s lawsuit. Accordingly, PhRMA “is free to challenge that interpretive rule, but such a challenge is beyond the scope of the instant action.”

To be continued . . . .

By Jennifer D. Newberger –

On August 20, 2014, CDRH issued a guidance document, “Unique Device Identifier System: Frequently Asked Questions, Vol. 1.”  The purpose, according to the guidance, is to “provide[] clarification of key provisions of the UDI Rule.”  We previously posted on the UDI rule here.

Clarification, in this instance, appears to be little more than a regurgitation of information contained in the rule itself, the preamble to the rule, the UDI website, and the Global Unique Device Identification (GUDID) guidance document.  It is not clear what new insights FDA intended this guidance to impart.  There are parts of the rule that do deserve further clarification, but those issues are not addressed. 

For example, the definition of an implantable device is one that “is intended to remain implanted continuously for a period of 30 days or more.”  21 C.F.R. § 801.3.  By this definition, extended wear contact lenses are considered implantable devices, since they are intended to remain in the eye for 30 days.  Nevertheless, we assume that FDA did not intend to include extended wear contact lenses in the definition of an implantable device.  It would be helpful for FDA to clarify this point, but failed to do so in the FAQ.

Additionally, we have been made aware that many retailers may not be able to read automatic identification and data capture (AIDC) codes for a number of years.  All labels are required to contain a UDI in plain text and AIDC format.  For devices available over-the-counter at retail stores, it is not clear how the presence of a code in AIDC format will benefit the public health (e.g., by facilitating a recall) if the retailer is unable to read the code.  Even though FDA rejected an overall exception to UDI requirements for devices available at retail establishments, it would be helpful to industry for FDA to discuss situations in which a UPC code may suffice as a UDI until retail technology catches up to the AIDC requirement.  Until then, requiring companies to place AIDC codes on retail devices with UPC codes is burdensome with no countervailing public health benefit.

The title of this guidance document states that it is “Vol. 1,” implying that there will at least be a “Vol. 2.”  Hopefully, future UDI guidance documents will do more than repeat information that is already available.

By Kurt R. Karst –      

This blogger’s oldest child started middle school this past week.  Naturally, I was excited to get his impressions of the first day of school.  “Good” was his initial comment – a now all too familiar one-word tween response with which I am still coming to grips.  So I pressed further: “Tell me more.”  “It’s all so different from elementary school,” he said.  “I got 8 pages of homework on the first day!”  While I expressed surprise, what I was really thinking was: “If only life could be that simple again.”  That thought is similar to this blogger’s first reaction after reviewing FDA’s latest draft guidance document issued in preparation for the October 1, 2014 implementation of the review and performance goals agreed to under the Generic Drug User Fee Amendments of 2012 (“GDUFA”): “Controlled Correspondence Related to Generic Drug Development.”  When did every little aspect of generic drug development – even simple correspondence to FDA – become so complicated?  Of course, we know the answer to that question: when GDUFA was enacted.  But just as we get used to new responsibilities as we move through the education process, the generic drug industry will step up to the task of evolving with GDUFA no matter how complicated things get.

So-called “controlled correspondence” has been a mainstay of the generic drug development and approval process for many years now.  It’s how many companies have been able to get answers from FDA’s Office of Generic Drugs (“OGD”) to questions like “What are the bioequivalence requirements for drug X?” and “How close is my formulation to that of the brand-name reference listed drug?”  OGD gets a ton of controlled correspondence each year.  Although the volume of controlled correspondence was reduced with OGD’s decision – after some internal FDA legal wranglings – to publish product-specific bioequivalence recommendations (see our previous post here), OGD continues to receive hundreds (if not thousands) of controlled correspondence requests each year.  Not surprisingly, there’s been a backlog of controlled correspondence awaiting a response from OGD.

For a long time there was no guidance (informal or formal) on how to submit controlled correspondence to FDA – or even what controlled correspondence encompassed.  Eventually, FDA posted some recommendations on the Agency’s website.  And then GDUFA came along . . . .

Early on in GDUFA negotiations it was suggested that timeframes be established for  controlled correspondence between FDA and industry to support application review targets.  Those suggestions were ultimately captured in the GDUFA review and performance goals letter where controlled correspondence was described (below) and where FDA agreed to response metrics.  The following is from the review and performance goals letter:

Controlled correspondence – FDA’s Office of Generic Drugs provides assistance to pharmaceutical firms and related industry regarding a variety of questions posed as “controlled documents.” . . . Controlled correspondence does not include citizen petitions, petitions for reconsideration or requests for stay.

Controlled Correspondence Metrics

• Controlled Correspondence
• FDA will respond to 70 percent of controlled correspondence in 4 months from date of submission in FY 2015.
• FDA will respond to 70 percent of controlled correspondence in 2 months from date of submission in FY 2016.
• FDA will respond 90 percent of controlled correspondence in 2 months from date of submission in FY 2017.
• If the controlled correspondence requires input from the clinical division, one additional month will be added to the goals outlined above.
• In the case of controlled correspondence which raises an issue or question that is the same as or related to the issue or question that is the subject of one or more pending citizen petitions, or petitions for stay or reconsideration, the above goals will apply from the date FDA issues responses to the pending petitions.

FDA’s draft controlled correspondence guidance, which is announced in an August 27, 2014 Federal Register notice and is the topic of a pre-recorded webinar, puts some meat on the bones of the review and performance goals letter.  We knew the draft guidance would be issued soon.  After all, FDA identified the guidance as a topic for discussion at a public hearing on GDUFA implementation scheduled for September 17, 2014 (see our previous post here). 

The draft controlled correspondence guidance provides, for the first time, a definition of “controlled correspondence” (at least for the purposes of GDUFA): “A correspondence submitted to the Agency, by or on behalf of a generic drug manufacturer or related industry, requesting information on a specific element of generic drug product development.”  It also limits controlled correspondence to inquiries and requests from generic drug manufacturers and related industry.  “Inquiries related to generic drugs submitted by other parties (for example, private citizens, financial firms, or public advocacy groups that are not directly involved in developing generic drug products) should be directed to CDER’s Division of Drug Information,” says FDA in the draft guidance.  From there, FDA puts some controls on what types of controlled correspondence are subject to the GDUFA metrics and when responses may be issued.  For example, FDA says that the goal dates for responding to controlled correspondence concerning issues raised in a pending citizen petition (including a petition for reconsideration or a request for stay) depend on when a petition response is issued:

If a controlled correspondence is submitted that raises an issue that is the same as or related to an issue or question that is the subject of one or more pending citizen petitions, petitions for reconsideration, or requests for a stay, the goal dates set forth in the GDUFA Commitment Letter for controlled correspondence will apply from the date FDA issues responses to the pending petitions.  Likewise, if a citizen petition, petition for reconsideration, or request for stay is submitted that raises an issue that is the same as or related to an issue or question in a pending controlled correspondence, the goal date for that controlled correspondence will apply from the date FDA issues a response to the related citizen petition, petition for reconsideration, or stay request.  For example, if a controlled correspondence is submitted in FY 2015 that relates to an issue in a pending petition, and the Agency responds in FY 2016 to that petition, the 4-month goal date for FY 2015, the year in which the controlled correspondence was submitted, will apply to the controlled correspondence from the 2016 date that the petition is answered.

For controlled correspondence related to matters still under consideration by FDA (e.g., requests for specific approval requirements for an ANDA for a complex drug product for which FDA is still considering the scientific standards for approval), parties may get a non-response response that will close the matter.  According to FDA:

For such questions that call for developing a new policy, FDA will respond to the controlled correspondence to notify the requestor that such a policy is under development, but that the Agency cannot provide information at that time because the matter is still under consideration.  The Agency will consider this response to close the controlled correspondence, and it will not provide additional direct communications to an inquirer on the matter.

Although FDA’s draft guidance does provide some specific examples of what inquiries and topics are appropriate for controlled correspondence (e.g., requests related to inactive ingredients, formulation assessments, and labeling standards for certain container/closure systems), along with general guidance that controlled correspondence should involve “inquiries on a specific element of generic drug development, and not general questions related to product planning,” FDA spends quite a bit of time explaining what topics fall outside the scope of controlled correspondence, as well as what controlled correspondence is excepted from GDUFA goals.  “First, the Agency considers any question related to a pending ANDA a review issue,” says FDA. “Such inquiries will not be treated as controlled correspondence and should be submitted only to the ANDA so they can be included as part of the full administrative record for that application.”  “Second, inquiries that are submitted to FDA that are not directly related to generic drug development will not be considered controlled correspondence for the purposes of GDUFA.” Finally, “general, open-ended, or insufficiently detailed questions related to product development are not the appropriate subject of [controlled correspondence].”

Excepted from the GDUFA goals are three types of inquiries that fall within the definition of controlled correspondence, but that FDA has historically treated differently than other inquiries on generic drug development: (1) requests for bioequivalence study recommendations for a specific drug produc; (2) requests for review of bioequivalence clinical protocols; and (3) requests for pre-ANDA meetings to discuss generic drug development.  “FDA will continue to respond to these inquiries consistent with its current practices, and to exclude these inquiries from the goal dates in the GDUFA Commitment Letter,” writes FDA.

Finally, the draft guidance provides detailed information on how generic drug manufacturers or related industry should go about submitting controlled correspondence, the specific components FDA expects to see in controlled correspondence, and what OGD disciplines might review and respond to controlled correspondence. 

The draft guidance is a lot to digest, but it’s also welcomed detail of an information request process that is intended to result in quicker ANDA approval.  Nevertheless, some questions still remain.  For example, how will FDA’s focus on addressing controlled correspondence submitted in Fiscal Years 2015-2017 affect controlled correspondence submitted during the first two years of GDUFA (and before)?  Will those pending requests be put on a backburner? 

By David C. Gibbons –

It is rare that we urge our readers to keep a copy of a court ruling or brief.  A Brief that FDA filed on August 21, 2014 is an exception.  Companies and others should read this brief and keep it close at hand. When someone wants to question FDA’s legal authority to compel a recall, this brief provides the clearest statement of FDA’s limited authority to compel a recall.

We previously described (here and here) the litigation commenced by Hospira, Inc. (“Hospira”) wherein the company filed suit against FDA following the Agency’s approval of generic PRECEDEX (see FDA Dear Dexmedetomidine Hydrochloride Injection NDA Holder/ANDA Applicant Letter (Aug. 18, 2014) (hereinafter “FDA Letter Decision”)).  In summary, Hospira sought, and was granted, a Temporary Restraining Order (“TRO”) that included a stay of FDA’s Letter Decision, rescission of any ANDA approvals predicated upon that Letter Decision, an order that FDA recall any product sold or distributed under such an ANDA approval, and an injunction prohibiting FDA from granting any further or additional approvals predicated upon the Letter Decision.  The court order directing FDA to recall a drug product based on a Hatch-Waxman dispute was unprecedented.

Generally speaking, FDA cannot compel a mandatory recall, except in very limited circumstances as authorized by statute, none of which apply to drugs (see here at § 7-5-3).  FDA can order a recall when the Agency:

• finds there exists a reasonable probability that a device intended for human use would cause serious, adverse health consequences or death (21 U.S.C. § 360h(e)(1)); 
• determines that a batch, lot, or other quantity of a biological product presents an imminent or substantial hazard to the public health (42 U.S.C. § 262(d)(1)); 
• determines that an adulterated or misbranded infant formula presents a risk to human health (21 U.S.C. § 350a(e); see also 21 C.F.R. § 107.200);
• finds there is a reasonable probability that a tobacco product contains a manufacturing or other defect not ordinarily contained in tobacco products on the market that would cause serious, adverse health consequences or death (21 U.S.C. § 387h(c)(1)); or
• determines there is a reasonable probability that an article of food (other than infant formula) is adulterated or misbranded and the use of or exposure to such article will cause serious adverse health consequences or death to humans or animals (21 U.S.C. § 350l(a));

Finally, FDA has the discretion to compel a mandatory recall when it finds that a human cell, tissue, or cellular and tissue-based product is a source of dangerous infection to humans, or does not provide adequate protections against the risks of communicable disease transmission.

Recalls, in situations other than those described above, are voluntary actions by a company expected to conform to FDA policy set forth in its regulations. 

Thus, as we circle back to the Hospira litigation, we arrive at a threshold question: can a court order FDA to order a recall?  The answer from the Defendant-Intervenors as well as FDA in this case is no.  FDA states clearly and succinctly in its Brief: “FDA cannot order recalls.”  The Agency goes on to argue that the recall ordered in the Hospira TRO could not even be requested by FDA because the basis for the recall was a patent dispute and not a matter of product safety or efficacy.  FDA says: “consumers should believe that recalled products present a risk to health or are grossly deceptive. That is decidedly not the case here.”  The Agency admitted that “[i]f a company chooses not to comply with an FDA request to recall, FDA has no mechanism to enforce its request because it does not have statutory authority to order drug recalls.” FDA also argued that the court-ordered recall was not in the public interest because the recall “threaten[ed] to disrupt the consistent regulatory standards for recalls.” Finally, the Agency makes the argument that a recall based, such as this, on a patent issue and not on a product safety or efficacy issue will undermine the perception of future recalls.  To this point, FDA says: “When other future products are recalled, consumers may question whether the recall is related to a legitimate public health concern, or whether it is merely another patent dispute in which safety or efficacy is not at issue. The public interest weighs strongly against” ordering a recall.

The district court held a hearing on August 26, 2014 to decide on a Motion for Reconsideration of the TRO entered on August 19th.  In the end, the court granted the Motion for Reconsideration in part and vacated that part of the TRO that ordered FDA to compel a recall of generic PRECEDEX.

By Riëtte van Laack –

As previously discussed, since at least 2006, the U.S. honey bee industry has been trying to get FDA to adopt a standard of identity for honey.   In 2006, the American Beekeeping Federation and honey industry groups petitioned FDA for a standard (Docket No. FDA-2006-P-0207).  More than five years later, in 2011 and despite continued prodding by different parties, FDA denied this petition.  FDA concluded that no standard of identity was needed.  As evidenced by the draft guidance issued in April 2014, FDA has maintained its position.  In this 2014 draft guidance, the Agency repeated its position that honey is “a thick, sweet, syrupy substance that bees make as food from the nectar of flowers and store in honeycombs.” According to FDA, this definition accurately reflects the common usage of the term honey. 

In the absence of a federal standard of identity, a number of states (including Wisconsin and Florida) have adopted, or proposed to adopt, their own state standards of identity or a definition for honey.  According to comments to the draft guidance, no two state standards or definitions are identical.  Apparently concerned about the potential effect of these state standards and definitions, and FDA’s continued refusal to adopt a federal standard, Congress, in the 2014 Farm Bill, tasked USDA’s Agricultural Marketing Service (“AMS”) with the preparation of a report on the need for a standard of identity for honey (Section 10012 of Public Law No. 113-79).  In its report, AMS is to address whether a federal standard of identity for honey would be in the interest of consumers, the U.S. honey industry, and U.S. agriculture.

As directed by the 2014 Farm Bill, AMS issued a notice seeking comments on the 2006 petition.  Specifically, AMS seeks comments regarding the adoption of deviations from the Codex Standard for Honey, CODEX standard 12–1981, Rev. 2 (2001), as defined in the petitioner’s request and on how a federal standard of identity for honey would benefit consumers, the honey industry, and U.S. agriculture.

At best, the AMS report might persuade FDA to reconsider its position.  Ultimately, it remains for FDA to decide on the adoption of a standard.  Comments are due Sept. 19, 2014.

By Karla L. Palmer –

The U.S. Drug Enforcement Administration (“DEA”) published last Friday a Final Rule rescheduling hydrocodone combination products (“HCPs”) from Schedule III to Schedule II.  We posted about the proposed rescheduling here (NPRM published February 27, 2014).  There was little doubt that DEA would up-schedule HCP’s, especially in light of HHS’s recommendation to do so.  It is disappointing, however, that DEA did not heed the request of industry and provide for more time for the implementation of the heightened security and other requirements.  

The Final Rule comes on the heels of more than a decade of review of the rescheduling issue for HCPs by both the Department of Health and Human Services (“HHS”) and DEA.  Back in 2004, in response to a petition, DEA first submitted a request to HHS for a scientific and medical evaluation, and scheduling recommendation for HCPs pursuant to 21 U.S.C. § 811(b).  In 2008, HHS recommended that HCPs remain controlled in schedule III of the CSA.  In 2009, DEA requested HHS re-evaluate their data and provide another scientific and medical evaluation and scheduling recommendation based on additional data and analysis. 

The 2012 FDA Safety and Innovation Act (“FDASIA”) (summarized here) included a provision requiring review, including public meetings, on rescheduling of HCPs. That statutorily mandated review included the creation of an FDA advisory committee (Drug Safety and Risk Management Advisory Committee), which after two days of public meetings in 2013, and review of 768 comments submitted by patients, patient groups, advocacy groups, and professional societies, voted in favor of rescheduling.  After review of scientific and medical evidence, and other considerations mandated by FDASIA, HHS completed its required eight-factor analysis under 21 C.F.R. § 811(b) and recommended in late 2013 that HCPs be placed in Schedule II.  DEA published its notice of proposed rulemaking in late February 2014.

DEA received 573 comments on the proposed rule; it reports that 52% (or 298 comments) supported (or supported with qualification) rescheduling, and 41% (235 comments) opposed rescheduling (many opposition comments were from pharmacists).  Seven percent of the comments did not take a definitive position.  The lengthy preamble addresses comments received, and the 45-day period for implementation of necessary changes by registrants as a result of the up-scheduling.  Although DEA received comments seeking a longer implementation window, those comments did not deter DEA from sticking with what is perceived by many to be a woefully short transition period.  Specifically, in order to prevent “continued misuse, abuse and diversion,” DEA deems it “necessary to set an effective date for this scheduling action, including security and labeling requirements, with all reasonable haste.  After careful consideration of the risk to the U.S. public health and safety related to the diversion and abuse of HCPs, the DEA believes the 45-day effective date is reasonable.”  Final Rule at 61.  DEA also stated that it may not refuse to reschedule a drug or other substance based on alleged “economic impacts” of the rescheduling.  Furthermore, as to retail pharmacies, DEA noted that they are “not required by the CSA or DEA regulations to place schedule II controlled substances in a vault or safe.”  Specifically, in accordance with 21 CFR § 1301.75(b), pharmacies “may disperse schedule II controlled substances throughout their stock of noncontrolled substances in such a manner as to obstruct the theft or diversion of the controlled substances.”

DEA clarified that the Final Rule affects hydrocodone combination products, which are those substances described in 21 C.F.R. § 1308.13(e)(1)(iii) and (iv).  DEA noted that all other products containing hydrocodone are already controlled under Schedule II.  It specifically pointed out that Zohydro™ ER does not meet the cited definition; it is currently controlled under 21 C.F.R. § 1308.12(b)(1)(vi).  However, excluding Zohydro™, all “pharmaceuticals containing hydrocodone currently on the market in the United States are HCPs and are subject to this rulemaking,” including cough suppressants containing HCPs.   DEA noted that HCPs are the “most frequently prescribed opioid in the United States with nearly 137 million prescriptions” for HCPs dispensed in 2013.  Final Rule at 13.  

As we previously posted, rescheduling HCPs from Schedule III to Schedule II affects the entire drug supply chain – every handler of controlled substances.  (The effects of rescheduling are included in that post).  Rescheduling imposes significantly more stringent regulatory requirements on manufacturers, distributors, pharmacies, physicians, importers and exporters. 

The preamble addresses a multitude of issues raised by the rescheduling, including but not limited to the following:

1.   Authority to Prescribe HCPs as Schedule IIs

Commenters were concerned that prescribing authority differed in states, and now mid-level practitioners and others with no CII prescribing authority in certain states would not be able to prescribe HCPs.  DEA responded that it is outside its authority to decide who has prescribing authority within any particular state.

2.  Transmission Methods of HCP Prescriptions as Schedule IIs

Commenters were concerned about the inability for prescribers to transmit oral and faxed prescriptions for Schedule II HCPs. DEA responded that rescheduling does not hinder legitimate access to HCPs, and that contrary to the concerns of commenters, in the event of an emergency situation as defined in DEA regulations, a practitioner would be able to prescribe, and a pharmacy would be able to dispense, HCPs in accordance with 21 C.F.R. § 1306.11(d).  It noted however, in particular, that a practitioner may not delegate to a nurse, pharmacist, or anyone else, authority to make a medical determination whether to prescribe a particular controlled substances.  Final Rule at 49.  

3.  Quantity and Frequency of Refills

DEA noted that many commenters expressed concern about the limitation on refills on CII prescriptions, that this would required more frequent physician visits, and cause doctors to prescribe large quantities of HCPs per prescription.  DEA responded that, while courts have recognized that prescribing “inordinate” amounts of controlled medications may be a violation of the CSA, neither DEA nor the CSA generally imposes a quantitative minimum or maximum on the amount of medication.  Nevertheless, DEA recognizes that limitations on quantities by states or benefit providers exist, and that registrants must comply with such limitations.  Although the CSA prevents refills of CII prescriptions, DEA stated that practitioners may issue multiple prescriptions covering up to a 90-day period, and that DEA regulations do not require patients to be seen on a monthly basis.  DEA’s regulations, however, should not be construed “as mandating or encouraging” individual practitioners to issue multiple prescriptions or see their physicians only once every 90 days. 

4.   Patient Access

DEA received many comments voicing concerns related to access to HCPs, including fear of criminal prosecution, and impact on availability.  DEA stated that rescheduling should not hinder access to legitimate use of the medication, and that increased criminal sanctions for wrongful use, or use of the CSOS or Form 222 ordering process, should not result in limited availability.   DEA noted it takes approximately 1 hour to complete an order using a Form 222, and approximately 3 minutes to complete an order for CIIs using CSOS.

5.   Impact on Long-Term Care Facilities (“LTCFs”)

Although several comments addressed the detrimental effect that rescheduling will have on access to HCPs for patients in LTCFs, DEA responded that regulations already in place, such as permitting transmission of a prescription through the practitioner’s agent under 21 C.F.R. § 1306.11(f), and permission for partial fills under section 1306.13(b) already accommodate the unique needs of LTCFs.  DEA denied any request for a LTCF exemption based on lack of likelihood of diversion in LTCF settings, instead citing data demonstrating high incidents of diversion and abuse in such settings. 

6.   Impact on Manufacturers and Distributors
 
The most notable issue for the Final Rule for manufacturers and distributors is likely the 45-day implementation window for various HCP security and handling requirements.  For example, manufacturers and distributors must secure schedule II substances in a safe, steel cabinet or vault while schedule III substances may be stored in a less secure controlled substance cage or other enclosure.   DEA stated that, in accordance with the Administrative Procedure Act, most scheduling actions have a 30-day implementation period.  Final Rule at 55.  DEA deems the 45-day period to be a reasonable amount of time for registrants to comply with the requirements, and “was established upon a full consideration of the totality of the circumstances specific to HCPs” — discussed at pages 55- 62 of the Final Rule.

7.   Distribution of C-III Labeled HCPs Post Implementation of the Final Rule

DEA states that manufacturers are required to print on the labeling of each “commercial container of HCPs they distribute the designation of HCPs as “C-II”.  Final Rule at 63.  Furthermore, “it shall be unlawful for commercial containers of HCPs to be distributed without bearing the label properly identifying them ….as C-IIs,” and all labels must comply with the labeling requirements “on or before the effective date established in the final order for the transfer or addition.”  Thus, DEA is specifically requiring that commercial containers of HCPs distributed 45 days from date of publication be labeled as “C-II” and be packaged in accordance with 21C.F.R. part 1302. 

Further, DEA states that a “distribution” after the effective date of the Final Rule requires the use of a DEA Form 222 to transfer the substance.  A registrant may transfer upstream commercial containers of HCPs labeled as “C-III”, with utilization of a Form 222 in accordance with 21 C.F.R. § 1305.03.  DEA notes that, as discussed in the Economic Impact section of the Rule, manufacturers and distributors can make “minor adjustments” during the implementation period to meet the effective date requirement.  And, distributors have the option of returning stock labeled “C-III” to the manufacturer.  DEA declined to exempt manufacturers and distributors from physical security requirements for C-IIs given, among other things, their high potential for diversion and abuse, and recommends that registrants work closely with local DEA offices regarding submission of materials necessary for compliance with DEA security requirements.  Final Rule at 65.

DEA also clarified that regulations pertaining to labeling of commercial containers applies to distributions by distributors and manufacturers.  The DEA does “not regulate the labeling and packaging of commercial containers of controlled substances downstream of distributors.”  Final Rule at 64. 

Despite the fact that HCPs have been prescribed and handled as Schedule III drugs for decades, are the most prescribed narcotic in the United States, and there are significant differences in the regulatory requirements between Schedule II and Schedule III drugs, DEA’s unwillingness to provide more than a 45-day compliance window is both surprising, and disappointing, especially because fighting the prescription drug abuse problem requires a cooperative effort between the medical community, industry and the government.

We understand that this blogpost is just a short synopsis of the entire publication of the Final Rule.  We will publish additional posts in the coming days and weeks to address specific issues that arise as the registrants grapple with the effects – and the tight implementation timeframe – of DEA’s rescheduling decision. 

By Alan M. Kirschenbaum –

Beginning with CY 2011, Section 9008 of the Patient Protection and Affordable Care Act (“ACA”) has imposed an annual fee on manufacturers and importers of “branded prescription drugs.”  The global 2014 fee for all manufacturers and importers is $3 billion, to be shared by covered manufacturers and importers in proportion to their relative sales of branded prescription drugs to government purchasers and payors.  You’ll find a summary of this provision of the ACA here.

On July 28, the IRS issued a final regulation to implement the Section 9008 industry fee.  The definition of “branded prescription drugs,” on which the fee is imposed, is straightforward and tracks the statute:  the term means a prescription drug approved under an NDA, or a prescription biological approved under a BLA.  See 26 C.F.R. § 51.2(c).  Accordingly, generic drugs approved under ANDAs are not subject to the fee.

However, interestingly, the IRS acknowledges in the preamble that certain generic drugs were approved under NDAs prior to the enactment of the Drug Price Competition and Patent Restoration Act of 1984 (Hatch-Waxman Amendments), when the ANDA provisions were added to the statute.  IRS is referring to FDA’s “Paper NDA” policy, described in a July 31, 1978 FDA staff memorandum (and eventually published in the Federal Register at 46 Fed. Reg. 27,396 (May 19, 1981)), under which FDA allowed approval of duplicate versions of brand name drugs that were approved after 1962.  Under this policy, a manufacturer could submit, among other things, published reports of studies as the main supporting documentation of safety and effectiveness.  In other words, Paper NDAs were the functional equivalent of ANDAs before the ANDA provisions were added to the Federal Food, Drug, and Cosmetic Act.  FDA revoked the “paper NDA” policy in 1989 when the Agency proposed regulations implementing the Hatch-Waxman Amendments (54 Fed. Reg. at 28, 890 (July 10, 1989)). 

The IRS is requesting comments on “whether a special rule is appropriate regarding the treatment of generic drugs for which applications were submitted under [NDAs] prior to the 1984 [Hatch-Waxman Amendments],” including comments on how to distinguish such generic products from other drugs approved under pre-1984 NDAs.  The preamble explains that any special rule would be prospective only.  Therefore, at least for 2014, drugs approved under pre-1984 Paper NDAs will be included in the industry fee.

Manufacturers marketing drugs that were approved under pre-Hatch-Waxman Paper NDAs should consider submitting comments advocating a special rule to exclude these drugs from the definition of “branded prescription drug.”  Although the preamble does not specify a deadline for comments, we have been informed by the IRS that comments must be received within 120 days after publication in the Federal Register – i.e., by November 25, 2014.

The Food and Drug Law Institute is sponsoring a conference titled "Food Safety: Latest FSMA Developments & Enforcement Actions in a Changing Business Climate," scheduled for September 9.  The conference will feature a regulatory update by Michael Landa (Director of FDA/CFSAN), an exploration of the seven proposed rules that have been issued to implement FSMA, a case study on recalls that includes Roberta Wagner (Deputy Director for Regulatory Affairs at CFSAN), and a discussion of FDA’s enhanced enforcement authorities that includes Jeffrey Steger (Assistant Director of the Consumer Protection Branch in DOJ’s Civil Division).  To close out the conference, HP&M’s Ricardo Carvajal will moderate a session on the business aspects of food safety.  More information on the agenda and registration is available here.