By Ricardo Carvajal –

In an effort to grant FDA additional authority over dietary supplements, Senators John McCain and Byron Dorgan have introduced the Dietary Supplement Safety Act of 2010.  The bill would require dietary supplement facilities to provide FDA with information on supplements and their ingredients on an ongoing basis, would substantially alter the requirements applicable to new dietary ingredients ("NDI’s"), would give FDA mandatory recall authority, and would expand adverse event reporting requirements, among other changes. 
 
Particularly noteworthy are the changes in the requirements applicable to NDI’s that would take effect if the bill were to become law.  Currently, FDCA § 413(c) defines an NDI as “a dietary ingredient that was not marketed in the United States before October 15, 1994 and does not include any dietary ingredient which was marketed in the United States before October 15, 1994.”  If a dietary ingredient meets the definition of an NDI, then a manufacturer or distributor must submit a 75-day premarket notification to FDA that provides the basis on which the manufacturer or distributor has concluded that a dietary supplement containing the NDI will reasonably be expected to be safe, with one exception.  A premarket notification need not be submitted if “the dietary supplement contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.”

In conjunction with the passage of the Dietary Supplement Health and Education Act of 1994, dietary supplement trade associations developed “grandfather” lists of dietary ingredients that were marketed in the U.S. before October 15, 1994, and therefore were not subject to regulation as NDI’s.  Although FDA does not regard these lists as dispositive of a dietary ingredient’s status as a grandfathered dietary ingredient, manufacturers and distributors continue to rely on the lists.  The proposed legislation would amend the existing definition of an NDI to eliminate the references to October 15, 1994, and instead authorize FDA to establish a list of “accepted dietary ingredients.”  Dietary ingredients not on that list would be regulated as NDI’s.  Further, all such ingredients would have to be the subject of a 75-day premarket notification to FDA because the proposed legislation would abolish the exception to the premarket notification requirement described above. 

In proposing the legislation, Sen. McCain referenced a previous GAO report that made numerous recommendations with regard to FDA’s regulation of dietary supplements, including a recommendation that FDA issue guidance to clarify when a dietary ingredient is a new dietary ingredient (that guidance has yet to issue).  Notably, GAO just sent out letters to a number of supplement manufacturers seeking information on specific dietary ingredients, including substantiation of any company determinations that submission of an NDI notification is not required.  Just as the previous GAO report is being cited in support of calls for reform, the results of the current GAO inquiry could well be seized upon by advocates of reform if that inquiry reveals any apparent shortcomings in FDA’s oversight of NDI’s.

By Alan M. Kirschenbaum –      

Late last year, we reported on a decision of the D.C. District Court upholding the Department of Defense’s ("DOD’s") authority to apply Federal Ceiling Price ("FCP") limitations to all prescriptions filled on or after January 28, 2008 under the TRICARE Retail Pharmacy Program.  While that decision represented a victory for DoD, the court also criticized DoD’s interpretation that the authorizing statute requires the discount pricing to be implemented through a refund system to the exclusion of other approaches, and the court remanded the implementing regulation back to DoD without vacatur to consider other approaches to implementing FCP pricing.

Although not required under the court order, DoD published a notice in the Federal Register yesterday soliciting additional public comments on its final rule establishing the current refund program (which we summarized when it was promulgated in March 2009), as well as comments on other possible approaches to implementing FCP pricing.  DoD will consider alternatives that are consistent with the Congressional intent and with best business practices, and that are practical to administer.  Comments are due by March 11, 2010.  In the interim, because DoD’s final rule was remanded without vacatur, the current refund program and Pricing Agreements will remain in effect.  It will take unusually persuasive comments to overcome the inertia of a refund program that has now been in effect since May 2009.

By Kurt R. Karst –      

Two recent rulings out of the U.S. District Court for the Eastern District of Pennsylvania stemming from allegations about antitrust violations from the submission of citizen petitions have once again raised the issue of so-called “sham” citizen petitions and, insofar as there are allegations of violation of Section 2 of the Sherman Act, Noerr-Pennington immunity.  In each case – In Re: Flonase Antitrust Litigation and Roxane Laboratories v. Smithkline Beecham – the plaintiffs allege that GlaxoSmithKline, Inc. (“GSK”) submitted a series of “sham” citizen petitions several years ago that delayed and restrained competition for generic versions of GSK’s FLONASE (fluticasone propionate) in violation of competition laws.  And in each case the court denied (here and here) motions from GSK to dismiss the actions.  The underlying competition issues have yet to be decided.  Based on the recent track record of challenging “sham” citizen petitions, however, the plaintiffs in each case have a difficult road ahead. 

Under the Noerr-Pennington doctrine, private entities are immune from antitrust liability in petitioning the government to influence the passage or enforcement of laws, even if the laws they advocate for would have anticompetitive effects.  See Eastern Railroad Presidents Conference v. Noerr Motor Freight, Inc., 365 U.S. 127 (1961); United Mine Workers v. Pennington, 381 U.S. 657 (1965).  Immunity extends to citizen petitions submitted to FDA.  The Noerr-Pennington doctrine is grounded in the First Amendment protection of political speech, and “upon a recognition that the antitrust laws, ‘tailored as they are for the business world, are not at all appropriate for application in the political arena.’” City of Columbia v. Omni Outdoor Advertising, Inc., 499 U.S. 365, 380 (1991) (quoting Noerr, 365 U.S. 127, 141 (1961)).

Noerr-Pennington immunity is not absolute, however.  When petitioning activity “ostensibly directed toward influencing governmental action[] is a . . . sham to cover what is . . . nothing more than an attempt to interfere directly with the business relationships of a competitor[, then] the application of the Sherman Act would be justified.”  Noerr, 365 U.S. at 144.  The sham exception requires that a petition be “(i) ‘objectively baseless,’ and (ii) ‘an attempt to interfere directly with the business relationships of a competitor through the use of the governmental process – as opposed to the outcome of that process – as an anticompetitive weapon.’”  Primetime 24 Joint Venture v. Nat’l Broad. Co., 219 F.3d 92, 100-01 (quoting Prof’l Real Estate Investors, Inc. v. Columbia Pictures Indus., Inc., 508 U.S. 49, 60 (1993)).

In 2009, the U.S. District Court for the Southern District of New York declined to find that a March 2005 citizen petition submitted on behalf of Sanofi-aventis concerning generic versions of ARAVA (leflunomide) was “objectively baseless” and denied the plaintiff’s – Louisiana Wholesale Drug Co., Inc. (“LWD’s”) – Motion for Judgment as a Matter of Law.  The ruling followed a jury verdict concluding that the petition was not “objectively baseless.”  

LWD argued that the ARAVA petition is a prime example of a sham citizen petition.  In the petition, Sanofi-aventis requested that:

(1) if an ANDA applicant is not seeking approval of a 100-mg leflunomide tablet that is bioequivalent to Arava 100-mg tablets, [FDA] require the applicant to perform in viva bioequivalence testing to confirm that five of its 20-mg tablets are bioequivalent to one Arava 100-mg tablet, and (2) the Agency withhold final approval of any leflunomide ANDA that either (a) does not seek approval of a 100-mg leflunomide tablet that is bioequivalent tom Arava 100-mg tablets or (b) does not establish in vivo bioequivalence between five 20-mg lleflunomide tablets and one Arava 100-mg tablet.

FDA uncharacteristically (at least at that time) denied the petition less than six months after it was submitted to the Agency and simulteneously approved ANDAs for generic ARAVA.  FDA ruled that it “will require the labeling for generic leflunomide products to include the labeling approved for the RLD, Arava, conceming the use of a 100-mg loading dose,” and that Sanofi’s concern about certain generic labeling omissions or changes “is unfounded.”

In ruling for Sanofi, the court commented that “[i]n short, there was ample evidence introduced at trial that tended to show that the issue raised by the Citizen Petition was sufficiently novel and unsettled to permit an objectively reasonable drug company to ‘perceive[] some likelihood’ that the FDA would grant the relief requested.”  A pretty high sham citizen petition standard to meet indeed!

Hyman, Phelps & McNamara's Jeffrey N. Wasserstein (co-chief blogger at fdalawblog.net and self-described social media guru) will be speaking on the regulation of social media at the American Conference Institute’s 8th Expert Regulatory Guide to Advertising, eMarketing and Promotions for the Pharmaceutical Industry, taking place in the City of Brotherly Love, (that's Philadelphia, PA) from April 14-April 15, 2010.   Registration materials for the conference can be found here.  Loyal readers of the blog may obtain a $200 discount by using discount code 876L10.S.

By Kurt R. Karst –      

FDA’s ability to force a prescription-to-over-the-counter switch (“Rx-to-OTC switch”) has been hotly contested over the past decade.  The crux of the debate concerning forced Rx-to-OTC switches is whether FDA, absent a New Drug Application (“NDA”) sponsor’s consent, has the authority to force an Rx-to-OTC switch; and if so, on what legal basis.  (Although FDA attempted a forced switch once – almost 30 years ago – when the Agency proposed to switch metaproterenol sulfate metered-dose inhaler drugs from Rx to OTC status under the OTC Drug Review, FDA did not carry through with the switch after extensive adverse comment.)  A little-known FDA response to a citizen petition, however, appears to have settled what FDA believes is its legal basis to effect a forced switch.  But first, some background . . . .

The 1951 Durham-Humphrey Amendments to the FDC Act gave FDA the authority to require that drugs be limited to Rx status when they cannot be used safely for OTC use.  Thus, the underlying presumption (then and now) is that Rx restrictions are the exception, and that if a drug can be used safely and effectively OTC it should be.  The Durham-Humphrey Amendments also amended the FDC Act (§ 503(b)(3)) to state that FDA “may by regulation remove drugs subject to [FDC Act § 505 [(i.e., new drugs)] from the requirements of [FDC Act § 503(b)(1)] when such requirements are not necessary for the protection of the public health.”  FDA’s regulation implementing § 503(b)(3) is codified at 21 C.F.R. § 310.200(b), and states that FDA may approve an Rx-to-OTC switch when Rx dispensing is:

not necessary for the protection of the public health by reason of the drug’s toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, and . . . [t]he drug is safe and effective for use in self-medication as directed in proposed labeling. 

There are two different mechanisms under the FDC Act for FDA to make an Rx-to-OTC switch: (1) FDC Act § 503(b)(3) explicitly provides FDA with the authority to issue a regulation changing the status of an Rx drug to an OTC drug; and (2) the FDC Act grants FDA the authority to approve and reject NDAs. 

FDA’s regulation at 21 C.F.R. § 310.200(b), which implements FDC Act § 503(b)(3), identifies processes for initiating consideration of an Rx-to-OTC switch.  Specifically, a proposal to exempt a drug from Rx-only requirements may be initiated by the FDA Commissioner or by “any interested person” in the form of a sponsor submitting an NDA or by a third party petitioning FDA.  Regardless of who initiates a request for an Rx-to-OTC switch, however, the evidence must demonstrate that the statutory Rx-only dispensing requirements are no longer necessary to protect the public health, and that the drug is safe and effective for use in self-medication as directed in proposed labeling. 

Those opposed to forced switches have argued that FDA can only authorize a switch over the NDA sponsor’s objections following a formal, trial-like administrative process known as an adjudication, and that FDA lacks the authority to force an Rx-to-OTC switch through rulemaking.  (The distinction between rulemaking and adjudication is based on the nature of the decision facing an agency.  Actions pursuant to generalized facts do not require an individual hearing and can be taken according to procedures applicable to rulemaking – either formal rulemaking, informal notice-and-comment rulemaking, or the rarely used negotiated rulemaking.  Actions pursuant to individualized facts require some level of hearing and are classified as an adjudication.)  Moreover, forced switch opponents have argued, among other things, that even if rulemaking is appropriate, FDA cannot use informal notice-and-comment rulemaking, but instead must use formal, hearing-based rulemaking.  

Forced switch proponents have argued, among other things, that the FDC Act expressly authorizes FDA to force a switch following rulemaking – not adjudication – and that FDA is free to undertake any type of rulemaking the Agency deems appropriate, such as informal notice-and-comment rulemaking. 

Over the past decade, FDA has been asked on at least three separate occasions to make a forced switch.  First, in July 1998, WellPoint (Blue Cross of California) submitted a citizen petition to FDA (Docket No. FDA-1998-P-0254) requesting that the Agency convert from Rx to OTC status several antihistamine drugs.  (The WellPoint petition was the subject of a joint meeting of the Nonprescription Drugs Advisory Committee & the Pulmonary – Allergy Drugs Advisory Committee in May 2001.)  Second, in March 2007, FDA was petitioned (Docket No. FDA-2007-P-0056) to force a switch of fexofenadine HCl and cetirizine HCl.  FDA has not substantively responded to either petition.   

Finally, in February 2001, the Center for Reproductive Rights petitioned FDA (Docket No. FDA-2001-P-0123) to force a switch of PLAN B (levonorgestrel) Tablets.  FDA denied the petition in June 2006 “because it did not contain sufficient data to satisfy the statutory and regulatory requirements for an Rx-only to OTC switch for Plan B.”  Moreover,  given the then-pending NDA supplement for OTC PLAN B, FDA refused to allow the petition to “circumvent the [NDA supplement] process to which the sponsor of the drug is entitled.”  Importantly, however, FDA noted in its response that:

Although your petition does not explicitly state that you are requesting FDA initiate notice-and-comment rulemaking, the Act . . . authorizes only two mechanisms for FDA to make an Rx to OTC switch: [informal] notice-and-comment rulemaking and approval of a drug application . . . . You are not yourselves applicants for drug approval, and you are not permitted to submit a supplement to another company’s application.  21 CFR 314.71(a).  Accordingly, your petition can only be construed as a request that we initiate notice-and-comment rulemaking proceedings pursuant to which a rule would be promulgated allowing Plan B and other emergency contraceptives to be made available OTC. [(emphasis added)]

In other words, FDA in its petition decision appears to have determined that informal notice-and-comment rulemaking is the appropriate route to effect a forced switch over an NDA sponsor’s objections, and that administrative adjudication is not necessary. 

By Michelle L. Butler –

This week, the parties in the Winston Laboratories case filed a Stipulation of Dismissal with Prejudice Pursuant to Fed. R. Civ. P. 41(a).  This case involved FDA’s interpretation of the term “affiliate” in its decision to deny Winston a small business waiver of the PDUFA fee for a new drug application.  Given the Court’s prior decision denying the Government’s Motion to Dismiss, it is likely that the parties settled the case on terms favorable to Winston.  We do not yet know how FDA will deal with similar small business waiver determinations going forward, but we will provide updates as information becomes available.

By Kurt R. Karst –      

Late last month, FDA denied a citizen petition submitted by Graceway Pharmaceuticals, LLC (“Graceway”) requesting that the Agency refuse to approve Abbreviated New Drug Applications (“ANDAs”) for generic versions of Graceway’s ALDARA (imiquimod) Cream, 5%, unless such applications contain, among other things, data from bioequivalence studies conducted in patients with each of ALDARA’s approved conditions – actinic keratoses (“AK”), primary superficial basal cell carcinoma (“sBCC”), and external genital and perianal warts/condyloma acuminata (“EWG”) – and pharmacokinetic studies under “maximal use” conditions in patients with EGW and AK.  ALDARA is approved under NDA No. 20-723.

The primary issue raised in the Graceway petition – whether an generic applicant can demonstrate bioequivalence for a multi-indication Reference Listed Drug with a comparative clinical trial in just one indication – was the topic of another citizen petition FDA denied in 2008.  In that case, FDA ruled, in the context of approving ANDAs for generic versions of EFUDEX (fluorouracil) Topical Cream, 5%, which is approved for AK and sBCC, that “even when clinical trials are needed, it has not been the Agency’s policy to require that bioequivalence be shown in every indication if drug release from the dosage form and appearance at the or sites of activity has been demonstrated.”  FDA’s decision was challenged in court, and in September 2009, the U.S. District Court for the Central District of California ruled in FDA’s favor. 

Graceway states in its petition that “[t]he straightforward application of FDA’s reasoning in the Efudex matter mandates that an ANDA for a generic version of Aldara contain data from a bioequivalence study in patients with EGW and a separate study in patients with sBCC.”  FDA disagreed, and concluded that a well-designed study in AK will suffice to show bioequivalence of a generic version of ALDARA:

[T]here is a reasonable scientific basis for concluding, and the Agency has in fact concluded, that the successful demonstration of equivalent drug delivery in AK is sufficient to show bioequivalence.  This conclusion is based on considerations including the following: (a) the site of topical imiquimod action is the same for all three conditions, (b) all three conditions are “related” in that they are responsive to topical treatments, such as imiquimod, that enhance local and cell-mediated immunity, (c) treatment success is dependent upon the induction of an effective host immune response in immunocompetent individuals, and (d) the stratum corneum is the primary barrier to topical drug delivery.

More generally, FDA commented that:

For a drug product with multiple indications, one aspect of appropriate study design is the choice of which indication or indications to study.  It is the Agency’s policy to require only those studies necessary to assess bioequivalence – if bioequivalence can be shown for a multiindication drug with a comparative clinical trial in just one indication, the other indications need not be studied. . . .

[W]hen the site of action is the same for all indications of a multi-indication drug, there is generally no need to conduct a comparative clinical study in more than one of those indications to show bioequivalence.  That is, clinical endpoint data from one indication showing equivalent drug delivery at the site of action are suffcient when all indications share the same site of action.  The question then becomes which indication or indications should be studied.  The answer will depend on the specific product.  For some products there may be a scientific basis for concluding that a study in one indication would be significantly more sensitive or discriminating than a study in any of the other indications, whereas for other products this may not be the case.

Whether Graceway will challenge FDA’s decision in court is unclear.  Regardless, we note that courts have uniformly held that FDA’s bioequivalence determinations fall squarely within the broad discretion of the Agency.

FDA is expected to rule on a second Graceway petition later this month.  In that petition, Graceway requests that FDA not approve any ANDA or 505(b)(2) application for a generic version of ALDARA Cream that substitutes another ingredient(s) for isostearic acid, unless the applicant has demonstrated that any substituted inactive ingredient does not affect the safety of the drug product by providing certain data, and that if such data are from animal or clinical investigations (other than bioavailability and bioequivalence studies), FDA should refuse to approve an ANDA and require the submission of a 505(b)(2) application. 

By Kurt R. Karst & Frank J. Sasinowski –      

We recently reported on the banner year FDA’s Office of Orphan Products Development (“OOPD”) had in 2009, surpassing the 2,000 orphan drug designation mark and designating a near-record 160 products for orphan (i.e., rare) diseases and conditions.  That followed a record 165 designations in 2008, which we reported on here.  As additional information has been made available, however, the 2009 designation figure is tempered by what appears to be a low success rate. 

According to our data (shown in the tables below), OOPD received 250 orphan drug designation requests in 2009, but only granted 160 designations, for a designation rate of 64%.  That is below the historical (cumulative) success rate of 70%, and far below the 2008 success rate of 89%.  To be fair, not all designations submitted in a particular calendar year are acted on in that year.  For example, a designation request submitted in December might not be acted on until February or March of the next calendar year.  And in some cases, it takes a couple of years for OOPD to grant designation because the data and information submitted with an orphan drug designation request are insufficient to support designation at that time, but later-acquired information adequately addresses OOPD concerns.  Nevertheless, the 2009 figure seems to validate a comment we made about the 2008 designation figure: 

It is unclear whether the recent increase in orphan drug designations reflects a shift in OOPD policy, or whether the Office is receiving more designation requests.  Our experience is that the depth and thoroughness of OOPD review has certainly not decreased.  In fact, OOPD seems to be placing a greater emphasis on the scientific rationale and medical plausibility components of an orphan drug designation request than it has in the past.  Thus, we believe the increase in orphan drug designations is largely a function of the quantity of requests OOPD is receiving.    

As orphan drug designation requests continue to stream into OOPD, companies need to be reminded that quality counts, and that OOPD appears to be scrutinizing designation requests more so today than it has in the past.  We’ll see how the 2010 designation figures pan out when we present them next year.

By Kurt R. Karst –      

As we predicted, Massachusetts-based The Medicines Company (“TMC”) has sued the U.S. Patent and Trademark Office (“PTO”) and FDA in connection with the company’s efforts to obtain a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering ANGIOMAX (bivalirudin).  FDA approved ANGIOMAX at 5:18 PM on Friday, December 15, 2000 under New Drug Application (“NDA”) 20-873, and TMC submitted its PTE application to the PTO on February 14, 2001 – 62 days after NDA approval (including the December 15, 2000 date of approval).

The Complaint and Motion for Summary Judgment, filed last week in the U.S. District Court for the Eastern District of Virginia (Alexandria Division), follows the PTO’s January 8, 2010 denial of TMC’s December 2009 Request for Reconsideration (see our previous post here) asking the PTO to employ a “rule of construction” under which the Office would consider the 60-day PTE application submission period at 35 U.S.C. § 156(d)(1) to commence on the first business day after the day the FDA transmits notice of NDA approval of the drug product if that transmittal occurs after normal business hours.  In the case of the PTE application for the ‘404 patent covering ANGIOMAX, that would mean the 60-day period would have begun on December 18, 2000 and the PTE application would have been timely filed within 35 U.S.C. § 156(d)(1).  The lawsuit also follows TMC’s failed attempts (see our previous post here) to get legislation enacted that would permit the PTO to accept late-filed PTE applications.  The ‘404 patent expires on March 23, 2010, but is subject to a 6-month period of pediatric exclusivity that will expire on September 23, 2010.  TMC claims that if a PTE were applicable to the ‘404 patent, it would extend the patent expiration date until December 2014. 

TMC’s Complaint alleges that the PTO’s denial of the company’s PTE application for the ‘404 patent and FDA’s decision regarding PTE application timeliness violated the Administrative Procedure Act (5 U.S.C. § 706(2)(A)).  Specifically, TMC alleges that:

The PTO’s denial of [TMC’s] application for a patent term extension, the PTO’s refusal to reconsider that determination, and the PTO’s and the FDA’s determinations that MDCO’s application for an extension of the term of [the ‘404 patent] was not timely filed under 35 U.S.C. § 156(d)(1) misinterpreted § 156, failed to provide adequate explanations for their conclusions, failed to respond to significant arguments raised by [TMC], reflected a misapprehension of agency authority under § 156, and misinterpreted agency regulations and, relevant case law.

Among other things, TMC argues that there is a discrepancy in how FDA (and the PTO) treats the dates of NDA receipt and approval:

[U]nder the government’s approach to [the PTE] statute, an application for approval of a new drug received by the FDA after business hours is deemed to be filed on the following business day.  By contrast, when a [NDA] is approved after business hours, the government deems the approval to have occurred on the same business day and takes the position that this day starts the 60-day period for filing a patent term extension application.  Despite this inconsistency, the PTO somehow concluded that its interpretation was mandated by statute and regulation.

As a result, TMC alleges that “[t]he PTO’s decision is not merely arbitrary and capricious; it is profoundly unfair and undermines the remedial design of the patent term restoration system.” 

TMC requests the court to vacate and set aside various PTO and FDA deicisions made in connection with the ‘404 patent PTE application, to declare that ANGIOMAX “received permission . . . for commercial marketing or use” within the meaning of 35 U.S.C. § 156(d)(1) no earlier than December 18, 2000 and that the company’s PTE application was timely filed, and to order the PTO to extend the ‘404 patent until December 2014.  TMC also requests the court to grant expedited consideration of the case and to “grant any preliminary injunctive relief necessary to maintain the status quo pending resolution of this case.” 

For heavily-regulated companies, such as those regulated by the Food and Drug Administration, it is common for companies to seek advice from in-house and outside counsel regarding whether proposed conduct would violate the law. It has become increasingly popular for federal prosecutors to target the company's actions that related to the legal advice that counsel previously rendered to a company or individual who is under criminal investigation or has actually been indicted.  A recently published article in the January/February 2010 issue of FDLI Update discusses the benefits and risks of a defendant presenting the testimony of a lawyer who previously provided legal advice.

By Kurt R. Karst –      

Is an ANDA applicant who cites a 505(b)(2) drug as the Reference Listed Drug (“RLD”) required to certify to Orange Book-listed patents covering the 505(b)(2) RLD drug as well as to Orange Book-listed patents covering the original listed drug approved under an NDA relied upon by the 505(b)(2) applicant for approval of its application?  No, according to FDA in a recent decision responding to a 2009 citizen petition submitted by Osmotica Pharmaceutical Corp. (“Osmotica”) involving Venlafaxine HCl Extended-Release Tablets. 

In May 2008, FDA approved Osmotica’s 505(b)(2) application for Venlafaxine HCl Extended-Release Tablets based on the Agency’s previous findings of safety and effectiveness for EFFEXOR XR Extended-Release Capsules and Osmotica’s bioequivalence data.  EFFEXOR XR and Osmotica’s Venlafaxine HCl Extended-Release Tablets share two common Orange Book patent listings; however, there are several other Orange Book-listed patents covering EFFEXOR XR that are not listed for Osmotica’s drug product.  At the time of approval of Osmotica’s drug product, there was a pending ANDA based on an approved suitability petition for Venlafaxine HCl Extended-Release Tablets.  As we previously reported, FDA determined in November 2008 (in response to a citizen petition) that Osmotica’s Venlafaxine HCl Extended-Release Tablets drug product became the RLD and that any generic applicant with a pending ANDA for Venlafaxine HCl Extended-Release Tablets would be required to identify Osmotica’s drug product as the RLD and to submit a new ANDA with appropriate bioequivalence information. 

In July 2009, Osmotica once again petitioned FDA requesting that the Agency, among other things:

Clarify that when an ANDA applicant relies on an RLD, the approval of which was pursuant to a [NDA] that is described in section 505(b)(2) of the Act . . . , and that 505(b)(2) application itself relied on an earlier approved NDA, the ANDA applicant must certify not only to the Orange Book-listed patents that cover the 505(b)(2) listed drug on which it directly relied, but also to the Orange Book-listed patents that cover the earlier approval on which the 505(b)(2) applicant relied.

By way of background, FDA’s long-standing policy has been to require that an ANDA that is submitted against another ANDA that was itself submitted and approved pursuant to a suitability petition contain an appropriate certification with respect to any Orange Book-listed patents covering the original RLD NDA relied on by the ANDA suitability petition applicant for approval. 

In 2002, FDA was first faced with the question of whether a generic applicant must certify to Orange Book-listed patents covering the  original NDA on which the approval of the generic applicant’s proposed RLD was based in the context of ANDA No. 75-250 for Prednisolone Sodium Phosphate Oral Solution.  In that case, FDA approved WE Pharmaceuticals, Inc.’s (“WE’s”) ANDA on January 4, 2002, but quickly rescinded that approval on January 17, 2002 “in light of the patent certification requirements of the [FDC] Act.”  According to FDA:

The ANDA submitted by [WE] does not meet the statutory requirements for approval, and did not do so at the time it was mistakenly approved by FDA.  The mistake arose from the status of the WE ANDA as a subsequent ANDA to that approved for Ascent Pharmaceuticals Orapred (ANDA 75-117).  Both your ANDA and the Ascent ANDA are for drug products for which a suitability petition was approved for a change to a listed drug (87P-0237/CP1).  The listed drug referenced in the approved suitability petition is Celltech Pharmaceuticals, USA’s (Celltech) Pediapred (NDA 19-157).  The listed drug product referenced in ANDA 75-250, by recent amendment, was Ascent’s Orapred, which has no listed patent protection.  Pediapred is subject to patent protection that expires on December 22, 2002: U.S. Patent No. 4,448,774 (the ‘774 patent).

Although the Agency considers Ascent’s Orapred to be the [RLD] for bioequivalence purposes, this does not obviate the need for WE to provide a patent certification and notification to the holder of the original listed drug upon which the approved suitability petition was based. [(emphasis added)] 

FDA later approved ANDA No. 75-250 after WE amended its pending ANDA to include a certification with respect to the Orange Book-listed patents covering Celltech’s PEDIAPRED and after WE and Celltech reached a settlement agreement concerning those patents.    

Following FDA’s determination, the Agency amended the Orange Book Preface in 2003 to include the following passage:

Patent Certification(s) Reference Listed Drug based upon a suitability petition.  An [ANDA] that refers to a [RLD] approved pursuant to a suitability petition must demonstrate that the proposed product is bioequivalent to the RLD, and it must include appropriate patent certification(s) and an exclusivity statement with respect to the listed drug which served as the basis for the approved suitability petition. [(emphasis added)]

Subsequent editions of the Orange Book have included this statement.  And in the 28th edition (2008), the statement was expanded to state:

Patent Certification(s) Reference Listed Drug based upon a suitability petition.  An [ANDA] that refers to a [RLD] approved pursuant to a suitability petition must demonstrate that the proposed product is bioequivalent to the RLD, and it must include appropriate patent certification(s) and an exclusivity statement with respect to the listed drug which served as the basis for the approved suitability petition.  This concept also applies to an ANDA applicant that cites a RLD that was based upon an NDA that is still covered by patent(s) and/or exclusivity, e.g. a second RLD that was selected when the in vivo determination of bioequivalence of the original RLD is self evident and the waiver of the in vivo determination of bioequivalence may be granted. [(emphasis added)]

Citing a 2004 FDA citizen petition response concerning Fenofibrate, Osmotica argued that FDA applies an analogous requirement with respect to a 505(b)(2) applicant who seeks to rely on the Agency’s findings of safety or effectiveness for a listed drug that is a 505(b)(2) application that itself relied on a previous 505(b)(1) NDA for approval.  Specifically, FDA stated in 2004 that:

Where a 505(b)(2) application seeks to rely on the finding of safety or effectiveness for a listed drug that is a 505(b)(2) NDA which, itself, relied on a previous finding of safety and effectiveness, the 505(b)(2) applicant should certify to the patents of the 505(b)(2) NDA relied on, as well as to the patents of any underlying NDA on which that approved 505(b)(2) NDA relied for approval. [(emphasis added)]

Given these precedents, Osmotica argued that:

FDA should announce and apply a similar policy here, where the ANDA applicant . . . relies on FDA’s previous findings of safety and effectiveness of a listed drug (Osmotica’s venlafaxine product) that was the subject of  a 505(b)2) application which, itself, relied on a previous finding of safety and effectiveness, namely FDA’s finding of safety and effectiveness of Effexor XR Capsules.

FDA determined otherwise, however, stating that “[t]here is no basis in the Hatch-Waxman statutory scheme and our implementing regulations for requiring an ANDA applicant seeking approval of a ‘duplicate’ of the RLD to provide a patent certification or statement with respect to any patents other than those filed by the NDA holder for the RLD for listing in the Orange Book.”  With respect to FDA’s policy that an ANDA that is submitted against another ANDA that was itself submitted and approved pursuant to a suitability petition must contain an appropriate certification with respect to any Orange Book-listed patents covering the original RLD NDA relied on by the ANDA suitability petition applicant for approval, FDA commented that:

There is a clear regulatory distinction between reliance on an RLD approved for safety and effectiveness under section 505(c) of the Act (i.e., a stand-alone NDA or a 505(b)(2) application) and reference to a petitioned ANDA designated as the RLD for bioequivalence testing. . . .  unlike a 505(b)(2) applicant, an ANDA applicant is not required (or permitted) by statute to file patent information with FDA for listing in the Orange Book.  Thus, a subsequent ANDA applicant that refers to a petitioned ANDA is required to submit an appropriate patent certification or statement for the listed drug identified in the suitability petition upon which the ANDA necessarily relies.  In the absence of this patent certification requirement, a subsequent ANDA applicant could circumvent the patent certification process by submitting an ANDA that references another ANDA and for which no patents can be listed . . . .

And with respect to FDA’s 2004 statement concerning 505(b)(2) applicants, FDA provided a hypothetical situation and commented that:

Although we noted in the Fenofibrate Petition Response that a 505(b)(2) applicant seeking approval for a drug product that relies upon FDA’s finding of safety and/or effectiveness for a drug product approved through the 505(b)(2) pathway ‘should certify to the patents of the 505(b)(2) NDA relied on, as well as to the patents of any underlying NDA on which that approved 505(b)(2) NDA relied for approval’ . . . this was not the situation at issue in the Fenofibrate Petition.  We subsequently have required an appropriate patent certification or statement to an ‘underlying NDA’ only if the subsequent 505(b)(2) applicant specifically relied for approval on the drug product approved in the underlying NDA. . . .” (italics in original; bold italics added).

By Ricardo Carvajal & Diane B. McColl –

In the fourth and most recent draft of the framework of its Animal Feed Safety System (“AFSS”), FDA provides a comprehensive overview of the system and of the significant gaps in that system that FDA intends to address (the AFSS is “FDA’s program for animal feed aimed at protecting human and animal health by ensuring production and distribution of safe feed,” and it covers both feed for food-producing animals and pet food).  FDA’s task is daunting, as illustrated by this partial list of items on FDA’s to-do list:

• In accord with the FDA Amendments Act of 2007 (“FDAAA”), FDA’s Center for Veterinary Medicine (“CVM”) intends to establish feed ingredient standards and definitions through notice-and-comment rulemaking.  Before enactment of the FDAAA, FDA had planned to establish a policy recognizing the acceptability of ingredients defined in the Association of American Feed Control Officials’ (“AAFCO”) Official Publication.

• CVM plans to develop process control regulations (e.g., HACCP) to address “feed safety issues associated with the manufacture, packaging, storage, and distribution of non-medicated feed ingredients and mixed feed” (such controls are already in place for medicated feed).

• CVM intends to modernize the GMP regulations for medicated feeds.

• As required by the FDAAA, CVM plans to issue a regulation that sets standards for the provision of nutrition and ingredient information on the label of pet foods.

The draft also confirms that CVM plans to start a pilot program to process voluntary notifications of self-determinations of Generally Recognized as Safe (“GRAS’) status for animal feed and pet food ingredients. An Ingredient Safety Team has been created in CVM’s Division of Animal Feeds to review the GRAS Notices. CVM's pilot GRAS Notice program is expected to commence upon publication of a forthcoming Federal Register notice, which we understand will explain the differences between the CVM GRAS Notice program and the Center for Food Safety and Applied Nutrition GRAS Notice program for human food ingredients.

By Kurt R. Karst –      

Now that we are a little more than six years after the December 8, 2003 enactment of Title XI of the Medicare Modernization Act (“MMA”), which, among other things, amended the FDC Act to create a new 180-day exclusivity regime for generic drugs – and as we patiently wait for FDA to issue proposed regulations to implement the forfeiture provisions, as well as a decision from the D.C. Circuit in the generic COZAAR/HYZAAR 180-day exclusivity litigation – we thought it would be a worthwhile exercise to take stock of the cases in which FDA has made a determination about 180-day exclusivity forfeiture. 

The MMA added six 180-day exclusivity forfeiture provisions at FDC Act § 505(j)(5)(D)(i).  Based on our research, FDA has made a total of 13 forfeiture decisions since 2003, with most (10) of those decisions concerning a first applicant’s failure to obtain tentative approval within 30 months of ANDA submission (FDC Act § 505(j)(5)(D)(i)(IV)).  However, we note that of these 10 decisions, 5 of them are so-called “punts” in which FDA did not make a formal forfeiture determination at the time of ANDA approval and stated it would do so only if another applicant becomes eligible for approval within 180 days after exclusivity is triggered.  None of these determinations were affected by a citizen petition.  (Congress clarified FDC Act § 505(j)(5)(D)(i)(IV) in the 2007 FDA Amendments Act, in which it provided that for an applicant eligible for 180-day exclusivity, if “approval of the application was delayed because of a 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)).)  In addition, there has been one case in which tentative approval was not obtained within 30 months of ANDA submission, but FDA determined that exclusivity was not forfeited because of a change in or review of ANDA approval requirements – ANDA No. 77-532 (Acarbose Tablets, 25 mg, 50 mg, and 100 mg); FDA Letter Decision (FDA ruled “that a change in bioequivalence requirements resulted in a delay in obtaining a tentative approval” and did not result in a forfeiture under FDC Act § 505(j)(5)(D)(i)(IV)).  In the Acarbose case, altough a citizen petition was submitted to FDA, because the petition was submitted after the date that was 30 months after ANDA submission, it did not implicate FDC Act § 505(q)(1)(G). 

Of the 3 remaining decisions, 2 of them (both litigated) are under the failure to market provisions (FDC Act § 505(j)(5)(D)(i)(I)) and one is under the withdrawal of application provision (FDC Act § 505(j)(5)(D)(i)(II)).  There do not appear to be any decisions with respect to 3 forfeiture provisions – amendment of certification (FDC Act § 505(j)(5)(D)(i)(III)), agreement with another applicant (FDC Act § 505(j)(5)(D)(i)(V)), expiration of all patents (FDC Act § 505(j)(5)(D)(i)(VI)).  The table below summarizes FDA’s forfeiture decisions by year and type.

Information on each of the 180-day exclusivity forfeiture decisions in the table above is provided below.

Failure to Market (FDC Act § 505(j)(5)(D)(i)(I)) – 

• ANDA No. 77-847 – Dorzolamide HCl, 2%; Timolol Maleate, 0.5%, Ophthalmic Solution (October 28, 2008); FDA Letter Decision

• ANDA No. 77-532 – Acarbose Tablets, 25 mg, 50 mg, and 100 mg (May 7, 2008); FDA Letter Decision

Withdrawal of Application (FDC Act § 505(j)(5)(D)(i)(II)) – 

• Guaifenesin Extended-Release Tablets, 600 mg and 1.2 gm (FDA Paragraph IV List notation added to June 15, 2009 list update)

Amendment of Certification (FDC Act § 505(j)(5)(D)(i)(III)) – None

Failure to Obtain Tentative Approval (FDC Act § 505(j)(5)(D)(i)(IV)) – 

Actual Forfeiture

• ANDA No. 77-461 – Nateglinide Tablets, 60 mg and 120 mg (September 9, 2009); FDA Letter Decision 

• ANDA No. 78-267 – Norethindrone Acetate, 0.02MG; Ethinyl Estradiol, 1 mg  (September 1, 2009)

• ANDA No. 77-170 – Cetirizine HCl, 5 mg; Pseudoephedrine HCl, 120 mg Extended-Release Tablets (February 25, 2008)

• ANDA No. 77-219 – Irinotecan HCl Injection, 20 mg/mL (February 20, 2008)

• ANDA No. 77-631 – Cetirizine HCl Chewable Tablets, 5 mg and 10 mg (January 11, 2008)

180-Day “Punt”

• ANDA No. 78-804 – Aspirin, 25 mg; Dipyridamole, 200 mg Extended-release Capsules (August 14, 2009)

• ANDA No. 78-104 – Triamcinolone Acetonide Nasal Spray, 0.055 mg (July 30, 2009)

• ANDA No. 78-115 – Carbamazepine Extended-Release Tablets, 100 mg, 200 mg, 400 mg) (March 31, 2009)

• ANDA No. 77-527 – Drospirenone, 3 mg; Ethinyl Estradiol, 0.03 mg Tablets (May 9, 2008)

• ANDA No. 76-969 – Metoprolol Succinate Extended-Release Tablets, 25 mg, 50 mg, 100 mg, 200 mg (July 31, 2006)

Agreement with Another Applicant, the Listed Drug Application Holder, or a Patent Owner (FDC Act § 505(j)(5)(D)(i)(V)) – None

Expiration of All Patents (FDC Act § 505(j)(5)(D)(i)(VI)) – None

Hyman, Phelps & McNamara, P.C.’s Josephine Torrente will be co-chairing and speaking at ACI’s upcoming two-day Risk Evaluation and Mitigation Strategies Conference.  Ms. Torrente will be presenting on post-marketing safety requirements and applicants’ obligations under FDAAA.  The conference is scheduled for April 19-20 at the Carlton on Madison in New York City.  Registration information is available here.  FDA Law Blog readers get a discount by using the code “FDA Law” when registering.

By James R. Phelps –

By a series of treaties, the nations of the world have given the United Nations (“UN”) a significant role in the development of systems of regulation of substances, including vitally needed medicines, that might be abused.  The World Health Organization (“WHO”) provides the medical and scientific recommendations for control of these medicines that the UN will make, and which the nations are committed to follow.  So the UN decisions concerning these substances have very real consequences and the WHO recommendations are critical to the process.

The WHO review of substances for potential regulation is in the hands of expert committees that make recommendations that the agency usually accepts without change.  Last week the executive board of WHO accepted a new set of guidelines – lugubriously called “Guidance on the WHO review of psychoactive substances for international control: proposed revision” – that those committees will use in arriving at their recommendations.  This is an important development.

The new guidelines direct WHO to assure that the committees use peer-reviewed reports in their deliberations.  They provide that interested parties will have an opportunity to participate in the process to present data.  They also provide that WHO will make the reports and recommendations of the committees available for public review.  In short, the new guidelines are a significant step toward ensuring a comprehensive review of substances that may be subject to international control and creation of the kind of processes and protections that are found in the U.S. Administrative Procedure Act. 

Adoption of these new guidelines helps to improve the ability of WHO to discharge its duties with a firmer scientific and medical base.

Members of this firm actively participated in development of the guidelines.