By Ricardo Carvajal & John R. Fleder –

On April 17, 2009, DOJ’s Office of Information Policy (“OIP”) issued guidance to federal agencies on President Obama’s FOIA Memorandum of January 21st and Attorney General (“AG”) Holder’s subsequent FOIA March 19th guidelines.  The President’s FOIA memorandum directed all agencies to administer the FOIA with a “clear presumption” in favor of disclosure.  In his subsequent guidelines, the AG encouraged agencies to make discretionary disclosures and avoid withholding information simply because it is legally possible.  In addition, the AG emphasized that agencies must consider whether partial disclosures can be made in the case of records that cannot be fully disclosed.  The AG’s guidelines also noted that DOJ will defend an agency’s denial of a FOIA request only if:

(1) the agency reasonably foresees that disclosure would harm an interest protected by one of the statutory exemptions, or
(2) disclosure is prohibited by law.

The AG’s guidelines explicitly rescinded AG Ashcroft’s FOIA memorandum of October 2001, which provided that DOJ would defend denials “unless they lack a sound legal basis or present an unwarranted risk of adverse impact on the ability of other agencies to protect other important records.”

OIP’s guidance describes the combined impact of the President’s Memorandum and the Attorney General’s guidelines as a “sea change in the way transparency is viewed across the government.”  The guidance sets out five points that are considered key to realizing the President’s directive to “usher in a new era of open government”:

(1) agency personnel “must alter their mind set” to “view all FOIA decisions through the prism of openness”;
(2) records should be reviewed “with a view toward determining what can be disclosed, rather than what can be withheld”;
(3) “information should not automatically be withheld just because an exemption technically or legally might apply”;
(4) where full disclosure is not possible, agencies should take reasonable steps to release both information that is nonexempt and information that, even though exempt, can be discretionarily released;
(5) records cannot be withheld to avoid embarrassing public officials, prevent the revelation of errors and failures, or “because of speculative or abstract fears.”

The OIP’s guidance makes clear that it will still be appropriate to withhold certain information to prevent harm to national security, personal privacy, and law enforcement interests, and that certain types of information are required to be withheld by other legal authorities (e.g., trade secrets and confidential commercial information under the Trade Secrets Act).

According to the OIP guidance, “[t]here is no doubt that records protected by Exemption 5  hold the greatest promise for increased discretionary release.”  Exemption 5 provides for the discretionary withholding of “inter-agency or intra-agency memorandums or letters which would not be available by law to a party other than an agency in litigation with the agency.”  It encompasses the deliberative process privilege, the attorney work-product privilege, and the attorney-client privilege.  Records covered by the deliberative process privilege (where government officials frequently discuss and debate what course of action they should take with regard to important government decisions) are the type of records that could be most affected by the guidance in terms of a new policy of openness and disclosure.

It is too soon to know what effect the OIP guidance will have on FDA’s information disclosure policies and practices.  However, the timing of the issuance of the President’s FOIA Memorandum, together with the prompt publication of the AG’s guidelines and OIP’s guidance, suggest that the issue of increased transparency is one of considerable importance to the new Administration.

By William T. Koustas –

On April 20th, the Federal Trade Commission ("FTC") announced that it has brought, and at the same time tentatively settled, charges of false advertising brought under the FTC Act against Kellogg, the world’s largest cereal maker.  The FTC accused Kellogg of falsely asserting that Frosted Mini-Wheats are “clinically shown to improve kids’ attentiveness by nearly 20%.”  Kellogg also asserted that children who eat Mini-Wheats experienced a 20% increase in attentiveness compared to children who ate no breakfast.  According to the FTC, the study Kellogg cited for substantiation of its claim shows that only about one in nine children who ate Mini-Wheats improved their attentiveness by 20% or more.  In comparison with children who ate no breakfast, children who ate Mini-Wheats were slightly less than 11% more attentive on average, with very few children actually being 20% more attentive.  

The proposed settlement Kellogg has agreed to consists of two major components: (1) prohibiting Kellogg from making similar claims regarding Frosted Mini-Wheats, or any of its cereals and snacks unless the claims are substantiated; and (2) barring Kellogg from misrepresenting the results of future studies regarding its products.  The FTC has unanimously approved the tentative settlement, but will publish it in the Federal Register seeking public comment.

In the late 1970s, the FTC embarked on a crusade against national advertisers of food products for children.  That effort was criticized by some as FTC’s attempt to act as “our Nation's Nanny.”  Will today’s action, under the FTC's new Chairman, Jon Leibowitz, signal a more broad-based effort in this area?

By Kurt R. Karst –      

We previously reported (here and here) on concerns as to whether a company submitting an ANDA (or a 505(b)(2) application) containing the results of an in vivo bioequivalence study must certify on Form FDA 3674 that new Public Health Service Act (“PHS Act”) § 402(j), as added by Title VIII of the FDA Amendments Act (“FDAAA”), applies and that in vivo bioequivalence studies  have to been registered at ClinicalTrials.gov.  PHS Act § 402(j)(1)(A) defines an “applicable drug clinical trial,” which is subject to the databank registration requirements,  to mean, in relevant part, “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .” (emphasis added).  In a recent comment submitted to the National Institutes of Health (“NIH”), the Generic Pharmaceutical Association (“GPhA”) requests that NIH clarify that a clinical endpoint bioequivalence study should not be considered an “applicable drug clinical trial.”

In December 2008, NIH issued a draft document, titled “Elaboration of Definitions of Responsible Party and Applicable Clinical Trial” discussing, among other things, the applicability of the FDAAA Title VIII requirements to bioequivalence studies.  The draft “elaborations” document was updated in March 2009 to clarify that it “represent[s] the [NIH’s] current thinking on this topic.” According to the draft document:

In the agency’s view, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) is considered to be a controlled clinical investigation. In this case, the control generally would be the previously approved drug product.

Although a bioequivalence study is a controlled clinical investigation, the draft guidance goes on to note that:

Under certain circumstances, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) will be considered to be a Phase 1 clinical investigation under 21 CFR § 312.21 for purposes of determining whether a particular clinical trial is an “applicable drug clinical trial” under Title VIII of PL 110‐85 (section 402(j)(1)(A)(iii) of the PHS Act).  Although Phase 1 clinical investigations are generally designed to fit sequentially within the development plan for a particular drug, and to develop the data that will support beginning Phase 2 studies, 21 CFR § 312.21(a) does not limit Phase 1 trials to that situation.  Bioequivalence or comparative bioavailability studies that fall within the scope of the studies described in 21 CFR § 320.24(b)(1), (2), and (3) share many of the characteristics of Phase 1 clinical investigations as described in 21 CFR § 312.21(a), and therefore will be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85. However, bioequivalence or comparative bioavailability trials that fall within the scope of 21 CFR § 320.24(b)(4) do not share the characteristics of Phase 1 trials as described in 21 CFR § 312.21(a), and thus would not be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85.

Elaborations Document at 10 (emphasis added).

Bioequivalence studies that fall within the scope of 21 CFR § 320.24(b)(4) and that are not exempt from reporting on ClinicalTrials.gov are generally clinical endpoint studies.  According to an FDA Manual of Policies and Procedures, such studies are typically “applied to dosage forms intended to deliver the active moiety locally, forms that are not intended to be absorbed, or drug products for which traditional pharmacokinetic studies are not feasible,” such as drug products in topical dosage forms. 

In advance of an April 20, 2009 public meeting to solicit input on issues that NIH will consider as it develops regulations to expand the clinical trial registry and results data bank in accordance with FDAAA Title VIII, GPhA submitted a letter to NIH requesting that the agency reconsider its position that a clinical endpoint bioequivalence study is an  “applicable drug clinical trial” that must be registered on ClinicalTrials.gov.  According to GPhA:

We agree with NIH’s determination that most bioequivalence studies are “Phase I” studies and therefore excluded from the “applicable drug clinical trial” definition.  However, we disagree with NIH’s decision to include bioequivalence studies that use clinical endpoints to establish bioequivalence within such definition.  NIH’s position is inconsistent and without scientific merit.  There is no basis to distinguish between bioequivalence studies based solely on the endpoints used to establish bioequivalence.  These studies are not intended to prove the safety or efficacy of a drug product.  In contrast, Section 505(j) states that these studies are only permitted to include information and data sufficient to compare the bioavailability of the reference (i.e., innovator) and test (i.e., generic drug).  ANDA applicants are permitted to establish bioequivalence in a variety of ways, but the end result is always the same—a comparison of the rate and extent to which the active ingredient becomes available at the site of action.  All bioequivalence studies are performed for the same underlying reason and therefore should receive similar treatment under the ClinicalTrials.gov database.  Specifically, they are all “Phase I” studies that are excluded from the definition of “applicable drug clinical trial.”

The GPhA letter also takes issue with a statement in the draft “elaborations” document, which states: 

When a clinical investigation includes sites both within the U.S. (including any territory of the U.S.) and outside of the U.S., if any of those sites is using (for purposes of the clinical investigation) a drug that is subject to section 505 of the FDC Act, then the agency will consider the entire clinical investigation to be an “applicable drug clinical trial,” assuming that it meets the rest of the statutory definition.  A clinical investigation that is being conducted entirely outside of the U.S. (i.e., does not have any sites in the U.S. or in any territory of the U.S.) may be an “applicable drug clinical trial,” depending on where the drug being used in the clinical investigation is manufactured. If the drug is manufactured in the U.S. or any territory of the U.S., and is exported for study in another country under an IND, pursuant to 21 CFR § 312.110, or pursuant to section 802 of the FDC Act, then the drug is considered to be subject to section 505 of the FDC Act or section 351 of the PHS Act (as applicable), and the clinical investigation may be an “applicable drug clinical trial,” if it meets the other statutory criteria.  If the drug is manufactured outside of the U.S. or its territories, the trial sites are all outside of the U.S., and the trial is not being conducted under an IND, then it would not be considered to be subject to section 505 of the FDC Act or section 351 of the PHS Act, and the clinical investigation would not be an “applicable drug clinical trial.”

Elaborations Document at 8 (emphasis added).

According to GPhA, the exemption highlighted above “will disadvantage U.S. companies and provide an incentive to move operations outside of the U.S.”

A videocast of the April 20, 2009 public meeting at which GPhA and several other organizations and firms that have submitted public comment to NIH will present, including PhRMA and BIO, can be viewed here.

By Ricardo Carvajal –      

According to a CVM Animal Feed Safety System update, the CVM Division of Animal Feeds has formed an Ingredient Safety Team that will begin accepting GRAS notification submissions for animal feed ingredients as part of a pilot program starting this summer.  According to the update

The Team will work with other components of CVM to review the notices.  Under the GRAS notification program, a notifier submits a summary of publicly available information in support of its claim that a substance (as described in the notification) should be considered GRAS under specific conditions of its intended use and not be considered a food additive, which requires pre-market approval by FDA. The information supplied by the notifier would address both the safety and utility of the substance. CVM will evaluate the submitted notification to determine whether it provides a sufficient basis for a GRAS determination or whether information in the notification or otherwise available to FDA raises issues that cause the Agency to question whether use of substance in feed, which includes pet food, is GRAS.

It appears that CVM’s program would be similar to the program that CFSAN has been operating for human food ingredients for several years, but CVM would consider “utility” in addition to safety.  At this time it is unclear what CVM means by "utility" and therefore whether consideration of "utility" would be consistent with the statuory definition of general recognition of safety in 21 U.S.C. § 321(s).  We look forward to learning more about the basis for CVM’s consideration of “utility” in the context of GRAS notifications, as well as what CVM ’s criteria for “utility” are.

By Kurt R. Karst –      

FDA’s April 15th decision to approve ANDAs for generic versions of Topiramate Sprinkle Capsules signals a new FDA interpretation of the 180-day generic drug exclusivity provisions of the FDC Act, which were amended in December 2003 under Title XI of the Medicare Modernization Act (“MMA”).  Although Topiramate Sprinkle Capsules is the first drug product approved that is subject to this new interpretation, according to FDA, there are other products that are affected.

Under the pre-MMA version of the statute, 180-day exclusivity was patent-based, such that an ANDA applicant (or different applicants) could be eligible for 180-day exclusivity with respect to different Orange Book-listed patents covering the Reference Listed Drug (“RLD”) if they submitted the first ANDA to FDA containing a Paragraph IV certification to a particular patent.  Pre-MMA 180-day exclusivity is triggered either by first commercial marketing (for all patents), or by a court decision favorable to an ANDA applicant (with respect to a particular patent).  The MMA amended the FDC Act such that the first company to submit an ANDA to FDA containing a Paragraph IV certification to any Orange Book-listed patent covering the RLD – i.e., a “first applicant” – is eligible for 180-day exclusivity.  Post-MMA, 180-day exclusivity is triggered by first commercial marketing of the drug product by any first applicant.  A first applicant can forfeit 180-day exclusivity eligibility under one or more forfeiture provisions created by the MMA. 

The MMA includes – at § 1102(b)(1) – an effective date provision for purposes of deciphering when the pre- or post-MMA 180-day exclusivity regime will apply.  That provision states:

. . . the amendment made by subsection (a) shall be effective only with respect to an [ANDA] filed . . . after [December 8, 2003] for a listed drug for which no [paragraph IV certification] was made before [December 8, 2003].

In explaining this provision, FDA’s October 2004 draft guidance document, titled “Guidance for Industry: Listed Drugs, 30-Month Stays, and Approval of ANDAs and 505(b)(2) Applications Under Hatch-Waxman, as Amended by the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 – Questions and Answers,” stated only that “[w]ith two exceptions, the [MMA] provisions relating to 180-day exclusivity govern only ANDAs filed after the date of the MMA’s enactment (December 8, 2003) that reference a listed drug for which no paragraph IV certification was made in any ANDA before that date.”  This had led some people to believe that the pre-MMA 180-day exclusivity regime would apply only when there was an ANDA pending pre-MMA containing a Paragraph IV certification.  In a “Dear ANDA Applicant” letter FDA issued on April 15th, however, FDA explains that this is not the case, and that while the MMA’s effective date provision at § 1102(b)(1) is ambiguous, the Agency interprets the law such that pre-MMA patent-by-patent 180-day exclusivity applies.  FDA’s letter states, in relevant part, that:

when one or more applications were submitted before December 8, 2003, but the first paragraph IV certification was submitted after December 8, 2003, the statutory effective date provision is ambiguous. . . .  After consideration of the statutory language and the nature of each approach to exclusivity, we have concluded that it is appropriate to apply the pre-MMA statutory 180-day provisions to these applications.

Applying this interpretation to Topiramate Sprinkle Capsules ANDAs, FDA determined that two applicants – Cobalt and Barr – are eligible for 180-day exclusivity as a result of their Paragraph IV certifications to a single Orange Book-listed patent covering the RLD.  Barr submitted the first ANDA to FDA pre-MMA.  That ANDA contained a Paragraph III certification to a patent that has since expired.  After the MMA’s enactment, Cobalt submitted the first ANDA to FDA containing a Paragraph IV certification to that now-expired patent.  Both Cobalt and Barr later amended their ANDAs to include a Paragraph IV certification to a later-listed Orange Book patent covering the RLD, and both companies, as a result of FDA’s interpretation of MMA § 1102(b)(1), are eligible for 180-day exclusivity.

We understand that FDA’s new interpretation could affect a handful (or two) of products for which an ANDA was first submitted to FDA before the MMA’s enactment – even if such ANDA did not include any patent certification (because, for example, there was no patent listed in the Orange Book pre-MMA).  Because FDA’s Paragraph IV Certification List only identifies the date on which an ANDA (that has been received by FDA) containing a Paragraph IV certification was submitted to FDA, it is unclear what products are affected by FDA’s new interpretation.  Hopefully, FDA will devise a method for identifying what drug products are subject to the Agency’s new interpretation.  Absent such identification, an applicant could be under the false impression that the MMA’s 180-day exclusivity regime applies and that it is a first applicant and that another applicant cannot qualify for 180-day exclusivity based on a later-listed Orange Book patent.

By William T. Koustas –      

On April 15th, the Department of Justice announced that the U.S. has entered into a global criminal and civil settlement with Quest Diagnostics Inc. (“Quest”) and its subsidiary Nichols Institute Diagnostics (“NID”).  NID pleaded guilty to a felony charge of misbranding its Advantage Intact Parathyroid Hormone (“PTH”) Assay (“Intact Assay”) in violation of the FDC Act.  The government alleged that NID distributed marketing materials describing the Intact Assay as having “excellent correlation” with the IRMA Assay.  However, the company allegedly was aware the Intact Assay did not produce such correlated results, but instead provided elevated PTH readings.  Under the guilty plea, NID admitted that it “knowingly, intentionally and with intent to mislead, introduce[d] into interstate commerce, and caused the introduction into interstate commerce of the [Intact Assay], that was misbranded.”  NID will pay a $40 million criminal fine.

The civil settlement arose from a whistleblower suit brought under the qui tam provisions of the Federal False Claims Act.  The relator and the government alleged that NID sold PTH assays knowing that they produced erroneous and unreliable results, thus causing clinical laboratories that purchased and used those tests to submit false claims for reimbursement to federal health care programs.  Interestingly, the government also alleged a second “tier” of false claims: the inaccurate results of the tests allegedly caused practitioners to prescribe vitamin D and parathyroidectomies that were not necessary, thereby resulting in the submission of false claims for those products and procedures.  Quest denied the allegations, other than those to which the company pleaded guilty under the FDC Act.  The civil settlement requires Quest and NID to pay $262 million plus interest.  Quest has also agreed to pay $6.2 million to settle state Medicaid claims and to enter into a Corporate Integrity Agreement with the Office of the Inspector General of the Department of Health and Human Services.  The whistleblower will receive approximately $45 million.

By Susan J. Matthees –

Last year we reported that FDA had moved to dismiss a lawsuit alleging that FDA had improperly denied HiFi DNA Tech, LLC’s (“HiFi’s”) petition for reclassification of an HPV nested DNA polymerase chain reaction detection device from Class III to Class II.  The U.S. District Court for the District of Connecticut recently granted FDA’s motion to dismiss the case. 

HiFi had submitted a 510(k) submission for its device, but FDA responded with a letter stating that the device would be classified as a Class III device and thus would require Premarket Approval from FDA.  HiFi responded to this letter with a request that FDA reclassify the device from Class III to Class II, which FDA denied.  HiFi filed a complaint in district court challenging FDA’s action.  

In dismissing the case, the court concluded “that the FDA’s denial of HiFi’s reclassification petition is not ‘arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law.’”  The court found that FDA gave HiFi’s petition a thorough review and responded to each of HiFi’s arguments.  Further, because FDA was interpreting its own statutes and regulations when it made its decision, the court was “especially deferential” of the agency’s decision. 
 

By Kurt R. Karst –      

On April 14, 2009, the Federal Trade Commission (“FTC”) announced that Chairman Jon Leibowitz has appointed six senior new staff members, including former Public Citizen Director David C. Vladeck.  According to the FTC announcement:

David C. Vladeck, who will serve as Director of the Bureau of Consumer Protection, has been a Professor of Law at Georgetown University Law Center, teaching federal courts, government processes, civil procedure, and First Amendment litigation.  He co-directed the Center’s Institute for Public Representation, a clinical law program for civil rights, civil liberties, First Amendment, open government, and regulatory litigation.  Vladeck previously spent almost 30 years with Public Citizen Litigation Group, including 10 years as Director.  He has argued a number of First Amendment and civil rights cases before the U.S. Supreme Court, and more than 60 cases before the federal courts of appeal and state courts of last resort.

Mr. Vladeck (in an essay co-authored with former FDA Commissioner Dr. David Kessler) was critical of the preamble to FDA’s January 2006 prescription drug labeling rule, in which the Agency articulated a pro-preemption policy.  Mr. Vladeck is the second Public Citizen Director to be associated with the federal government.  As we previously reported, in late 2008, Dr. Sidney Wolfe was named a permanent member of FDA’s Drug Safety and Risk Management Advisory Committee. 

By Kurt R. Karst –      

We recently reported on a complaint filed in the U.S. District Court for the District of Columbia by Actavis Elizabeth LLC (“Actavis”) against FDA in which Actavis requested the court to enter an injunction directing FDA to rescind the Agency’s grant of 5-year New Chemical Entity (“NCE”) exclusivity for the ADHD drug VYVANSE (lisdexamfetamine dimesylate) Capsules.  NCE exclusivity was created under Title I of the 1984 Hatch-Waxman Amendments.

Actavis filed the lawsuit after the company submitted and FDA refused to accept an ANDA for a generic version of VYVANSE earlier this year.  FDA’s Orange Book states  that VYVANSE is a Type 1 new molecular entity covered by a period of NCE exclusivity that is scheduled to expire on February 23, 2012.  The VYVANSE labeling states that the drug product is a therapeutically inactive pro-drug that is metabolically converted to dextroamphetamine, a previously approved drug (e.g., ADDERALL).  Actavis states in its complaint that FDA should not have granted 5-year NCE exclusivity for VYVANSE, and that “FDA’s blanket distinction between covalent derivatives and non-covalent derivatives for purposes of awarding NCE exclusivity is inconsistent with the FDCA, its legislative history and FDA’s own regulations.” 

On April 13, 2009, the court granted an Unopposed Motion to Stay Proceedings pending further order of the court.  According to the Unopposed Motion to Stay Proceedings, “Actavis sued FDA . . . before the agency had a meaningful opportunity to consider the arguments that Actavis had raised in its February 6, 2009 brief concerning the application of the governing statute and regulation . . . .”  FDA also stayed its decision refusing to accept Actavis’ ANDA and opened a public docket (Docket No. FDA-2009-N-0184) to solicit comment on the issues raised by Actavis.  FDA anticipates that the docket will close with an Agency decision by September 25, 2009.  Comments are due to FDA by June 1, 2009. 

FDA’s letter soliciting public comment includes a February 6, 2009 letter brief submitted to the Agency on behalf of Actavis supporting the company’s position that FDA erroneously awarded 5-year NCE exclusivity to VYVANSE.  According to that letter brief:

In granting NCE exclusivity to Vyvanse, FDA appears to have applied a blanket rule that all covalent derivatives other than esters should be considered “active ingredients” (or “active moieties”), while non-covalent derivatives should not.  This rigid distinction between covalent and non-covalent derivatives, however, is arbitrary and capricious and contrary to the plain meaning of the statute and its legislative history.  Specifically, [FDC Act §] 505(j)(5)(F)(ii) directs that NCE exclusivity be based on the approval of a new “active ingredient,” which in the context of this provision means a new active moiety.  The active moiety, in turn, is the molecule or ion (or portion thereof) that provides the therapeutic effect at the site of drug action.  FDA’s blanket distinction between covalent derivatives and non-covalent derivatives for purposes of awarding NCE exclusivity is inconsistent with the statute, its legislative history and, indeed, FDA’s own regulations.  Instead, an award of NCE exclusivity should focus on the active moiety, i.e., the molecule or ion (or portion thereof) that provides the therapeutic effect at the site of drug action.

Interestingly, the meaning of the terms “active ingredient” and “active moiety” have also recently been the subject of litigation for purposes of Patent Term Extensions (“PTE”), which were created under Title II of the 1984 Hatch-Waxman Amendments.  As we previously reported, in late March 2009, the U.S. District Court for the Eastern District of Virginia sided with PhotoCure ASA in a lawsuit against the U.S. Patent and Trademark Office (“PTO”), and applied an “active ingredient” interpretation instead of the PTO’s  “active moiety” interpretation with respect to a PTE request for METVIXIA (methyl aminoevulinate hydrochloride).  It seems likely that the PTO will appeal that decision. 

By Ricardo Carvajal –      

The USDA Animal and Plant Health Inspection Service (“APHIS”) will hold a public meeting on April 29 and 30 to foster discussion of  certain issues that were raised during the comment period for its proposed rule on Importation, Interstate Movement, and Release into the Environment of Certain Genetically Engineered Organisms.  The agency has also reopened and extended the comment period for the proposed rule until June 29.  Discussion during the public meeting will focus on:

(1) Scope of the regulation and which [Genetically Engineered (“GE”)]  organisms should be regulated;
(2) Incorporation into APHIS regulations of the Plant Protection Act’s noxious weed authority;
(3) Elimination of notification procedure and revision of the permit procedure;
(4) Environmental release permit categories and regulation of GE crops that produce pharmaceutical and industrial compounds.

As we noted in a prior posting, APHIS hosted a scoping session on March 13 to ferret out additional significant issues that might merit discussion at the public meeting.  No word yet on which additional issues, if any, APHIS considers worthy of inclusion in the agenda for the public meeting.

By Kurt R. Karst –      

Over the past year or so, the U.S. Court of Appeals for the Federal Circuit has addressed the proper jurisdictional scope of the “case or controversy” requirement under Article III of the U.S. Constitution for a court to have jurisdiction in ANDA Hatch-Waxman declaratory judgment actions where a patent covering the Reference Listed Drug is listed in the Orange Book.  These decisions came in the wake of the U.S. Supreme Court’s January 2007 decision in Medimmune, Inc. v. Genentech, Inc., in which the Court ruled that a dispute must be “definite and concrete” and “real and substantial” to support the exercise of a district court’s subject matter jurisdiction, and the Federal Circuit’s March 2007 decision in Teva Pharms. USA, Inc. v. Novartis Pharma. Corp., in which the court, consistent with the Supreme Court’s Medimmune decision, rejected the “reasonable apprehension of imminent suit” test the court had followed for several years, and instead adopted an “all the circumstances” standard for determining when a justiciable controversy for declaratory judgment actions exists. 

In a decision issued earlier this year by the U.S. District Court for the District of Delaware in Dey L.P. and Dey Inc. v. Sepracor Inc. concerning Dey’s ANDAs for generic versions of Sepracor’s XOPENEX (levalbuterol HCl), the court found that Dey’s declaratory judgment action presented a justiciable Article III controversy.  The opinion, which is currently the subject of a motion to stay pending resolution on interlocutory appeal, provides an important precedent on ANDA declaratory judgment jurisdiction actions that fall in between the Federal Circuit’s opinions in Caraco Pharmaceutical Laboratories, Ltd. v. Forest Laboratories, Inc. and Janssen Pharaceutica, N.V. v. Apotex, Inc. 

In one “bookend” decision – Caraco, concerning LEXAPRO (escitalopram oxalate) – the Federal Circuit held that an ANDA applicant’s declaratory judgment action for non-infringement met the Article III “case or controversy” requirement notwithstanding that the patentee had granted the generic applicant a covenant not to sue.  In that case, the Federal Circuit determined that “Forest’s covenant not to sue did not eliminate the controversy between the parties.”  In the other “bookend” decision – Janssen, concerning RISPERDAL (risperidone) Oral Solution – the Federal Circuit dismissed a declaratory judgment action for non-infringement notwithstanding a covenant not to sue, because the “alleged harm of indefinite delay of [ANDA] approval was too speculative to create an actual controversy to warrant the issuance of a declaratory judgment,” and therefore, did not meet the Article III requirement.  Although the factual scenarios presented to the Federal Circuit in Caraco and Janssen were very similar, the point of difference that led the Federal Circuit to rule against declaratory judgment jurisdiction in Janssen was that the ANDA applicant, Apotex, stipulated to the validity, infringement, and enforceability of one Orange Book-listed patent covering RISPERDAL (that was not the subject of the declaratory judgment action).  As a result, according to the Federal Circuit, the potential harm to Apotex changed, in that Apotex eliminated any possibility of going to market until the expiration of that patent even if the company could claim victory in its declaratory judgment action concerning 2 other Orange Book-listed patents. 

In the instant case – Dey – Sepracor listed 6 patents in the Orange Book covering XOPENEX.  One generic applicant, Breath, submitted the first ANDA containing a Paragraph IV certification (with respect to all 6 Orange Book-listed patents), thereby making Breath a “first applicant” eligible for 180-day exclusivity.  Sepracor sued Breath for patent infringement, and the parties later settled the lawsuit.  Under a royalty-bearing license agreed to by the companies, Breath would be allowed to market its generic version of XOPENEX in 2012, prior to expiration of 3 of the 6 Orange Book-listed patents. 

Dey subsequently submitted ANDAs for generic versions of XOPENEX.  Dey’s ANDAs also contained a Paragraph IV certification to all 6 Orange Book-listed patents.  Sepracor sued Dey for patent infringement on 5 of the 6 patents, and Dey brought a declaratory judgment action seeking a declaration of non-infringement on the single patent with respect to which Sepracor did not sue – U.S. Patent No. 6,341,289 (“the ‘289 patent”).  Sepracor then provided Dey with a covenant not to sue on the ‘289 patent, and argued that as a result of the covenant, there is no declaratory judgment jurisdiction and the case should be dismissed because Dey is not under threat of suit.

In finding declaratory judgment jurisdiction, the district court in Dey explained that:

The instant case is intermediate to Caraco and Janssen.  Like Janssen, there appears to be a possibility that if the Court were to recognize declaratory judgment jurisdiction, the primary ANDA filer, Breath, could lose its 180-day exclusivity period.  Specifically, because of the settlement agreement between Breath and Sepracor, Breath may not go to market until August 2012.  If, more than 254 days prior to this Dey were to attain a court judgment of non-infringement or invalidity of Sepracor’s Orange Book patents, Breath’s exclusivity period would be completed entirely before Breath could go to market. 

However, unlike Apotex in the Janssen case, Dey has not precluded itself from going to market prior to the primary ANDA filer.  Indeed, Dey has not, like Breath, agreed to forego marketing its generic until August 2012.  Put another way, in the instant case, the Court finds nothing equivalent to Apotex’s stipulation to the infringement and validity of the [relevant] patent. . . .  Here, . . . Dey has not stipulated to be on equal foot with Breath.  Thus, unlike as in Janssen, if Dey were to prevail on its declaratory judgment action, the sole effect would not be to simply destroy Breath's exclusivity period.  Rather, Dey could also potentially go to market well in advance of August 2012, the earliest date that Breath could go to market under its settlement agreement with Sepracor.  On these facts, the Court finds that the policy objectives of the Hatch-Waxman Act . . . tilt towards granting declaratory judgment jurisdiction.

Sepracor’s Motion for Certification of the Court’s Order and to Stay Proceedings Pending Resolution of Appeal, which is currently before Judge Joseph J. Farnan, Jr., will reportedly be decided on the papers submitted by the parties.  Whatever Judge Farnan decides, this case appears to be destined for an appeal to the Federal Circuit. 

By Kurt R. Karst –      

We previously reported on FDA’s recent drug-based marketed unapproved drug enforcement action concerning certain narcotics.  In that case, FDA issued 9 Warning Letters to companies concerning 14 narcotic drug products, including morphine sulfate, hydromorphone, and oxycodone.  Late on April 9, 2009, FDA announced that the Agency will reverse course to allow the continued marketing and distribution of one of the drug products subject to its enforcement action – morphine sulfate oral solution, 20 mg/ml – on an interim basis due to concerns over a drug shortage.  According to FDA:

The FDA took this action in response to concerns from patients and health care professionals in the palliative care community that the action taken on March 30 would cause a shortage of 20 mg/ml morphine sulfate oral solution. This product is widely used to alleviate pain in terminally-ill patients. The agency has determined that this dosage form is medically necessary, and should remain on the market until an approved alternative becomes available to the patients that need it.

In another announcement made earlier today, FDA stated that the Agency obtained a permanent injunction barring Neilgen Pharmaceuticals Inc. (which reportedly does business as Unigen Pharmaceuticals Inc.) of Westminster, Maryland, its parent company, Advent Pharmaceuticals, Inc., of East Windsor, New Jersey, and two of their officers, from manufacturing and distributing any unapproved, adulterated, or misbranded drugs.  The products subject to FDA’s enforcement action primarily include prescription cough/cold products.  According to FDA’s marketed unapproved drugs website, the Agency’s action against these companies and individuals is FDA’s 17th firm-based action since FDA issued its Compliance Policy Guide in June 2006.  FDA states in its announcement that:

The FDA sought an injunction after the defendants failed to comply with previous warnings and continued to manufacture drugs in violation of federal law.  Multiple FDA inspections of both the Unigen and Advent facilities found that the companies continued to manufacture unapproved new drugs. FDA inspections also revealed numerous and recurring violations of the cGMP requirements for drugs in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act).  Both Unigen and Advent failed to respond adequately to issues raised by the FDA’s inspection findings. 

By Kurt R. Karst –      

We learned earlier today that Michael M. Landa, Esq. was named as FDA’s new Acting Chief Counsel.  Mr. Landa, who will assume his new role on April 13, 2009, has a long history with FDA.  Since July 2004, Mr. Landa has served as Deputy Director for Regulatory Affairs of FDA’s Center for Food Safety and Applied Nutrition.  Between January 2000 and July 2004, Mr. Landa served as FDA’s Deputy Chief Counsel, except that from March 2001 until August 2001, he was Acting Chief Counsel.  Mr. Landa also served in FDA’s Office of the Chief Counsel as the Associate Chief Counsel for Medical Devices, Enforcement and Veterinary Medicine during various periods between 1978 and 1993 before entering private practice.  There is some speculation that once a new Commissioner is installed at FDA, the “Acting” designation will likely be dropped from Mr. Landa’s title.

By Jennifer B. Davis –

The April 9, 2009 Federal Register will contain the official notice of an FDA order requiring manufacturers of 25 types of Class III “preamendments” devices to submit information on such devices, including adverse safety and effectiveness data not already submitted to the agency, by August 7, 2009.  The order also applies to manufacturers of devices marketed based on 510(k) determinations of “substantial equivalence” to the 25 identified preamendments devices.  FDA warns that failure to comply is a prohibited act, and will cause any affected device to be to be misbranded.  The agency also says it “does not anticipate extending the time for submitting the required information,” and “will use its enforcement powers to deter noncompliance.”  FDA intends to use the information submitted to decide the final classification for such devices.

A news release posted on April 8, 2009 on the agency’s website calls the order a “first step towards completing the review of Class III device types predating the 1976 law, as was recommended by the U.S. Government Accountability Office (GAO) in a January 2009 report to Congress.”  The FDA Amendments Act of 2007 ordered GAO to study FDA’s 510(k) process.  The GAO report found that the agency’s process for reclassifying or requiring PMAs for class III devices was incomplete, and recommended completion of that task to ensure the most stringent (PMA) review process for high-risk devices. 

Section 513 of the FDC Act (21 U.S.C. § 360c), added by the Medical Device Amendments of 1976 (“MDA”), requires FDA to classify all devices into one of three risk-based categories:  Class I, Class II, or Class III.  Devices assigned to Class III, representing the highest risk, must obtain premarket approval from the agency before they can be marketed.  21 U.S.C. § 360e(a).  However, under section 515(b)(1) of the Act (21 U.S.C. § 360e(b)(1)), devices initially assigned to Class III, which were marketed prior to the May 28, 1976 enactment of the MDA – so-called “preamendments” devices, do not require submission of a premarket approval application (“PMA”) until after FDA issues a final rule requiring a PMA for that device, or, FDA publishes a final classification placing the device in Class III.  In addition, the statute allows devices introduced to the market on or after May 28, 1976, which can be shown to be “substantially equivalent” to a Class III pramendments device, to be marketed through a 510(k) instead of a PMA unless and until FDA calls for a PMA, or finally classifies the preamendments device in Class III.

As of May 1994, there were approximately 149 preamendments devices  which FDA had initially classified or proposed to classify in Class III.  The agency has since reclassified (into Class I or II), or published a regulation requiring PMA submission for 122 of those devices, leaving 27.  The order to be published in the April 9, 2009 Federal Register addresses the following 25 devices.  (FDA has already initiated the process for the other two devices.)

1. 21 CFR 868.5610 Membrane lung for long-term pulmonary support.
2. 21 CFR 870.3535 Intra-aortic balloon and control system.
3. 21 CFR 870.3545 Ventricular bypass (assist) device.
4. 21 CFR 870.3600 External pacemaker pulse generator.
5. 21 CFR 870.3610 Implantable pacemaker pulse generator.
6. 21 CFR 870.3680(b) Cardiovascular permanent pacemaker electrode.
7. 21 CFR 870.3700 Pacemaker programmers.
8. 21 CFR 870.3710 Pacemaker repair or replacement material.
9. 21 CFR 870.4360 Nonroller-type cardiopulmonary bypass blood pump.
10. 21 CFR 870.5200 External cardiac compressor.
11. 21 CFR 870.5225 External counter-pulsating device.
12. 21 CFR 870.5310 Automated external defibrillator.
13. 21 CFR 872.3640(b)(2) Endosseous dental implant (blade form).
14. 21 CFR 872.3960 Mandibular condyle prosthesis (temporary implant).
15. 21 CFR 876.5540(b)(1) Implanted blood access device.
16. 21 CFR 876.5870 Sorbent hemoperfusion system.
17. 21 CFR 882.5800 Cranial electrotherapy stimulator.
18. 21 CFR 882.5940 Electroconvulsive therapy device.
19. 21 CFR 884.5330 Female condom.
20. 21 CFR 888.3070(b)(2) Pedicle screw spinal system (certain uses).
21. 21 CFR 888.3320 Hip joint metal/metal semi-constrained, with a cemented acetabular component, prosthesis.
22. 21 CFR 888.3330 Hip joint metal/metal semi-constrained, with an uncemented acetabular component, prosthesis.
23. 21 CFR 890.5290(b) Shortwave diathermy (certain uses).
24. 21 CFR 890.5525(b) Iontophoresis device (certain uses).
25. 892.1990 Transilluminator for breast evaluation.
  
Manufacturers of the above-listed devices must, by August 7, submit “a summary of, and citation to, any information known or otherwise available to them respecting the devices, including adverse safety and effectiveness data that has not been submitted under section 519 of the act” (e.g., medical device reports, reports of corrections and removals).  Additional details respecting the format and content for such submissions can be found in FDA’s order.

By Kurt R. Karst –      

Earlier today, FDA announced the approval of Novartis’ combination drug product COARTEM (artemether; lumefantrine) for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least five kilograms.  Accompanying the approval is the first Priority Review Voucher (“PRV”) granted by FDA.  There has been significant debate about the value of a PRV, and any decision by Novartis to sell the PRV will be closely watched.

The FDA Amendments Act of 2007 (“FDAAA”), amended the FDC Act to add § 524 – “Priority Review to Encourage Treatments for Tropical Diseases.”  FDC Act § 524 provides for a transferable priority review program – the so-called “treat and trade” program – in which applicants for certain new drugs and biologics for “tropical diseases” that have received priority review may receive a PRV entitling the holder to a 6-month priority FDA review of another application that would otherwise be reviewed under FDA’s standard 10-month review clock.  The priority review voucher may be used or sold by the company granted the voucher for an application “submitted after the date of the approval of the tropical disease product application.”  FDA recently clarified in a draft guidance document that although FDC Act § 524 allows for only a single actual transfer of a PRV from the original recipient to another sponsor, “contractual arrangements such as the use of an option or transfer of the right to designate the voucher’s recipient could comply with the terms of the statute.” 

The tropical diseases that can qualify an applicant are enumerated in FDC Act § 524(a)(3) and include malaria.  Applicants that use a priority review voucher are required to pay FDA a priority review user fee in addition to other required user fees, and no such fee may be waived, reduced, or refunded.  FDA must establish the amount of the PRV user fee before the beginning of each fiscal year.  FDA may not collect user fees in connection with a PRV for a particular fiscal year until Congress has passed a law appropriating funds for such fees.  Congress has not yet done so for Fiscal Year 2009.

The idea to stimulate tropical disease drug development by offering a voucher system was first proposed in a 2006 Health Affairs article authored by three Duke University professors as an alternative to promoting tropical disease drug development through other incentive mechanisms, such as a patent term extension.  The PRV concept was adopted by Senator Sam Brownback (R-KS), who, along with Senators Sherrod Brown (D-OH) and Joseph Lieberman (I-CT), successfully amended a bill that would eventually become FDAAA. 

In order for a drug product to be eligible for a PRV, four requirements must be met:

(1) The application must be for a listed tropical disease;

(2) The application must be submitted either as a 505(b)(1) NDA or a 505(b)(2) application;

(3) The drug that is the subject of the application must not contain a previously-approved active moiety; and

(4) The application must qualify for a 6-month priority review under FDA’s policies.

FDA’s draft PRV guidance appears to limit PRV availability (and use) to a 505(b)(1) NDA.  According to the draft guidance, to be eligible for a PRV, “[t]he application must be submitted under section 505(b)(1) of the Act” (emphasis added).  However, FDC Act § 524(a)(4) refers more broadly to a “human drug application as defined in [FDC Act] section 735(1)” (emphasis added).  FDC Act § 735(1) identifies 505(b)(1) NDAs and 505(b)(2) applications as “human drug applications.”  Moreover, a 505(b)(2) application is an application submitted under FDC Act § 505(b)(1).  As such, a 505(b)(2) application that otherwise meets the requirements of FDC Act § 524 should also qualify for a PRV.  Indeed, during a December 2008 public hearing concerning additions to the list of tropical diseases identified at FDC Act § 524, FDA noted that 505(b)(2) applications are eligible for PRVs. 

Once an applicant receives a PRV, FDC Act § 524 places certain limitations on its use for another drug product submission, including: 

(1) The application using the PRV must be a 505(b)(1) NDA or a 505(b)(2) application, and is not limited to products for tropical diseases;

(2) At least one year in advance, the sponsor planning to use the PRV must notify FDA of its intent to use the voucher and the date on which the sponsor intends to submit the application;

(3) A sponsor using the PRV must pay an additional user fee to support the review of the application; and

(4) The PRV sponsor may make a one-time transfer of the voucher to another human drug application sponsor; however, “contractual arrangements such as the use of an option or transfer of the right to designate the voucher’s recipient could comply with the terms of the statute.” 

The value of a PRV is untested and unclear.  When the idea of a PRV was first introduced in Congress, it was thought that it “would be worth hundreds of millions of dollars.”  This estimate was presumably based on the 2006 Health Affairs article noted above in which the authors estimated that a PRV may be worth several million dollars.  More recently, BIO Ventures for Global Health, a non-profit organization that has created a website to track the PRV program and to help build a market for the vouchers, stated that “[e]stimates from different sources vary, but many experts place the value of a PRV somewhere between US$50 million and US$500 million.”   

Ultimately, the value of a PRV must be based on two considerations: (1) the prospect of saved approval time; and (2) the anticipated sales of a new drug.  It is difficult  to predict either with any certainty, although some have attempted to do so.