In a surprising and likely controversial decision regarding so-called “Section 340B covered entities,” the U.S. Court of Appeals for the Ninth Circuit in County of Santa Clara v. Astra U.S.A., Inc. recently reversed the U.S. District Court for the Northern District of California’s dismissal of a complaint under Federal Rule of Civil Procedure 12(b)(6) for failure to state a claim.  Applying federal common law of contracts, the court held “that the covered entities are intended direct beneficiaries of these agreements and thus have a right to enforce the agreements’ discount provisions against the Manufacturers and sue them for reimbursement of excess payment,” a controversial stance in the absence of a contractual right to sue or statutory private right of action.

Under § 602 of the Veterans Health Care Act of 1992, Pub. L. No. 102-585, section 340B entities, also known as federally funded medical clinics, may purchase prescription drugs at a discount from drug manufacturers under a standardized agreement – called a Pharmaceutical Pricing Agreement (“PPA”) – between the federal government and drug companies.  The Ninth Circuit court pointed out that the intent underlying § 602 is to “require a manufacturer to extend the same price reduction to a covered entity for a drug or biological as is provided under the Medicaid outpatient drug rebate program.”  Joint Explanatory Statement on H.R. 5193, 138, reprinted in 2002 U.S.C.C.A.N. 4186, 4211. 

In this case, Santa Clara County alleged that it was overcharged for drugs in violation of a PPA.  The Ninth Circuit court reasoned that “[p]ermitting covered entities to sue as intended beneficiaries of the PPA is  . . . wholly compatible with the Section 340B program’s objectives.”  And later, “the section 340B program was created to give covered entities discounts so they could ‘stretch scarce Federal resources as far as possible, reaching more eligible patients and providing more comprehensive services.’”

In its decision, the Ninth Circuit court also found that covered entities who are direct beneficiaries of a PPA may enforce the manufacturers’ ceiling price obligations under the federal common law of contracts and that although the statute mandating the PPA does not create a federal private cause of action, allowing the county’s contract claim to go forward is consistent with Congress’ intent in enacting the legislative scheme.  The Ninth Circuit concluded that the case lies within the conventional competence of the courts and is not within the primary jurisdiction of the Department of Health and Human Services because it does not present a far-reaching question that requires expertise or uniformity in administration. 

By Serafina E. Lobsenz & Jeffrey N. Wasserstein

More than one might guess.  On September 26, 2008, the Government Accountability Office (“GAO”) released a report, titled "Food Safety:  Improvements Needed in FDA Oversight of Fresh Produce."  As the title suggests, the report is somewhat critical in tone, although it does acknowledge FDA’s efforts to address fresh produce safety.  Some observations and conclusions in the report are that: (1) federal spending on food safety oversight has not kept pace with the volume of goods (particularly imports) moving in commerce or the increase in FDA’s other food safety responsibilities; (2) FDA’s science base has eroded to the point where it can not conduct or fund the research needed to collect the data needed to devise appropriate solutions; (3) FDA’s efforts are hampered by its inability to get information from industry; (4) FDA has to cannibalize other programs to fund its fresh produce safety activities; and (5) FDA is in a reactive mode, with much of FDA’s attention being diverted to address counterterrorism and outbreaks of foodborne illness.  The report recommends that FDA focus on its research and information-gathering activities, update its guidance and regulations, and seek additional statutory authorities.

Now for the fun, if disturbing, part of the exercise.  One can substitute “nanotechnology” for “fresh produce/food/food safety” in the preceding paragraph and end up with a series of true statements.  That is a hint to the systemic nature of the challenges facing FDA as it seeks to stay ahead of the curve on issues that range from the seemingly humble (getting a salad to the consumer’s table) to the more exotic (evaluating the safety of an article that crosses the boundaries between drugs, biologics, and devices).  In light of those challenges, it seems a bit curious that GAO would recommend that FDA issue new regulations.  While true that a preventive approach is generally more efficient than a reactive one, it’s not clear how FDA could hope to effectively and efficiently regulate a problem that it does not yet fully understand.  In fact, it was not until October 3, 2008 that FDA announced OMB approval of the Agency’s proposal to survey domestic and foreign FDA-registered food manufacturing and processing facilities to obtain more information about their current manufacturing practices.   

By Ricardo Carvajal

Earlier this week, Senator Sherrod Brown (D-OH) announced the introduction of S. 3633, the “Transparency in Drug Labeling Act.”  The bill, also know as the “COOL Pharmaceutical Bill,” would amend the FDC Act to require Country-Of-Origin (“COO”) labeling on prescription and Over-The-Counter (“OTC”) drug products.

Specifically, the bill would amend FDC Act § 502 so that a prescription drug would be misbranded unless the labeling of such drug bears the following two separate lists:

(1)       The identity of the country of manufacture of each active ingredient of the drug, listed in descending order based on the percentage of the number of active ingredients in the final dosage form manufactured in such countries; and

(2)       The identity of the country of manufacture of each inactive ingredient of the drug, listed in descending order based on the percentage of the number of inactive ingredients in the final dosage form manufactured in such countries.

Similarly, an OTC drug would be misbranded unless the label of such drug bears the following two separate lists:

(1)       The identity of the country of manufacture of each active ingredient of the drug, listed in descending order based on the percentage of the number of active ingredients in such drug manufactured in such countries; and

(2)       The identity of the country of manufacture of each inactive ingredient of the drug, listed in descending order based on the percentage of the number of inactive ingredients in such drug manufactured in such countries.

Sen. Brown has been a champion of COO labeling.  Earlier this year, Sen. Brown reportedly led a successful effort to include mandatory COO labeling for meat and produce in the 2008 Farm Bill.  Also earlier this year, Sen. Brown sent letters to Pfizer and Merck (see July 24, 2008 Pharmalot post) requesting information on the extent to which Pfizer purchases active pharmaceutical ingredients from foreign countries, and how Merck guarantees the safety of pharmaceutical ingredients and its finished drugs.  Sen. Brown has also requested that FDA evaluate drug company outsourcing and its effects on drug safety. 

S. 3633 has been referred to the Senate Health, Education, Labor, and Pensions Committee.  It seems unlikely, given ongoing debate over the economic stabilization package and the upcoming election, that S. 3633 will be passed in the 110th Congress.

By Kurt R. Karst    

Section 920 of the FDA Amendments Act (“FDAAA”) amended the FDC Act to create new § 505(t) – “Database for Authorized Generic Drugs” – that requires FDA to compile and publish a complete list of all authorized generic drugs identified in annual reports submitted to the Agency since January 1, 1999. FDC Act § 505(t) defines an “authorized generic” as a drug listed in FDA’s Orange Book that was approved under FDC Act § 505(c) (i.e., a “full” 505(b)(1) NDA or 505(b)(2) application) and that “is marketed, sold, or distributed directly or indirectly to retail class of trade under a different labeling, packaging (other than repackaging as the listed drug in blister packs, unit doses, or similar packaging for use in institutions), product code, labeler code, trade name, or trade mark than the listed drug.” FDAAA requires that the authorized generic list be updated on a quarterly basis.  FDA first published its authorized generic list earlier this year.  Among other uses, this list is intended to assist the Federal Trade Commission as that agency moves ahead with its study of the competitive effects of authorized generics.

On September 29, 2008, FDA issued a direct final rule, as well as a companion proposed rule, to implement FDAAA § 920.  (If FDA receives any significant adverse comments on the Agency’s direct final rule, then FDA will withdraw the direct final rule and proceed to respond to comments under the proposed rule using the usual notice and comment procedures.  If no significant adverse comments are submitted to FDA, then the direct final rule will become effective on February 11, 2009.  Comments on both rules are due by December 15, 2008.)  Both rules would amend FDA’s regulations to require that NDA holders submit certain information in an annual report regarding authorized generic drugs.

Specifically, the proposals would amend FDA’s regulations at 21 C.F.R. §  314.3 to add the definition of an “authorized generic drug” (the same definition as in FDAAA § 920), and would amend FDA’s postmarketing reporting requirements to add 21 C.F.R. § 314.81(b)(2)(ii)(b) regarding the marketing of authorized generic drugs.  Under the new postmarketing reporting requirements, NDA holders must include information in their annual reports detailing: (1) the date each authorized generic entered the market; (2) the date each authorized generic ceased being distributed; and (3) the corresponding brand name drug.  FDA considers each dosage form and/or strength to be a different authorized generic drug that should be separately listed in an annual report.  Moreover, “[t]he first annual report submitted after implementation of this regulation must provide information regarding any authorized generic drug that was marketed during the time period covered by an annual report submitted after January 1, 1999.”  FDA also notes that when information is included in an annual report about an authorized generic drug, the Agency requires “that a copy of that portion of the annual report be sent to a central office in the agency that will compile the list and update it quarterly.” 

By Kurt R. Karst    

We previously reported (April 25, 2007, May 22, 2007, August 14, 2007) on a trend in policing promotional and advertising claims by FDA’s Division of Drug Marketing, Advertising, and Communications (“DDMAC”), in which DDMAC has focused on ensuring that all claims are supported by substantial evidence and that all safety data are properly presented.  On September 25, 2008, this pattern re-emerged as FDA issued Warning Letters to five manufacturers of Attention Deficit Hyperactivity Disorder (“ADHD”) drug products.  DDMAC’s top concerns?  Promotional statements that broadened the drugs’ claims and overstated their efficacy without the requisite substantial evidence or “substantial clinical experience” to support them.  This dovetails with the caution we issued last year:  that substantial evidence was the “watchword” for companies trying to avoid running afoul of DDMAC.  Interestingly, these five letters target a particular therapeutic class – ADHD products – and for claims made in a range of material, from sales aids to a video featuring Ty Pennington posted on youtube.com.

Specifically, DDMAC sent Warning Letters to the following companies for promotional claims on the following drugs:  (1) Johnson & Johnson, Concerta® extended-related tablets; (2) Novartis Pharmaceuticals Corporation, Focalin XR® extended-related capsules; (3) Shire Development Inc., Adderall XR® capsules; (4) Eli Lilly & Corporation, Strattera®; and (5) Mallinckrodt Inc., Methylin® chewable tablets and oral solution (generic Ritalin).  The alleged FDA violations are broken down as follows:

Concerta^® extended-related tablets

(Johnson & Johnson)

Drug was misbranded under 21 U.S.C. §§ 352(a), 352(n), and 321(n) by promotional claims included on convention panels and a webpage that:

(1) Overstated its efficacy; and

(2) Omitted facts.

Focalin XR^® extended-related capsules

(Novartis)

Drug was misbranded under 21 U.S.C. §§ 352(a) and 352(n) by promotional claims included on a professional slide deck and webpage that:

(1) Overstated its efficacy; and

(2) Broadened its indication.

Methylin^® chewable tablets and oral solution (Mallinckrodt)

Drug was misbranded under 21 U.S.C. §§ 352(a) and 321(n) by promotional claims included on a patient brochure that:

(1) Overstated its efficacy;

(2) Omitted and/or minimized risk information; and

(3) Made unsubstantiated claims, including comparative claims.

Strattera^®

(Eli Lilly)

Drug was misbranded under 21 U.S.C. §§ 352(a) and 321(n) by promotional claims included on a professional sales aid that:

(1) Overstated its efficacy; 

(2) Broadened its indication;

(3) Omitted material fact; and 

(4) Minimized risk information.

(3) Omitted material fact; and 

(4) Minimized risk information.

The conclusion that the companies had overstated the efficacy and broadened the indications of their drugs rested mainly on material that discussed the consequences of not treating ADHD in teenagers and adults.  For example, a Shire web page listed “[d]ifficulties caused by ADHD in adolescence” when left untreated, which included “academic problems,” “difficulty maintaining friendships,” “impulsive behavior,” and sexual promiscuity.  The Agency concluded that the references Shire cited did not support these statements, rendering the claims misleading, because they implied that the drug prevented these ADHD “side effects” without substantial evidence.  In one example, FDA stated that although a study Shire cited examined the “academic and social outcomes in young adults diagnosed with ADHD” it failed to “study the effects of drug treatment on those outcomes.” 

FDA made similar conclusions about the claims made by Eli Lilly, Novartis, and Mallinckrodt about the consequences of untreated ADHD. This begs the question of whether DDMAC is being overly cautious in its review of the claims for this drug class, one company simply pushed the proverbial promotional envelop too far and other companies followed suit, or if DDMAC is clamping down even harder on studies purported to be substantial evidence of promotional claims.  In any event, these Warning Letters serve as another important reminder that DDMAC demands a high level of “substantial evidence” in support of promotional claims. 

By Carrie S. Martin

In response to an urgent request of the European Commission, Health and Consumers Directorate, the European Food Safety Authority ("EFSA") conducted an exposure assessment for biscuits and confectionery contaminated with melamine.  Although milk and milk products originating from China currently are prohibited from importation into the EU, composite foods that contain milk powder originating from China (e.g., biscuits and chocolate) have been imported into the EU.  The exposure assessment released on September 24th concludes that, “in worst case scenarios with the highest level of contamination, children with high daily consumption of milk toffee, chocolate, or biscuits containing high levels of milk powder would exceed the TDI.  Children who consume both such biscuits and chocolate could potentially exceed the TDI by more than threefold.”  “TDI” refers to Tolerable Daily Intake, which is defined as an estimate of the amount of a substance that can be ingested daily over a lifetime without appreciable risk.  Although the exposure assessment notes that “it is presently unknown whether such high level exposure scenarios may occur in Europe,” the conclusions of the safety assessment are likely to intensify actions on the part of government agencies and industry to identify potentially contaminated foods and to further examine the integrity of their supply chains. 

On this side of the Atlantic,FDA’s latest melamine advisory, dated September 26th, alerts consumers to a recall of several instant coffee and milk tea products manufactured in China because of possible contamination with melamine.  The advisory further states that “FDA has broadened its domestic and import sampling and testing of milk-derived ingredients and finished food products containing milk, such as candies, desserts, and beverages that could contain these ingredients from Chinese sources.”  The advisory is silent as to the relevance of EFSA's exposure assessment to the U.S. population.

By Ricardo Carvajal

Yesterday, the U.S. Senate passed S. 3560, the “QI Program Supplemental Funding Act of 2008.”  Section 4 of the bill would amend the FDC Act to add new subsection 505(v) – “Antibiotic Drugs Submitted Before November 21, 1997” – to create Hatch-Waxman benefits for so-called “old” antibiotics.  “Old” antibiotics are antibiotic active ingredients (and derivatives of such ingredients) included in an application submitted to FDA for review prior to November 21, 1997, the date of enactment of the FDA Modernization Act (“FDAMA”).  The 1984 Hatch-Waxman Amendments excluded antibiotic drugs, which were then approved under FDC Act § 507, from the Act’s patent and non-patent market exclusivity provisions (except for the availability of a patent term extension).

FDAMA repealed FDC Act § 507 and required all NDAs for antibiotic drugs to be submitted under FDC Act § 505.  FDAMA included a transition provision declaring that an antibiotic application approved under § 507 before the enactment of FDAMA would be considered to be an application submitted, filed, and approved under FDC Act § 505. 

Congress created an exception to this transition provision.  FDAMA § 125(d)(2) exempts certain applications for antibiotic drugs from those provisions of § 505 that provide patent listing, patent certification, and market exclusivity.  Specifically, FDAMA § 125(d)(2) exempts an antibiotic application from Hatch-Waxman benefits when “the drug that is the subject of the application contains an antibiotic drug and the antibiotic drug was the subject of an application” received by FDA under § 507 of the FDC Act before the enactment of FDAMA (i.e., November 21, 1997). 

Thus, applications for antibiotic drugs received by FDA prior to November 21, 1997, and applications submitted to FDA subsequent to November 21, 1997 for drugs that contain an antibiotic drug that was the subject of an application received by FDA prior to November 21, 1997 are within the FDAMA § 125(d)(2) exemption and are not currently eligible for Hatch-Waxman benefits.  Applications for antibiotic drugs not subject to the FDAMA § 125(d)(2) exemption – so-called “new” antibiotics – are eligible for Hatch-Waxman benefits.  A 1998 FDA guidance document explains the effects of FDAMA § 125 in greater detail.  On January 24, 2000, FDA published proposed regulations in the Federal Register that include a list of “old,” pre-FDAMA antibiotic drugs not subject to Hatch-Waxman benefits.  FDA has not yet promulgated final regulations.  In addition to the specific chemical substances listed, the list also includes “‘any derivative’ of any such [listed] substance, such as a salt or ester of the [listed] substance.”

S. 3560, if passed by the U.S. House of Representatives (as widely anticipated) and signed into law, would effectively undo FDAMA § 125.  Under the bill, for those antibiotic drugs approved before November 21, 1997, a sponsor can obtain 3-year exclusivity for a new condition of use.  For those antibiotic drugs submitted before November 21, 1997, but not approved, a sponsor may elect to be eligible for 3-year exclusivity, 5-year exclusivity, or a patent term extension (provided the applicable legal and regulatory requirements are met).  The bill would also make the Hatch-Waxman Amendments fully applicable to those antibiotic drugs subject to new FDC Act § 505(v).  Finally, the bill includes three “transition provisions.”   Those provisions: (1) require antibiotic drug NDA sponsors to submit to FDA for Orange Book listing information on applicable patents within 60 days of enactment of S. 3560; (2) require FDA to list those patents in the Orange Book not later than 90 days after the enactment of S. 3560; and (3) create “fist applicant” status (for 180-day exclusivity purposes) for each ANDA applicant that not later than 120 dates after enactment of S. 3560 amends a pending application to contain a Paragraph IV certification to a newly listed antibiotic drug patent.  A summary of the bill is available here. 

Section 4 of S. 3560 is not new.  It was included in the Staff Agreement version of the FDA Amendments Act (§ 1111), but due to cost concerns was removed immediately before passage of the bill in the House of Representatives.  Also, earlier this year, there was a failed attempt to add the provision to the Animal Drug User Fee Amendments of 2008 as part of a technical corrections package.

By Kurt R. Karst 

UPDATE:

• President Bush signed S. 3560 into law on October 8, 2008 – Pub L. No. 110-379.   

We previously reported that it has been unclear whether a company submitting an ANDA 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 the studies have been registered at ClinicalTrials.gov.  That is, it has been unclear whether an in vivo bioequivalence study is an “applicable drug clinical trial” subject to the PHS Act § 402(j) databank registration requirements.  New PHS Act § 402(j)(1)(A) defines an “applicable drug clinical trial” to mean “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .” 

Under PHS Act § 402(j), the responsible party of an “applicable drug clinical trial” must submit to the National Institutes of Health certain required information for inclusion in the clinical trial data bank at ClinicalTrials.gov.  Currently, only descriptive information about the trial design and enrollment is required to be registered at ClinicalTrials.gov; however, certain results of those studies will also be required to be posted within the next few years.  Under FDC Act § 301(jj), as amended by FDAAA, the failure to submit a certification, knowingly submitting a false certification, failing to submit required clinical trial information to ClinicalTrials.gov, and submitting false or misleading information to ClinicalTrials.gov is a prohibited act subject to a new civil monetary penalties provision, as well as to other enforcement sanctions under the FDC Act.   

Earlier this month, the Generic Pharmaceutical Association (“GPhA”) sent a letter to Representative John Dingell (D-MI) expressing concern “that FDA will incorrectly interpret the statute to include bioequivalence studies as ‘applicable drug clinical trials,’” and strongly urging that Congress “amend the definition of ‘applicable drug clinical trial’ at PHS Act § 402(j)(1)(A)(iii) to specifically exclude bioequivalence studies.”  According to GPhA:      

Congress passed FDAAA § 801 to give physicians and consumers greater access to the safety and efficacy data generated on drug products.  Indeed, in large part, FDAAA § 801 came about because of the belief that pharmaceutical companies did not always make public all available safety or efficacy data regarding their drug products.  Proponents often cited to Vioxx® as an example of a drug where public access to additional, available safety or efficacy data could have been important to physicians and consumers.  Importantly, bioequivalence studies, which are not studies of safety and effectiveness, were never mentioned during Congress’ consideration of FDAAA § 801, or in any of the predecessor bills to this legislation going back to the 108th Congress.  Instead, the clinical trial registration requirements were explicitly limited to studies of “safety and effectiveness” . . . .  [B]ioequivlence studies do not generate new or additional meaningful safety or effectiveness information about a drug product. Likewise, because bioequivalence studies are usually performed in healthy volunteers rather than in patients with a particular medical condition, enrolling subjects in these studies does not provide patients with opportunities to try new experimental therapies. Hence, there is no public health benefit by publishing bioequivalence study information.

The GPhA letter goes on to note “significant negative consequences on the generic industry and on the public health” that would allegedly result from in vivo bioequivalence study registration, including “[giving] brand companies a significant new ‘heads up’ regarding the existence of a generic filer.”

Earlier this year, we learned that FDA is in the process of drafting a guidance document that will provide the Agency’s interpretation of the scope of the term “applicable drug clinical trial.” Last week at the GPhA Policy Conference in Washington, D.C., FDA’s Chief Counsel, Gerald Masoudi, when questioned about the status of FDA’s decision as to whether or not the Agency will consider in vivo bioequivalence studies to be “applicable drug clinical trials,” said that his office is working on the issue.

By Kurt R. Karst    

As any blogger can tell you, writing a blog is a labor of love.  It takes a lot of time to put together thoughtful and informative posts – and before the news gets stale.  So, when our blog is mentioned as one of the top blogs in the health care industry, we naturally want to take a moment to pat ourselves on the back and say “atta boy!”

Last week, RNCentral.com issued its “100 Best Health Care Policy Blogs.”  FDA Law Blog joins some other usual suspects in the “Drugs/Pharma” category, including Pharmalot and Eye on FDA. 

Jeffrey K. Shapiro of Hyman, Phelps & McNamara, P.C. will be speaking at American Conference Institute’s 8th National Conference on Reducing Legal Risks in the Sale and Marketing of Medical Devices, November 17-18, 2008 at the Allerton Hotel on the Magnificent Mile in Chicago, IL. A copy of the program is available here. 

The conference features a faculty of leading outside counsel, distinguished in-house counsel and compliance officers, as well as 9 government enforcers and regulators. They will help those in attendance:

• REASSESS compliance programs as a result of the Deferred Prosecution Agreements
• DISSEMINATE peer-reviewed studies of off-label uses and AVOID off-label scrutiny
• AVOID anti-kickback red flags when handling activities involving prescribers and purchasers
• DESIGN compliant policies and procedures for consulting arrangements
• RESPOND to government inquiries and NEGOTIATE and IMPLEMENT CIAs
• REDUCE the risk of FCPA investigations and violations
• OVERCOME the current coverage, coding, and payment challenges with device reimbursement
• EXAMINE the appropriate circumstances for discounting, bundling and price concessions
• IDENTIFY legal parameters of DTC marketing, including "new media"
• TRACK state legislative initiatives and HARMONIZE inconsistent state obligations

Additional details and registration information are available at www.AmericanConference.com/MedicalDevices or by calling 888-224-2480.

The latest FDLI Update “Enforcement Corner” article by Hyman, Phelps & McNamara, P.C. discusses the fact that government entities, including FDA, are taking enforcement actions against companies that market cosmetics and cosmetic-like products.  The article highlights recent enforcement actions in this area, and also notes possible future areas of enforcement against cosmetics.  A copy of the article is available here. Contact Bryon F. Powell for additional information.

Representatives John Dingell and Bart Stupak are investigating advertising claims made for Wyeth Pharmaceuticals’ Centrum Cardio multi-vitamin.  The inquiry stems from a review of direct-to-consumer advertising for pharmaceutical products by the Committee on Energy and Commerce and its Subcommittee on Oversight and Investigations.  In a September 12, 2008 letter to Wyeth, the Congressmen requested documentation for advertising claims that Centrum Cardio can reduce cholesterol within four weeks, reduce the risk of heart disease, block cholesterol absorption, and significantly lower LDL cholesterol.  Some of the claims appear in TV advertisements, and others appear on the Company’s web site.  Both the Food and Drug Administration ("FDA") and the Federal Trade Commission ("FTC") can assert jurisdiction over web site content:  the FDA, as labeling, the FTC, as advertising.

Wyeth appears to be basing many of these advertising claims on FDA’s health claim regulation and enforcement discretion letter for products containing plant sterol/stanol esters.  Qualifying products can bear the health claim as well as other information described in the regulation related to plant sterol/stanol esters and coronary heart disease – specifically, that plant sterol/stanol esters may reduce the risk of coronary heart disease and lower blood total and LDL cholesterol levels. 

The claims Wyeth makes for Centrum Cardio appear to substantially comply with FDA’s plant sterol/stanol health claim regulation and enforcement discretion letter.  Although some of the claims may be more aggressive than the wording in FDA’s regulation (e.g., lowers cholesterol within a month), the claims generally follow the spirit of the health claim regulation. 

Moreover, for the claims appearing in pure advertising – for example, radio or TV advertisements – Wyeth technically need only be sure that its claims are truthful, not misleading, and adequately substantiated, which is the standard employed by the FTC.  Therefore, Wyeth should be able to make claims for Cardio Centrum in advertising that go beyond those provided in FDA’s plant sterol/stanol esters health claim regulation as long as the Company has adequate substantiation to support the claims. 

For claims related to health, the FTC typically consults with scientific experts – that is, experts in the field that relates to the claim – to see whether they agree that there is sufficient substantiation, based on “competent and reliable scientific evidence,” to support the claim.  How Congress expects to make the determination as to whether the claims are substantiated, however, is unclear. 

By Cassandra A. Soltis 

FDA has denied a petition for administrative reconsideration of its June 2005 decision on qualified health claims for green tea and certain cancers.  In that decision, FDA stated its intent to consider the exercise of enforcement discretion for two weakly worded qualified health claims for the relationship between consumption of green tea and a reduced risk of breast cancer and prostate cancer, but denied qualified health claims for the relationship between consumption of green tea and a reduced risk of various other cancers. 

Under 21 C.F.R. § 10.33(e), a request for reconsideration must demonstrate that FDA did not consider or adequately consider relevant information or views contained in the administrative record, among other things.  According to FDA, the request for reconsideration failed to meet this test.  FDA’s denial further asserts that, even if the request for reconsideration were granted under 21 C.F.R. § 10.33(d) as being in the public interest and in the interest of justice, FDA would reach the same decision as it reached in 2005.  FDA’s denial notes that the agency may revisit its decision as warranted by the emergence of new scientific evidence or changes in consumption patterns.

By Ricardo Carvajal

Over the past several months, FDA has responded to or companies have submitted citizen petitions to FDA requesting that the Agency refrain from approving ANDAs for generic drugs with less than complete labeling – so-called “skinny labeling.”  That got us thinking – what is the scorecard on labeling carve-out citizen petitions?  Below, after a brief discussion of the topic, is a listing of labeling carve-out citizen petitions that FDA has responded to or that are pending before the Agency.  We will update the lists from time to time as new FDA petition responses are issued and new petitions are submitted to FDA.

In the report accompanying the 1984 Hatch-Waxman Amendments, Congress stated that a generic applicant:

need not seek approval for all of the indications for which the [Reference Listed Drug (“RLD”)] has been approved.  For example, if the [RLD] has been approved for hypertension and angina pectoris, and if the indication for hypertension is protected by patent, then the application could seek approval for only the angina pectoris indication.

This view was codified in FDC Act § 505(j)(2)(A)(v), which states that an ANDA must contain “information to show that the labeling proposed for the new drug is the same as the labeling approved for the [RLD] except for changes required because of differences approved under a [suitability petition] or because the new drug and the [RLD] are produced or distributed by different manufacturers.”  In addition, FDA’s implementing regulations at 21 C.F.R. § 314.94(a)(8)(iv) state:

Labeling (including the container label and package insert) proposed for the drug product must be the same as the labeling approved for the [RLD], except for [certain differences] . . . .  Such differences between the applicant’s proposed labeling and labeling approved for the [RLD] may include. . . omission of an indication or other aspect of labeling protected by patent or accorded exclusivity under [FDC Act § 505(j)(5)(D)].

However, FDA’s regulations at 21 C.F.R. § 314.127(a)(7) further provide that to approve an ANDA that omits an aspect of labeling protected by patent or exclusivity, FDA must find that the “differences do not render the proposed drug product less safe or effective than the listed drug for all remaining, non-protected conditions of use.”

In Bristol-Myers Squibb Co., v. Shalala, 91 F.3d 1493 (D.C. Cir. 1996), the U.S. Court of Appeals for the District of Columbia Circuit held that FDA may approve an ANDA for a generic drug even though the labeling of the generic product does not include one or more indications that appear in the labeling of the RLD upon which the ANDA is based.  Similarly, in Sigma Tau Pharma. Inc. v. Schwetz, 288 F.3d 141 (4th Cir. 2002), the U.S. Court of Appeals for the Fourth Circuit held that FDA did not violate the Orphan Drug Act when the Agency approved generic CARNITOR (levocarnitine) where the labeling omitted an indication protected by orphan drug exclusivity. 

FDA Citizen Petition Responses Permitting a Labeling Carve-Out

• FDA Response, Docket Nos. 2001P-0495, 2002P-0191, 2002P-0252 (June 11, 2002) – ULTRAM (tramadol HCl)
• FDA Response, Docket No. 2001P-0495 (Mar. 31, 2003) – ULTRAM (tramadol HCl)
• FDA Response, Docket No. 2003P-0321 (Apr. 6, 2004) – REBETOL (ribavirin)
• FDA Response, Docket No. 2005P-0383 (Dec. 1, 2006) – OXANDRIN (oxandrolone)
• FDA Response, Docket No. 2006P-0410 (Mar. 13, 2008) – ETHYOL (amifostine)
• FDA Response, Docket No. FDA-2007-P-0169 (Apr. 25, 2008) – MARINOL (dronabinol)
• FDA Response, Docket No. FDA-2008-P-0304 (June 18, 2008) – ALTACE (ramipril)
• FDA Response, Docket No. FDA-2008-P-0069 (July 28, 2008) – CAMPTOSAR (irinotecan HCl)

FDA Citizen Petition Responses Denying a Labeling Carve-Out

• FDA Response, Docket No. 2003P-0518 (Sept. 20, 2004) – RAPAMUNE (sirolimus)

Pending Labeling Carve-Out Citizen Petitions

• FDA Docket No. 2007P-0354 – THALOMID (thalidomide)
• FDA Docket No. 2007P-0322 – ACTOS (pioglitazone)
• FDA Docket No. FDA -2008-P-0343 – PRANDIN (repaglinide)

If there is a single take away message from FDA’s various petition responses over the years it is that 21 C.F.R. § 314.127(a)(7) is controlling.  FDA will permit skinny labeling when the omission of protected RLD labeling information does not render the proposed generic drug product less safe or effective than the RLD for all remaining, non-protected conditions of use.  Conversely, if FDA believes that a labeling carve-out would render the proposed generic drug product less safe or effective than the RLD, then the Agency will not permit a labeling carve-out. 

By Kurt R. Karst    

On September 12, 2008, the U.S. Court of Appeals for the District of Columbia heard oral argument and ruled in Teva Pharmaceuticals USA, Inc. v. Leavitt, which concerns the availability of 180-day exclusivity for a generic version of Janssen Phaemaceutica’s schizophrenia drug RISPERDAL (risperidone) Tablets based on Teva’s Paragraph IV certification to U.S. Patent #5,158,952 (“the ‘952 patent”).  As we previously reported, Teva sued FDA in March 2008 after the Agency denied a citizen petition Teva submitted in August 2007 requesting that FDA relist the ‘952 patent in the Orange Book and confirm Teva’s eligibility for 180-day exclusivity. 

According to Teva’s citizen petition, Teva submitted an ANDA to FDA on August 28, 2001.  The ANDA contained a Paragraph IV certification to the ‘952 patent.  In October 2001, FDA notified Teva that the ‘952 had been delisted from the Orange Book, and required the company to amend its patent certification to reflect that the ‘952 patent was no longer listed in the Orange Book as claiming RISPERDAL Tablets.  Teva complied and submitted the ANDA amendment.  After the U.S. Court of Appeals for the District of Columbia Circuit decided in Ranbaxy Laboratories Ltd. v. Leavitt in November 2006 that FDA may not delist a patent from the Orange Book following the submission of an ANDA with a Paragraph IV certification to that patent, however, Teva reportedly reviewed its ANDA portfolio for any potential unlawful patent delistings that could affect the company’s eligibility for 180-day exclusivity.  This review led to the company’s August 2007 citizen petition.

Teva argued in its citizen petition that because the “official Orange Book” (that is, the printed edition of the Orange Book) listed the ‘952 patent when the company submitted its ANDA, “FDA’s putative delisting of the ‘952 patent did not become effective until January 2002, when the official Orange Book reflected the delisting of that patent.”  As such, according to Teva, given the decision in Ranbaxy, FDA could not have lawfully delisted the ‘952 patent because of the company’s Paragraph IV certification to that patent, and the company remains eligible for 180-day exclusivity.  Teva also contends that because FDA “failed to provide official notice of the ‘delisting’ for several months following the submission of Teva’s ANDA,” the delisting does not affect Teva’s “entitlement” to 180-day exclusivity. 

On April 11, 2008, Judge Royce C. Lamberth of the U.S. District Court for the District of Columbia issued a 2-page order siding with Teva.  Judge Lamberth’s order declared that the delisting of the ‘952 patent was unlawful, ordered FDA to relist the patent in the Orange Book and to restore Teva’s Paragraph IV patent certification, and enjoined FDA from approving any generic RISPERDAL Tablets ANDAs until Teva’s 180-day exclusivity expires.  FDA approved Teva’s ANDA with 180-day exclusivity and appealed Judge Lamberth’s decision.

After being fully briefed on the issues raised in this case, the D.C. Circuit (a 3-judge panel of Circuit Judges Brown, Kavanaugh, and Senior Circuit Judge Williams) filed a per curiam judgment (without memorandum) on September 12, 2008 – the same date on which oral argument was heard.  The court’s order vacates the district court’s April 11, 2008 injunction and reverses the court’s order.  Also, in a rather unusual move, the court issued its mandate on September 12, 2008.

ADDITIONAL READING:

• Reuters Article
• Teva’s Appellate Brief
• FDA’s Appellate Brief
• FDA’s Reply Brief

By Kurt R. Karst