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    

Human history is replete with examples of the use of lethal or debilitating agents in war and by terrorists.  As early as the 6th Century B.C., the Assyrians are reported to have poisoned the wells of their enemies with ergot of rye (causing ergotism), and Solon of Athens reportedly poisoned the water supply with hellebore, a purgative agent, during the siege of Krissa.  During World War I, munitions filled with the irritants ethyl bromoacetate and chloroacetone were used to limit the effectiveness of unprotected troops, and German troops at Ypres, Belgium discharged 180,000 kilograms of chlorine gas from 5,730 cylinders against the Allied positions.  More recently, in the fall of 2001, letters containing weapons-grade anthrax were mailed to locations in New York, Florida, and Washington, D.C. resulting in several deaths.

The likelihood that a terrorist attack using Chemical, Biological, Radiological, or Nuclear (“CBRN”) substances might occur in the United States led FDA to promulgate regulations on May 31, 2002 intended to expedite the development and approval of new drug and biological products.  The final rule, titled “New Drug and Biological Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible” (commonly referred to as the “Animal Efficacy Rule”), amended FDA’s drug and biologic regulations to “allow appropriate studies in animals in certain cases to provide substantial evidence of effectiveness of new drug and biological products used to reduce or prevent the toxicity of [CBRN] substances.”  Although given relatively little attention since it was promulgated, the Animal Efficacy Rule creates a new regulatory paradigm for measuring efficacy by permitting FDA to approve drugs and biologics for counterterrorism uses based on animal data when it is unethical or unfeasible to conduct human efficacy studies. 

Under the Animal Efficacy Rule (21 C.F.R. § 314.610, drugs; § 601.91, biologics), FDA can rely on the evidence from animal studies to provide substantial evidence of effectiveness only when:

1. There is a reasonably well-understood pathophysiological mechanism of the toxicity of the CBRN substance and its prevention or substantial reduction by the product;

2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans;

3. The animal study endpoint is clearly related to the desired benefit in humans (generally the enhancement of survival or prevention of major morbidity); and

4. The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans allows selection of an effective dose in humans.

Since it was promulgated in 2002, FDA has approved two products under the Animal Efficacy Rule: (1) Pyridostigmine Bromide (NDA #20-414) for prophylaxis against the lethal effects of Soman nerve agent poisoning; and (2) CYANOKIT (hydroxocobalamin) (NDA #22-401) for the treatment of known or suspected cyanide poisoning.

On September 9, 2008, FDA issued a draft concept paper, titled “Animal Models – Essential Elements to Address Efficacy Under the Animal Rule.”  According to FDA the draft concept paper “is intended to identify the critical characteristics of an animal model that should be addressed when efficacy of the product under development will be established under the Animal Rule. It should also help determine whether an animal model can be considered sufficiently well-characterized to propose that the effect demonstrated in a single animal species can be used to support approval/licensure.”  Essential elements identified by FDA include the characteristics of the CBRN agent that influence the disease or condition, host susceptibility and response to etiologic agent, natural history of disease (pathophysiologic comparability), and characterization of medical intervention.  FDA emphasizes throughout the draft concept paper that sponsors should initiate early and frequent discussion with FDA regarding the essential data elements for the development and evaluation of animal models.

Over the past few years, several companies have reportedly expressed interest in pursuing approval of their products under the Animal Efficacy Rule.  FDA’s concept paper should provide a useful aid in the development of such products.

By Kurt R. Karst

In United States v. Stein, the United States Court of Appeals for the Second Circuit recently upheld a lower court’s decision to dismiss charges against former employees of KPMG on the basis that the prosecutors interfered with the employees’ constitutional right to counsel. 

Ex-employees of KPMG, a large accounting firm, were indicted after the Department of Justice (“DOJ”) investigated KPMG’s role in devising and marketing allegedly fraudulent tax shelters.  KPMG had initially advanced the ex-employees their legal fees but stopped after the government threatened KPMG that paying the legal fees would be used against the company in the investigation.  KPMG then stopped paying the legal fees.   

In January 2006, the ex-employees moved to have the indictments dismissed on the basis that the government had interfered with KPMG’s willingness to pay their legal fees.  The lower court found that but for the government’s interference, KPMG would have paid the employees’ legal fees and that the government’s conduct interfered with the employees’ Sixth Amendment rights. 

In July 2007, the lower court dismissed the indictment against the ex-KPMG employees.  On review, the Second Circuit has now held that KPMG stopped paying the ex-employees’ legal fees due to government pressure and therefore KPMG’s conduct “amounted to state action.”  The court also held that the government interfered with the defendants’ right to counsel in violation of the Sixth Amendment.  As a result, the Second Circuit upheld the dismissals. 

Coincidentally, the decision in Stein occurred on the very day the DOJ issued new guidelines for prosecuting corporate crimes.  In particular, the guidelines states that “credit for cooperation will not depend on the corporation’s waiver of attorney-client privilege or work product protection, but rather on the disclosure of relevant facts.”  The guidelines further state that when evaluating cooperativeness, prosecutors should not consider whether a corporation advanced attorney’s fees to employees.  In addition, participation in a joint defense agreement “will not render a corporation ineligible for cooperation credit” and prosecutors “may not consider whether a corporation has sanctioned or retained culpable employees in evaluating whether to assign cooperation credit to the corporation.” 

By Susan J. Matthees

On March 5, 2008, FDA published a notice in the Federal Register announcing an opportunity for public comment on a proposed collection of information concerning the new clinical trial certification requirement created by Title VIII of the FDA Amendments Act (“FDAAA”).  We previously reported on this new requirement here and here. 

Pursuant to PHS Act § 402(j)(5)(B), as amended by FDAAA § 801(a)(2), drug and device sponsors must include a certification (Form FDA 3674) with their regulatory submissions that they have complied with new PHS Act § 402(j), under which the responsible party of an “applicable clinical trial” must submit to the National Institutes of Health certain required information for inclusion in the clinical trial data bank at ClinicalTrials.gov.  Specifically, PHS Act § 402(j)(5)(B) states:

At the time of submission of an application under [FDC Act §§ 505, 515, 520(m), or PHS Act § 351], or submission of a report under [FDC Act § 510(k)], such application or submission shall be accompanied by a certification that all applicable requirements of [PHS Act § 402(j)] have been met.  Where available, such certification shall include the appropriate National Clinical Trial control numbers.

Since FDA published its March 2008 notice, several issues have been raised about the applicability of the new certification requirement.  Chief among these concerns is whether INDs are subject to the new requirement.  Indeed, several comments were submitted to FDA questioning whether IND submissions are “applications” in the terminology of the FDC Act.  For example, the Biotechnology Industry Organization (“BIO”) contends in a docket submission that “an IND submission is not an ‘application’ within the meaning of the FD&C Act” because FDC Act § 505(i) (concerning INDs) “does not refer to INDs as ‘applications’ but as ‘submissions’ for purposes of obtaining an ‘exemption,’” and that “the legislative history of Title VIII of FDAAA makes clear that Congress considered – and expressly rejected – the application of the certification requirement to INDs.”  The Pharmaceutical Research and Manufacturers of America (“PhRMA”) makes similar arguments in its docket submission.

On August 25, 2008, FDA published a second Federal Register notice announcing that a proposed collection of information concerning the FDAAA clinical trial certification requirement was submitted to the Office of Management and Budget for review and clearance.  In that notice, FDA addresses several issues, including those issues raised by BIO and PhRMA about IND submissions, and states:

FDA does not agree with these conclusions.  FDA agrees that the word “application” is not used in section 505(i) of the FD&C Act in reference to an IND.  However, section 505(i)(1) directed the Secretary of Health and Human Services to issue regulations exempting from the requirements of section 505 of the FD&C Act drugs intended solely for investigational use.  The regulations issued by FDA under this authority define an IND as “an investigational new drug application.”  21 CFR 312.3 (emphasis added).  Furthermore, these regulations repeatedly use the term “application” in reference to an IND.  Therefore, FDA considers an IND to be an application under section 505 of the FD&C Act .  Congress is familiar with FDA regulations and could have specifically exempted INDs from the certification process by directly excluding 505(i) from the scope of section 402(j)(5)(B) of the PHS Act. . . .  Congress understood the difference between marketing applications and IND submissions and exemptions.  FDA has concluded that the reference to section 505 of the FD&C Act was simply a streamlined reference to all applications and submissions possible under section 505 of the FD&C Act.

Several comments also questioned whether or not the clinical trial certification requirement should apply to trials over which the manufacturer/sponsor had no control – e.g., published reports of clinical studies included in a 505(b)(2) application.  FDA responded –

The certification provision, section 402(j)(5)(B) of the PHS Act, does not make a distinction between trials conducted by the sponsor and trials relied upon in the application but conducted by entities other than the sponsor.  FDA is aware that sponsors or applicants will be required to certify as to trials they did not conduct or register in the clinical trials data bank.  FDA has addressed this concern by requiring the submitter to declare that the information submitted is accurate, true, and complete “to the best of her/his knowledge.”

FDA also adds to the August 2008 notice an estimated annual reporting burden for ANDAs.  The March 2008 notice did not include ANDAs in the burden calculation, “but have since been determined to require a certification form . . . .”  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 PHS Act § 402(j) 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 clinical trial” subject to the PHS Act § 402(j) databank registration requirements.  Although FDA’s August 2008 notice does not address specifically whether an in vivo bioequivalence study is an “applicable clinical trial,” its “determination” that the clinical trial certification must accompany ANDA submissions announced in that notice may be a signal that FDA is headed in the direction of concluding that in vivo bioequivalence studies are, in fact, “applicable clinical trials” that must be registered.  FDA is reportedly in the process of drafting a guidance document that will provide the Agency’s interpretation of the scope of the term “applicable clinical trial” and that should provide greater clarity to industry on the types of studies to which FDA believes PHS Act § 402(j) applies.   

By Kurt R. Karst    

Kurt R. Karst of Hyman, Phelps & McNamara, P.C. (and co-chief blogger of FDALawBlog.net) will be speaking at the Center for Business Intelligence’s Pharmaceutical Congress on Paragraph IV Disputes, October 15 – 16, 2008, at the Marriott Philadelphia Downtown in Philadelphia, Pennsylvania.  A copy of the program is available here.  At the event, preeminent members of the nation’s Food and Drug Bar will address a broad range of topics, including: 

• FTC address on pharmaceutical antitrust
• In depth analysis of recent court cases and their implications on brand and generic companies
• Effects of KSR on brand and generic litigation strategies
• Panel discussion on acceptable settlement strategies for paragraph IV disputes
• Litigating paragraph IV disputes with multiple ANDA filers
• Interpreting forfeiture provisions for better business decisions
• Pre-suit preparedness strategies for paragraph IV disputes
• Citizen petitions and their impact on generic entry
• Declaratory judgments
• At-risk launches

For more information or to register, please contact the Center for Business Intelligence toll-free by phone at 1-800-817-8601 or via e-mail at cbireg@cbinet.com.