Hyman, Phelps & McNamara, P.C. is pleased to announce that Diane B. McColl has been elected to serve as the new Vice President of the International Society of Regulatory Toxicology and Pharmacology (“ISRTP”).  ISRTP’s mission is to provide an open public forum for policy makers and scientists promoting sound toxicologic and pharmacologic science as a basis for regulation affecting human safety and health, and the environment.

Ms. McColl, who is both an attorney and a pharmacist, is also an elected member to the U.S. Pharmacopeial Convention’s Expert Committee for the Food Chemicals Codex (Monographs – Food Ingredients) for the 2010-2015 cycle.

By Susan J. Matthees –

A new development in the ongoing battle involving sodium thiopental, one of the drugs used for lethal injections, surfaced today when the Drug Enforcement Administration (“DEA”) seized Georgia’s supply of the drug.  According to the Atlanta Journal-Constitution, a DEA spokesperson confirmed that the drug had been seized and stated that “[t]here were questions about the way the drugs were imported.”  DEA did not make any further statements.

As we reported two weeks ago, attorney John Bentivoglio sent a letter to Attorney General Eric Holder alleging that Georgia violated the Controlled Substances Act by importing sodium thiopental.  Inmates in 3 other states have sued FDA over the allegedly illegal importation of the drug from Europe.   

By Nisha P. Shah –

Effective March 28, 2011, sponsors and investigators of human drug and biological products subject to either an investigational new drug application ("IND") or bioavailability ("BA") or bioequivalence ("BE") studies exempt from IND requirements will have revised safety reporting requirements under the FDA regulations.  FDA issued its final rule on September 29, 2010, which amends the IND safety reporting requirements under 21 CFR Part 312 and adds safety reporting requirements for persons conducting BA or BE studies under 21 CFR Part 320.  75 Fed. Reg. 59935 (Sept. 29, 2010). 

FDA had published a proposed rule to revise its premarketing and postmarketing safety reporting regulations on March 14, 2003.  The agency decided to bifurcate the premarketing and postmarketing safety reporting requirements in separate rulemakings, and this final rule focuses only on the premarketing safety reporting regulations.  Simultaneous to finalizing the regulations, FDA issued draft guidance on the topic, “Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies,” and published a Q&A on the agency’s website.  The revised requirements are designed to clarify and improve the quality of safety information reported to FDA, harmonize international reporting standards and definitions, and improve safety monitoring by sponsors and investigators.  However, the regulations appear to impose a greater burden on sponsors to determine when an adverse event is reportable.

Definitions

Under the existing IND safety reporting regulations, sponsors were required to notify FDA and all investigators of any adverse event “associated with the use of the drug” that was both serious and unexpected and any results from animal studies which suggested a significant risk for humans.  FDA believed that sponsors were reporting frequently serious adverse experiences for which there was little evidence of a causal relationship between the drug and the event.  The final regulations, available at Revised 21 C.F.R. § 312.32, set forth five new or revised definitions which help clarify when a safety report should be submitted:

“Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.”

An adverse event or suspected adverse reaction is considered a “life-threatening adverse event or life-threatening suspected adverse reaction” if, in the view of the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.

An adverse event or suspected adverse reaction is considered “serious” if the investigator or sponsor believes any of the following outcomes may occur: “death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require  medical or surgical intervention to prevent one of the outcomes listed in this definition.”

“Suspected adverse reaction” is considered “any adverse event for which there is a reasonable possibility that the drug caused” the event. “Reasonable possibility” suggests there is a causal relationship between the drug and the adverse event.  “Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.”

An adverse event or suspected adverse reaction is “unexpected” if “it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended.  The term ‘unexpected’ also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.”

Safety Reporting Requirements

The new definitions change when sponsors are to submit expedited safety reports and distinguish circumstances in which it is appropriate to submit individual cases compared to cases which should be aggregated and compared to a control group.  Below are some highlights of the final regulations and guidance:

Prompt Review of Safety Information: Similar to the former regulations, a sponsor must continue to “promptly” review all safety information obtained from foreign or domestic sources.  However, the sources of information listed in the regulation has expanded to include “any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and reports of foreign commercial marketing experience for drugs that are not marketed in the United States.” Revised 21 C.F.R. § 312.32(b).  The guidance recommends that the sponsor also conduct literature searches at least annually to find new safety information for reporting purposes. 

Submission of Serious Risks: Sponsors will be required to notify FDA and all participating investigators in an IND safety report of potential serious risks from clinical trials or any other source within 15 calendar days after the sponsor determines that it is reportable. Revised 21 C.F.R. § 312.32(c)(1).  The sponsor must identify all other IND safety reports previously submitted to FDA concerning similar suspected adverse reactions and analyze the significance of the suspected adverse reaction in light of the other reports.  The sponsor must submit an IND safety report when any of the following criteria are met:

1. Serious and unexpected suspected adverse reaction (Revised 21 C.F.R. § 312.32(c)(1)(i): the event must be serious, unexpected, and suspected adverse reaction.  Under the revised reporting requirements, the definition of “suspected adverse reaction” imposes a greater burden on sponsors to determine whether the drug caused the event. 

2. Findings from other sources (Revised 21 C.F.R. § 312.32(c)(1)(ii)): the event must suggest a significant risk in humans exposed to the drug.  Other sources may include epidemiological studies, pooled analysis of multiple studies, and clinical studies other than those conducted under the present IND.

3. Findings from animal or in vitro testing (Revised 21 C.F.R. § 312.32(c)(1)(iii)): the event must suggest a significant risk to humans exposed to the drug.  This requirement expands a sponsor’s reporting obligations to include findings from in vitro studies.  Findings from carcinogenicity, mutagenicity, teratogenicity, and other organ toxicity studies are types of studies that could reveal a significant risk.  The guidance advises sponsors to determine whether the finding suggests a significant risk to humans or is too early to interpret without further investigation.

4. Increased occurrence of serious suspected adverse reactions (Revised 21 C.F.R. § 312.32(c)(1)(iv)): any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.  The decision about whether to report depends on several factors, including study population and the nature and seriousness of the event.

Submission of Unexpected Fatal or Life-Threatening Risks:  Similar to the former regulations, a sponsor must continue to notify FDA of any unexpected fatal or life-threatening suspected adverse reaction within 7 calendar days after the sponsor’s receives the information.  Revised 21 C.F.R. § 312.32(c)(2). 

Reporting of Certain Study Endpoints: FDA clarified that study endpoints must not be reported as IND safety reports for trials that are designed to evaluate the effect of the drug on disease-related mortality or morbidity.  Revised 21 C.F.R. § 312.32(c)(5).  The sponsor must report study endpoints to FDA as described in the protocol.  However, if a serious and unexpected adverse event occurs for which a causal relationship between the drug and the event is suggested, the event must be reported under § 312.32(c)(1)(i) as a serious and unexpected suspected adverse reaction even if it is a component of the study endpoint.

Unblinding: FDA acknowledged that breaking the blind may be necessary to determine the reportability of serious, unexpected, suspected adverse reactions.  Knowledge of the treatment may provide important safety information and could impact the ongoing conduct of a clinical trial.  If the sponsor believes that breaking the blind may compromise study integrity, the sponsor can propose an alternative reporting format to maintain the blind.

Investigator Reporting Requirements: FDA’s revised regulations imposes additional investigator reporting requirements.  Under the final regulations, investigators must report immediately to the sponsor any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and the report must include a causality assessment.  Revised 21 C.F.R. § 312.64(b).  Study endpoints that are serious adverse events must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event.  In that case, investigators are required to report the event immediately to the sponsor. 

Bioavailability and Bioequivalence Studies: Under the former regulations, certain in vivo BA/BE studies in humans were exempt from the IND safety reporting requirements.  The final rule contains safety reporting requirements for such BA/BE studies that are conducted in the United States.  The person conducting the study, including any contract research organization, must notify FDA and all participating investigators of any serious adverse event that is observed in a BA/BE study.  This requirement does not apply to human BA and BE studies exempt from the IND requirements that are conducted outside of the United States. 

Timing of Safety Reports Submission: The timing of the safety reports remains unchanged.  Safety reports must be submitted to FDA and all participating investigators no later than 15 calendar days after the sponsor or person conducting the study becomes aware of the event, except for fatal and life-threatening adverse events which must be submitted no later than 7 calendar days.

Format of Safety Reports: The format for IND safety reports is based on the type of expedited report; for individual case reports, a sponsor would use FDA Form 3500A, though FDA will accept foreign suspected adverse reaction reports on a CIOMS I Form. Revised 21 C.F.R. § 312.32(c)(1)(v).  For reports of overall findings or pooled analyses, a narrative format must be used.  FDA may require a sponsor or a sponsor may request to submit IND safety reports in a different format or frequency than that prescribed in the regulations.  Revised 21 C.F.R. § 312.32(c)(3).  For BA/BE studies, each report must be submitted on FDA Form 3500A or in an electronic format that FDA can process.  Revised 21 C.F.R.§ 320.31(d)(3).

By Kurt R. Karst –      

Each year, thousands – indeed, tens of thousands – of pages are written concerning the Hatch-Waxman Amendments.  As we were clearing out our in-box this past weekend, we came across two scholarly articles from some Hatch-Waxman “regulars” that we think merit a read-through by our FDA Law Blog readers (not that we agree or disagree with the views expressed in the articles). 

The first article – published in the University of Florida Law Review – comes to us from Michael A. Carrier, a professor at the Rutgers University School of Law-Camden, and is titled “A Real-World Analysis of Pharmaceutical Settlements: The Missing Dimension of Product Hopping.”  Professor Carrier, an opponent of patent settlement agreements (or what opponents call “pay-for-delay” or “reverse payment” agreements), explores the intersection of patent settlement agreements and so-called “product hopping.”  Federal Trade Commission (“FTC”) Commissioner Rosch recently defined “product hopping” in a speech (pages 14-17) as the practice of “introducing new patented products with minor or no substantive improvements in the hopes of preventing substitution to lower-priced generics.”  One example of product hopping, also known as “evergreening,” “line extension,” or “product switching,”  is when a company switches the market, usually around the time generic competition is expected, from one dosage form to another.

According to Professor Carrier, patent settlement agreements and product hopping create a “lethal combination” that “erects a significant roadblock to pharmaceutical competition.”  Specifically:

For a settlement that prevents patent challenges for a period of time – even if less than the duration of the patent – gives the brand firm the space in which it can comfortably switch the market to the new product.  By the time, years later, when the generic enters, the market will have already been switched to the new product.  As a result, the generic firm, which can no longer take advantage of state drug product selection laws, fails to provide meaningful competition.

Although we are certainly not antitrust or patent settlement experts, it seems to us that one way generic drug companies can and do attempt to shield themselves from the potential effects of product hopping (or at least dampen its potential effects) is to include in agreements provisions that create a trigger to early marketing based on some market erosion target. 

The second article that caught our eye is a working paper co-authored by Columbia Law School Professor C. Scott Hemphill and Stanford Law School Professor Mark A. Lemley.  Titled “Earning Exclusivity: Generic Drug Incentives and the Hatch-Waxman Act,” the article, like the Carrier article, discusses patent settlement agreements and product hopping, but suggests an  overhaul to the 180-day generic drug marketing exclusivity incentive created by the Hatch-Waxman Amendments (and significantly modified by the Medicare Modernization Act) that reminded us of those 1980’s Smith Barney commercials with the legendary John Houseman – “We make money the old-fashioned way.  We earn it.”

According to Professors Hemphill and Lemley, the original intent of creating the 180-day exclusivity incentive – i.e., to encourage generic drug companies “to challenge weak patents and enter the market earlier, lowering prices and benefiting consumers” – has been “hijacked.”  Today, they argue, 180-day exclusivity “is a tool that encourages weak challenges to patents in the hopes of prompting settlement, and leads generic firms to settle even strong challenges for delayed entry in exchange for keeping their exclusivity.” 

As an alternative that harkens back to and is inspired by FDA’s old “successful defense” prerequisite to 180-day exclusivity that the D.C. Circuit struck down in the late 1990s finding it inconsistent with the statute (see e.g., Mova Pharm. Corp. v. Shalala, 140 F.3d 1060 (D.C. Cir. 1998)), Professors Hemphill and Lemley argue that “first-filing generic drug companies should be entitled to 180 days of exclusivity only if they successfully defeat the patent owner, for example, by invalidating the patent or by proving that they did not infringe that patent.”   Under their approach, “if the generic firm files a Paragraph IV certification, is sued, and wins the suit, it receives the [180-day exclusivity] bounty.  If the generic firm instead loses the suit, it loses the exclusivity.  Nor can it receive the bounty if it settles for delayed entry.”  The professors “suggest that this change could be implemented without any legislative action, for example, by the FDA in interpreting the Hatch-Waxman Act, and by the [FTC] in its enforcement of the FTC Act.” 

The Hemphill/Lemley earned exclusivity proposal is interesting, and if seriously considered, will certainly garner some criticism from those who think the current system created by the MMA is adequate with some tweaks, such as addressing the circumstances under which 180-day exclusivity is forfeited if an ANDA sponsor fails to obtain timely tentative approval.

By Jennifer B. Davis –

Three and a half years ago, Congress directed FDA to identify lower risk devices for reporting malfunction MDRs on a quarterly basis in summary form.  FDA still has not done so. 

Specifically, the Food and Drug Administration Amendments Act of 2007 (“FDAAA”), Title II, section 227, amended section 519(a) of the FDC Act.  The amendment directed FDA to identify in a Federal Register notice, or through letters to manufacturers, those Class I and Class II devices (if not permanently implantable, life supporting, or life sustaining) that the agency determined should remain subject to the Part 803 Medical Device Reporting requirements, and to establish new, less burdensome criteria for reporting malfunctions for such devices in summary form on a quarterly basis.  (The reporting requirements for Class III devices, and for Class II devices that are permanently implantable, life supporting, or life sustaining were not affected by FDAAA.  We also note that some devices could, if FDA so determines, be altogether exempt from malfunction reporting.)

Since the enactment of FDAAA, FDA has taken no action to implement this amendment,  prompting understandable industry confusion as to what the current malfunction reporting requirements really are – until now, that is.  Last week, FDA published a Federal Register notice clarifying that manufacturers and importers of class I and class II not permanently implantable, life supporting, or life sustaining devices “must continue to report in full compliance with part 803, pending further FDA notice . . . as to specific device types subject to part 803, and the establishment of [alternative reporting] criteria.”  Notwithstanding congressional intent that the reporting burden be reduced, the agency maintains “it is necessary to subject all such devices to part 803 in the interim, in order to protect the public health by ensuring that there is no gap in malfunction reporting for any device.”  Given the uncertainties about whether and how FDA actually reviews and uses malfunction medical device reports once they are submitted, this rationale seems questionable.  The notice does not say when FDA plans to propose regulations implementing the amendment.  The wait continues . . . .

By Peter M. Jaensch & John R. Fleder –

On January 18, 2011, the President issued a significant Order entitled a “Memorandum for the Heads of Executive Departments and Agencies.”  The Memorandum directs “agencies with broad regulatory compliance and administrative enforcement responsibilities” to, within 120 days, “develop plans to make public information concerning their regulatory compliance and enforcement activities accessible, downloadable, and searchable online.”

On March 11, 2011, this firm sent a letter to the FDA Chief Counsel, Ralph S. Tyler, calling on FDA to commit to posting on its website information regarding its enforcement activities, including:

• the names and judicial districts of all lawsuits filed by the government with regard to activity regulated by FDA;
• the names and judicial district of all lawsuits filed against the FDA (and/or its officials) in connection with FDA’s regulatory or enforcement activities; and
• all briefs and other pleadings publicly filed in such cases.

Although some agencies already post online much of this type of information, FDA’s website has not provided a comprehensive picture of the agency’s activities in court. We believe that making all public information available online will promote consistency in FDA actions, and permit industry and the general public to make informed decisions about FDA-regulated products.  Whether FDA will agree – or respond – remains to be seen.

By Ricardo Carvajal - 

In an upcoming issue of the Federal Register, FDA is announcing a public meeting scheduled for March 29 to solicit comment on the import safety provisions of the Food Safety Modernization Act ("FSMA").  At the meeting, appropriately titled “Food Safety Modernization Act; Title III – A New Paradigm for Importers,” attendees will have “multiple opportunities . . . to actively express their views by making presentations at the meeting, participating in break-out sessions . . . , and submitting comments to the docket” on the four major import safety provisions of the FSMA:

• The foreign supplier verification program under section 301, which “requires importers to conduct risk-based foreign supplier verification activities to verify that imported food is not adulterated under [FDC Act section 402] or misbranded under [FDC Act section 403(w)] (relating to allergens) and is produced in compliance with FDA’s preventive controls requirements and produce safety standards, where applicable;"

• The voluntary qualified importer program under section 302, which “requires FDA to establish a voluntary, user-fee funded program to expedite entry into the United States of imported food from eligible, qualified importers;”

• The mandatory import certification authority under section 303, which authorizes FDA, “based on risk considerations, to require an article of food offered for import into the United States to be accompanied by certifications or other assurances that the food complies with relevant provisions” of the FDC Act; and

• The third-party auditor accreditation system provided for by section 307, which “directs FDA to establish a system for the recognition of accreditation bodies that accredit third-party auditors to issue certifications for purposes of” the import certification provision and the voluntary qualified importer program.

FDA is also announcing a public hearing scheduled for March 30-31 to solicit views on international comparability assessments and equivalence determinations, and to obtain information on “policies, practices, and programs used by foreign regulators to ensure the safety of imported foods and animal feed.”  FDA expects that “initiatives discussed at the 2-day hearing will align with and help support FSMA implementation.”

The scheduling of these hearings within three months of the FSMA’s enactment suggests that FDA intends to adhere to an aggressive timetable for the new law’s implementation – resources permitting.

By Susan J. Matthees –

The USDA’s Economic Research Service (“ERS”) recently published an article titled “Will Calorie Labeling in Restaurants Make a Difference?” that considers the potential impact of the new menu labeling requirements for chain restaurants.  As we previously reported (here and here), § 4205 of the Patient Protection and Affordable Care Act requires chain restaurants and retail food establishments to include calorie information on their menus.  In an effort to determine the potential impact of the law, ERS reviewed studies of consumer food choices conducted in geographical areas with menu labeling requirements already in place as well as studies on consumer eating behavior.  The studies had conflicting results, and ERS was inconclusive as to whether the menu labeling requirements will have any impact on consumer food choices. 

According to the article, studies suggest that Americans generally underestimate the calorie and fat content in restaurant menu items.  It would seem to follow that disclosing nutrition information on menus would lead Americans to choose lower calorie and lower fat foods, but ERS researchers found that this is not necessarily the case.  The article cites studies showing that people’s knowledge about health and nutrition has less impact on what they choose to eat when they are away from home than when they eat at home, and people dieting tend to choose less healthy options when eating out.  Also, the article points to two experiments that suggest that consumers may be primed to believe that foods that are identified as low in fat are not as satisfying as non-low fat foods. 

The article also points to conflicting results of studies of New York City’s calorie labeling law as an indication that it may be too soon to tell how federal law will change consumers’ habits.  New York City began requiring chain restaurants to disclose calorie information on their menus in 2008, and studies on the impact of the law have found conflicting results.  One study conducted in low-income, minority neighborhoods in New York City and similar neighborhoods in Newark, NJ, before and after the law went into effect, showed that although 88% of consumers in New York City said they were purchasing fewer calories, receipts from their purchases showed that people in New York City purchased about the same number of calories before and after the law took effect and about the same amount as people in Newark.  Research by Stanford University, however, showed that mandatory calorie posting lead to a 6% decrease in calories per transaction for food purchases at Starbucks in New York City. 

FDA intends to publish regulations implementing the menu labeling requirements by March 23.  Some in industry believe the regulations could cost in the hundreds of millions of dollars to implement, and for now, it seems it will be wait and see as to whether the regulation will have any impact on consumer’s food choices.   

By Kurt R. Karst –      

In what is, to our knowledge, the first instance in which a company has asserted the patent delisting counterclaim provisions added by the Medicare Modernization Act (“MMA”) in the context of a 505(b)(2) application – and even in the context of an ANDA outside of a patent use code challenge – Intelliject, Inc. (“Intelliject”) alleges in a recent court filing that U.S. Patent No. 7,794,432 (“the ‘432 patent”), which is listed in the Orange Book for Meridian Medical Technologies, Inc.’s (“Meridian’s”) EpiPen and EpiPen Jr Auto-Injectors (epinephrine injection) solution, 0.3mg/ml and 0.415/0.3 ml, approved under NDA No. 19-430, must be delisted from the Orange Book.  Intelliject’s request for a court order requiring Meridian to remove – or “delist” – the ‘432 patent from the Orange Book is among several counterclaims Intelliject asserts in responding to Meridian’s patent infringement lawsuit filed in the U.S. District Court for the District of Delaware after Intelliject notified Meridian of Paragraph IV certifications to the ‘432 patent and U.S. Patent No. 7,449,012 (“the ‘012 patent”) included in Intelliject’s 505(b)(2) application No. 201739 for its “epi-Card” epinephrine product.  Among other things, a court decision could provide an answer to a question posed to FDA several years ago about drug delivery device patent Orange Book listings. 

The patent delisting counterclaim provisions at FDC Act §505(c)(3)(D)(ii)(I) applicable to 505(b)(2) applications, as added by the MMA, state that:

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

The MMA also added almost identical counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I) applicable to ANDA sponsors.  Both counterclaim provisions refer to  FDC Act §§ 505(b) and (c), under which an NDA holder must submit with its application and after NDA approval “the patent number and the expiration date of any patent which claims the drug for which the applicant submitted the application or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture use, or sale of the drug.”

The ‘432 patent, which is titled “Automatic injector with kickback attenuation,” is listed in the Orange Book as a drug product patent.  Intelliject alleges in the company’s patent delisting counterclaim that “[t]he ‘432 patent does not claim either a composition or a formulation of epinephrine” and “does not disclose a composition or a formulation of epinephrine.”  Because “the ‘432 patent does not claim either the drug for which Meridian’s NDA was approved or an approved method of using the drug,” according to Intelliject, “the ‘432 patent must be delisted from the Orange Book” pursuant to FDC Act §505(c)(3)(D)(ii)(I).

The ‘432 patent, which was issued on September 14, 2010, appears to be in a general class of drug delivery system patents that some NDA sponsors have decided to submit to FDA for Orange Book listing.  As we previously reported, since 2005, FDA has received, but has not substantively responded to, several advisory opinion requests on the Agency’s policy for the submission of patents for Orange Book listing that cover drug delivery systems.  For example, one request asks FDA the following question:

If a patent claims a drug delivery device or elements of a drug delivery device approved as part of a [NDA], but the patent does not specifically claim the active ingredient or mention the active ingredient or ingredients contained in the approved drug product, or if a patent claims the protective overwrapping of a drug delivery device, should information concerning that patent be submitted to the FDA for listing in the Orange Book? [(italics in original)]

The advisory opinion requests were apparently prompted by FDA’s response to comments stated in the preamble to the Agency’s June 2003 regulations implementing the FDC Act’s patent listing provisions.  Those comments sought clarification as to whether patents claiming delivery devices or containers “integral” to a drug product should be submitted to FDA for Orange Book listing.  FDA did not directly address the issue, but rather stated that the key factor in determining whether a drug product patent must be submitted for Orange Book listing is “whether the patent being submitted claims the finished dosage form of the approved drug product.” 

A court decision with respect to Intelliject’s ‘432 patent delisting counterclaim, although limited to that patent, could provide some helpful guidance on the listability of similar patents – as well as fodder for other companies challenging or defending similar patents.  (And for those of you wondering, if there is a court order requiring the delisting of the ‘432 patent, it would not result in a “failure-to-market” event triggering a forfeiture of 180-day exclusivity under FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC), because, according to FDA’s Paragraph IV Certification List, the first ANDA submitted to FDA containing a Paragraph IV certification occurred a few years ago when the only Orange Book-listed patent was the ‘012 patent.)

By Kurt R. Karst –      

On March 7th, the U.S. Supreme Court denied yet another Petition for Writ of Certiorari concerning whether patent settlement agreements (what opponents call “pay-for-delay” agreements or “reverse payments”) are unlawful and violate the antitrust laws.  As we previously reported, the case, Louisiana Wholesale Drug Co., Inc., et al. v. Bayer AG, et al. (Docket No. 10-762), involves manufacturers of Ciprofloxacin HCl (CIPRO) and whether a particular patent settlement agreement is per se lawful under the Sherman Act.  The Supreme Court was asked to review the case after the U.S. Court of Appeals for the Second Circuit, in September 2010, denied without comment a Petition for Rehearing and Rehearing En Banc that a panel of the judges on the Court invited in their April 2010 decision affirming (3-0) a 2005 decision by the U.S. District Court for the Eastern District of New York granting summary judgment for defendants (i.e., Ciprofloxacin HCl manufacturers).  Some opponents to patent settlement agreement had pinned high hopes that the Supreme Court would take up the case.  Justices Sotomayor and Kagan took no part in the consideration or decision of the Petition for Writ of Certiorari.

Opponents to patent settlement agreements have a dwindling number of ongoing cases remaining on which to pin new hopes.  Those cases concern K-DUR (potassium chloride) in the Third Circuit, ANDROGEL (testosterone gel) in the Eleventh Circuit, and PROVIGIL (modafinil) in the U.S. District Court for the Eastern District of Pennsylvania. 

Meanwhile, in Congress, Senator Herb Kohl (D-WI) continues his push for passage of the Preserve Access to Affordable Generics Act.  As we previously reported, the latest iteration of that bill, S. 27, was introduced in January 2011 and would, like its predecessor bills, effectively ban patent settlement agreements.  In addition, the President’s Budget for Fiscal Year 2012 seeks to effectively end such agreements, saying that “[t]he Administration proposal would give the [FTC] the authority to prohibit pay-for-delay agreements in order to facilitate access to lower-cost generics.”

By William T. Koustas –

We have previously reported on the long running legal battle between the Federal Trade Commission (“FTC”) and the American Bar Association (“ABA”) over the implementation of the FTC’s Red Flags Rule (“the Rule”).  Last Friday, the United States Court of Appeals for the District of Columbia Circuit (“the Court”) ruled that the case is moot.  ABA v. FTC, No. 1:09-cv-01636, Mar. 4, 2010.  The ruling stemmed from Congress' enactment of the Red Flag Program Clarification Act of 2010 (“Clarification Act”) on December 18, 2010, Public Law No. 111-319, 124 Stat. 3457. 

The Fair and Accurate Credit Transactions Act of 2003 (“FACT Act”) directed the FTC to promulgate regulations that required creditors to enact procedures to prevent identity theft.  In 2007, the FTC adopted the Rule, which required creditors to implement these procedures to prevent identity theft.  16 C.F.R. § 681 et seq.  In April 2009, the FTC issued a document explaining that the Rule applied to various professions, including attorneys and healthcare providers because they bill their clients after services are rendered, thus extending credit.  The ABA filed suit against the FTC in August 2009 challenging the FTC’s application of the Rule to attorneys.  The ABA argued that the FTC was intruding on the regulation of the practice of law, which is an area of regulation traditionally left to the states.  The District Court enjoined the FTC from enforcing the Rule against lawyers.  ABA v. FTC, 671 F. Supp. 2d, 64 (D.D.C. 2009).  The FTC appealed that decision.  However, the Clarification Act was enacted shortly after the Court heard oral arguments. 

The Court ruled that passage of the Clarification Act rendered the case between the ABA and FTC moot.  The FACT Act defined the term “creditor” and “credit” such that attorneys and other professionals who bill their clients for services render could, according to the FTC, be considered creditors and required to comply with the Rule.  However, the Clarification Act defined a creditor such that the definition specifically exempts a person who “advances funds on behalf of a person for expenses incidental to service provide by the creditor to that person.”  Pub. L. No. 111-319, § 2(a).  As such, the issue at the center of the case, whether attorneys are considered creditors under the FACT Act, appears to have been mooted by the new statute.  Therefore, the Court vacated the District Court’s decision and remanded the case back to the District Court with instructions to dismiss the case as moot.

This ruling will end this litigation unless either party seeks further review from either the D.C. Circuit or the U.S. Supreme Court.

ADDITIONAL READING:

• Statement by FTC Chairman Jon Leibowitz Regarding Court Ruling on Red Flags Rule

Whether you say it in English, German (“Alles Gute zum Geburtstag FDA Law Blog!”), Hebrew (“Yom Huledet Same'ach FDA Law Blog!”), Hindi (“Janam Din ki badhai FDA Law Blog!”), Japanese (“Otanjou-bi Omedetou Gozaimasu FDA Law Blog!”), Zulu (“Ilanga elimndandi kuwe FDA Law Blog!”), or any other language, on March 6th, 2011, we’re happy to accept all Happy Birthday wishes.  On that day we turn the big 4.  Oh, and what a year it was.  We had about 360 posts, for a total of more than 1,160 posts since we started this gig.  (That’s a lot of writing!)  Our readership and subscribers continue to grow, with about 5,200 folks getting our posts on a daily basis, and we’re poised to top the 1 million hit mark for our blog webpage. 

We are particularly proud that for the second year in a row the American Bar Association named FDA Law Blog as one of the top legal “blawgs” in the blogosphere when the organization announced the “Blawg 100” last November.   Blog search engine Technorati consistently ranks FDA Law Blog well within the top 1% of all blogs in the English-language blogosphere, and with a high “authority” – the measurement of a blog’s standing and influence in the blogosphere.

And we would, of course, be remiss if we did not thank our loyal readers!  We appreciate your support and your thoughtful comments.  We also thank our Hyman, Phelps & McNamara, P.C. colleagues for their time and dedication to writing interesting and informative posts.

By John R. Fleder & Anne K. Walsh –

Perhaps Yogi Berra's most famous quote was: "This is like déjà vu all over again."  Recently proposed amendments to the Sentencing Guidelines applicable to U.S. courts suggest that companies and their executives regulated by FDA may be going through a déjà vu moment.  On January 19, 2011, the United States Sentencing Commission issued a Federal Register notice.  Relevant portions of that notice are contained here. 

The issue that raises a major concern is what may be the third proposal to amend the Sentencing Guidelines seeking to impose harsh sentences against persons convicted of "strict liability" offenses under the FDC Act.  Whether intended or not, the proposed amendments could well be interpreted to require many persons convicted under the misdemeanor provision of the FDC Act, 21 U.S.C. 333(a)(1), to be sentenced under the Guidelines that are currently applicable to fraud, the Section 2B guidelines, rather than the current "regulatory" guideline, 2N2.1.

In 1996, the Commission proposed eliminating the 2N.2.1 Guideline entirely, and in its place would have had courts sentence all FDC Act cases under the harsher fraud guidelines.  Based at least in part upon the industry's strong negative response to the proposal, the Commission withdrew it.  In 2008, FDA sought wholesale revisions to the 2N2.1 Guideline.  The Commission proposed a number of FDA's suggested amendments for public comment.  As one could probably imagine, all the proposed changes were intended to increase sentences that would be imposed under that Guideline.  Our firm submitted testimony to the Commission which started with the basic premise that there was no evidence that the courts were imposing sentences under the 2N2.1 guideline that were too lenient.  Our firm recommended that with the exception of one change that the Commission had proposed that we thought had merit, the Commission should not modify the 2N2.1 Guideline.  The Commission rejected most of FDA's proposed amendments to that Guideline.

We have recently discussed (here and here) FDA's renewed efforts to employ the so-called "Park Doctrine", under which corporate executives can be prosecuted and convicted of FDC Act violations even though an executive did not participate in, or even know about, the violation.  As a result of the Agency's renewed efforts to employ the Park Doctrine, any changes to the sentencing scheme for such violations will have a dramatic impact on persons regulated by FDA.  For instance, over the past twenty or so years, many prosecutors have shied away from bringing "Park" cases because they believed that the sentences imposed when a person is prosecuted under the Park Doctrine did not result in sufficient penalties.  Although there seems to be little or no evidence to support that proposition, any change in the Sentencing Guidelines applicable to Park cases could have dramatic effects in terms of prosecutors being willing to take on those cases. 

FDC Act violations can be prosecuted as misdemeanors without a showing of any mens rea, a unique characteristic of the law that emphasizes the highly regulated nature of FDA-related activities.  The Park Doctrine imposes a higher standard on those that involve themselves in such activities.  FDC Act violations also can be prosecuted as felonies if there is evidence of an intent to defraud or mislead, or if the defendant was convicted previously of a violation of the Act.  By their nature, felony violations typically involve more egregious conduct, often involving more impact on public health, or repeat offenders. 

FDC Act violations not involving felony conduct or fraud are sentenced under Guideline 2N2.1.  The unintended impact of the Commission’s proposed amendment is that strict liability misdemeanor offenses could be sentenced at the same levels as felony violations.  This equal consideration of strict liability and felony crimes undermines the purpose of the two-tiered approach contained in the FDCA.  (There also could be potential due process concerns raised for calculating sentences of a defendant convicted of an FDC Act strict liability misdemeanor.) 

With this background we turn to the Commission's proposed amendments.  They largely stem from provisions of the Patient Protection and Affordable Care Act (“PPACA”), enacted by Congress on March 23, 2010.  Relevant portions of that Act can be found here.

Under the section titled “Health Care Fraud Enforcement” (§ 10606), the PPACA directed the Sentencing Commission to amend the Guidelines to ensure that the Guidelines and policy statements:

• Reflect the serious harms associated with health care fraud and the need for aggressive and appropriate law enforcement action to prevent such fraud; and
• Provide increased penalties for persons convicted of health care fraud offenses in appropriate circumstances.  

From the number of times the word “fraud” is used in this short section, four in all, it should be clear the Act contemplates that any amendments to the Sentencing Guidelines should affect only those cases involving fraud.  In other words, the statutory amendments were intended to address conduct that involves a level of behavior that rises to the level of fraud on the government health care programs. In effect, however, the Commission’s proposed changes could go well-beyond raising the penalties for only fraud cases. 

The Commission proposal would amend the Guidelines with regard to "persons convicted of Federal health care offenses involving Government health care programs."  76 Fed. Reg. 3203, column 1.  As proposed, there would be no limitation with regard to the types of health care offenses involving health care programs that would be subject to the increased sentencing levels.  As a result, if adopted, prosecutors could argue that this language applies to strict liability misdemeanor cases.

The proposed Amendments contain one important limitation.  They would only apply to health care offenses "involving Government health care programs."  As we have seen from recent criminal prosecutions of many companies regulated by FDA, the government certainly believes that the term "Government health care programs" involves so-called "off-label use" cases.  However, we suspect that the government would include other more traditional FDC Act violations under the description of an offense involving a government health care program.  Thus, the proposed change could increase penalties for conduct that has nothing directly to do with the provision of health care services, such as those involving current Good Manufacturing Practice ("cGMP") violations, failing to report adverse events, or refusing to produce certain records during an FDA inspection.  Not to diminish the importance of complying with the law in these areas, but because the FDC Act’s prohibited act section covers almost all aspects of regulatory authority vested in FDA, prosecutors may well argue to courts if the proposed amendments are adopted that sentencing for a vast number of FDCA violations must be calculated under the “fraud” guidelines when in fact no fraud is involved, and even, potentially, when there is no direct impact on government health care programs.
 
The Commission appears to be well-meaning enough by proposing to amend the definition of “federal health care offense” in section 2B1.1 of the Sentencing Guidelines (the “fraud” guidelines) to have the same meaning as in 18 U.S.C. § 24.  Indeed, it proposes to amend that definition because the PPACA amended 18 U.S.C. § 24 to include FDC Act “prohibited acts” under 21 U.S.C. § 331.  But without carving out from this section the FDC Act “prohibited acts” that do not involve fraud, the Commission could be inviting courts to impose greater sentences for FDC Act crimes that have nothing to do with fraud. 

We suspect that the Commission may not be intending to make strict liability FDC Act violations subject to the fraud sentencing Guidelines.  The Sentencing Commission would have explicitly proposed changes to section 2N2.1 had it wanted non-fraud FDC Act violations covered by the proposed amendments to the Guidelines.  The Commission should explicitly preclude prosecutors from misapplying the fraud guidelines to FDC Act misdemeanor cases.

The Commission has invited comments to be submitted to the Sentencing Commission’s proposal by March 21, 2011.  There was a public hearing on the proposed amendments on February 16, 2011.  It does not appear that there was any discussion about the proposal discussed in this posting.

By Karla L. Palmer & Larry K. Houck –

Consistent with its November 24, 2010 Notice of Intent, the Drug Enforcement Administration (“DEA”) published its Final Order temporarily placing five synthetic cannabinoids into Schedule I under the Federal Controlled Substances Act (“CSA”) to avoid imminent hazard to the public safety.  76 Fed. Reg. 11,075 (Mar. 1, 2011).  Effective March 1, 2011, the synthetic cannabinoids known as JWH-018, JWH-073, JWH-200, CP-47,497 and cannabicyclohexanol are subject to the Schedule I regulatory controls and administrative, civil and criminal sanctions imposed by the CSA and its implementing regulations.

DEA has authority to temporarily place a substance into Schedule I for one year without having to comply with the usual scheduling requirements under 21 U.S.C. § 811(b) if the agency finds such action necessary to avoid imminent hazard to the public health.  DEA last invoked temporary scheduling in April 2003 when it temporarily placed alpha-methyltryptamine and 5-methoxy-N,N-diisopropyltryptamine in Schedule I.  These substances were permanently placed in Schedule I in September 2004 following an extension of the temporary scheduling.  See 68 Fed. Reg. 16,427 (Apr. 4, 2003); 69 Fed. Reg. 17,034 (Apr. 1, 2004); 69 Fed. Reg. 58,050 (Sept. 29, 2004).

In making its determination, DEA considered three of the eight statutory scheduling factors (as it is required to do under 21 U.S.C. § 811(h)(3)): Each substance’s history and current pattern of abuse; its scope, duration and significance of abuse; and what, if any, risk each poses to the public health.  DEA explained that temporary placement of the cannabinoids into Schedule I is necessary to avoid imminent hazard to the public safety because they are not intended for human consumption and “there has been a rapid and significant increase in their abuse throughout the United States.  Id.  These substances, marketed under such names as “Spice” and “K2,” are sold as herbal incense or plant food, and although labeled as “not for human consumption,” are abused for their psychoactive properties.  Id. at 11,076.  DEA observed that at least eighteen states, the U.S. military and several countries have banned the substances.  DEA concluded that the substances “have the potential to be extremely harmful and, therefore, pose an imminent hazard to the public safety.”  Id. at 11,075.

DEA explained that synthetic cannabinoids are “a large family of chemically unrelated structures functionally (biologically) similar to THC,” the primary psychoactive substance in marijuana.  DEA noted that the five cannabinoids were originally developed for research purposes in the early 1980s and mid-1990s, and are not intended for human consumption.  The rise in use of these substances represents what DEA believes is a “recent phenomenon in the U.S. designer drug market” and “are perceived by the public as ‘legal’ alternatives to marijuana despite the fact that they are typically advertised as herbal incense or plant food.”  Id. at 11,076.  DEA concluded that each of the cannabinoids meet Schedule I criteria: They have a high potential for abuse; they have no currently accepted medical use in treatment in the United States; and they lack accepted safety for use under medical supervision.

The substances will remain in Schedule I for one year with the possibility of a six-month extension, during which time DEA and the Department of Health and Human Services will study the propriety of permanent control and scheduling.

Temporary placement of the cannabinoids into Schedule I subjects them to the regulatory controls and administrative, civil and criminal sanctions applicable to their manufacture, distribution, possession, importation and exportation.  Schedule I regulatory controls include registration by DEA of legitimate handlers, security to protect against their diversion, specific labeling and packaging, manufacturing quotas, physical inventories, recordkeeping, reporting and transfer by DEA-222 Official Order Forms.  Id. at 11,077-78.

By Kurt R. Karst –      

FDA’s Unapproved Drugs Initiative, which began in June 2006 when the Agency issued its final version of “Marketed Unapproved Drugs – Compliance Policy Guide Sec. 440.100,” took a major step with the Agency’s March 2, 2011 announcement that FDA plans to take enforcement action against what appears to be hundreds of allegedly “unapproved and misbranded oral drug products that are labeled for prescription use and offered for relief of symptoms of cold, cough, or allergy and persons who manufacture or cause the manufacture of such products.”  FDA’s announcement, which specifically covers oral extended-release, tannate, and immediate-release drug products, comes just one day after FDA denied (here, here, and here) three citizen petitions concerning marketed unapproved tannate-containing drug products and Generally Recognized as Safe and Effective (“GRASE”) status.  The announcement also comes about two months after FDA issued a Federal Register notice in January 2011 intended to finalize certain Drug Efficacy Study Implementation ("DESI") proceedings related to cough, cold, or allergy drug products (see our previous post here).

FDA’s Federal Register notice on today’s announced enforcement action is scheduled for publication on March 3rd, and separately discusses the legal status of the affected oral extended-release, tannate, and immediate-release cough, cold, or allergy drug products.  FDA states in the notice that the Agency plans to take enforcement action under two tracks.  (In a separate Federal Register notice scheduled for publication on March 3rd, FDA announced the closure of the remaining DESI dockets that were the subject of a January notice.  FDA also commented on the regulatory status of dihydrocodeine bitartrate in a separate letter.)

First, FDA plans to take enforcement action against any drug product covered by the notice that was not listed with FDA pursuant to FDC Act § 510 before March 2, 2011, and is manufactured, shipped, or otherwise introduced or delivered for introduction into interstate commerce by any person on or after March 3, 2011.  In addition, FDA says that the Agency plans to take enforcement action against any drug product covered by the notice that is listed with FDA in full compliance with FDC Act § 510 “but is not being commercially used or sold in the United States on March 2, 2011 and that is manufactured, shipped, or otherwise introduced or delivered for introduction into interstate commerce by any person on or after [March 3, 2011].”

Second, for drug products covered by the March 3rd notice that are commercially used or sold in the U.S., that have a National Drug Code number listed with FDA, and are in full compliance with FDC Act § 510 before March 2, 2011 – termed as “currently marketed and listed” drugs in the notice – FDA says that the Agency intends to exercise its enforcement discretion in the following manner:

FDA intends to initiate enforcement action against any currently marketed and listed product covered by this notice that is manufactured on or after [June 1, 2011] or that is shipped on or after August 30, 2011.  Further, FDA intends to take enforcement action against any person who manufactures or ships such products after these dates. 

And for anyone under the impression that the submission of a marketing application might save them from enforcement action, FDA notes that “[a]ny person who has submitted or submits an application for a drug product covered by this notice but has not received approval must comply with this notice.”

FDA’s March notice is reportedly the 17th action on a drug class the Agency has taken as part of the Unapproved Drugs Initiative.  In addition to action related to marketed unapproved cold, cough, or allergy drug products, FDA also recently initiated a seizure action concerning Auralgan Otic Solution, a marketed unapproved prescription drug used to treat pain and inflammation associated with ear infections.  In that case, the manufactuer is reportedly holding firm that its drug product is GRASE.   Finally, FDA is fighting, in the U.S. Court of Appeals for the Tenth Circuit, an appeal of a Wyoming district court decision concerning the “new drug” status of marketed unapproved Morphine Sulfate Solution Immediate-Release 20mg/mL drug products.