By Jennifer D. Newberger –

On April 25, 2011, FDA announced the availability of two guidance documents issued by the Center for Tobacco Products ("CTP").  The first, a final guidance document issued in March 2011, is titled “Civil Money Penalties and No-Tobacco-Sale Orders for Tobacco Retailers.”  The second, a draft guidance document issued April 22, 2011, is titled “Establishing that a Tobacco Product was Commercially Marketed in the United States as of February 15, 2007.”  They are discussed in turn below.

I.    Civil Money Penalties and No-Tobacco-Sale Orders for Tobacco Retailers

The Federal Food, Drug, and Cosmetic Act ("FDCA") provides for civil money penalties and no-tobacco-sale orders for violations of FDCA requirements relating to restrictions on the sale and distribution of tobacco products, including the sale or distribution of tobacco products to minors.  This guidance document describes FDA’s policies with respect to these penalties, including how FDA will identify FDCA violations, when reliance on a false identification constitutes good-faith, when FDA may seek civil money penalties and/or no-tobacco-sale orders, and the procedures that apply if it chooses to do so.   With the finalization of this guidance document, the provisions of section 103(q) of the Tobacco Control Act are effective. 

A.    FDCA Violations

To determine whether retailers are violating the applicable FDCA provisions, FDA intends to conduct compliance check inspections.  These inspections may be conducted by officers or employees of FDA or other federal departments or agencies, or certain state officers or employees commissioned by FDA.

B.    Good-faith Reliance

The FDCA provides that good-faith reliance on a photographic government-issued identification will not constitute a violation of the prohibition against sale of tobacco products to minors.  The statute provides examples of steps retailers should take to prevent violating restrictions against sales to minors, and FDA has adopted these without modification:

• adopting and enforcing a written policy against sales to minors;
• informing its employees of all applicable laws;
• establishing disciplinary sanctions for employee noncompliance; and
• requiring its employees to verify age by way of photographic identification or electronic scanning device.

C.    When FDA May Seek Civil Money Penalties and/or No-Tobacco-Sale Orders

Upon first identifying a violation at a retail outlet, FDA will generally issue a warning letter before taking further regulatory action.  FDA then intends to conduct a follow-up compliance check without providing notice to the retailer.  If FDA identifies violations of the FDCA during a follow-up compliance check or during a subsequent inspection of that retailer, FDA intends to seek civil money penalties.  If FDA finds repeat violations, it may also seek a no-tobacco-sale order.

D.    Applicable Procedures if FDA Seeks Civil Money Penalties and/or No-Tobacco-Sale Orders

FDA will file a Complaint with the Division of Dockets Management and will serve the Complaint upon the retailer found to be in violation of the FDCA.  The retailer may then either (1) pay the penalty or comply with the terms of the no-tobacco-sale order, or (2) file an Answer with the Division of Dockets Management contesting some or all of FDA’s allegations within 30 days of the date of service of the Complaint.  Timely filing of an Answer entitles the retailer to a hearing.

FDA and the retailer may engage in settlement discussions.  However, even if the parties agree to a settlement, “any violations that occurred will be counted in determining the total number of violations for purposes of subsequent enforcement actions.” 

E.    Amount of Civil Money Penalties FDA May Assess

The statute provides two schedules of penalties—one for retailers with an approved training program, and one for retailers without such a program.  FDA has not yet established standards for an approved retailer training program, and so, at this time, will seek penalties within the range for retailers with an approved program. 

If a retailer violated a restriction on the sale and distribution of tobacco products (section 906(d) of the FDCA), and paid penalties to the State for such violation, the amount of that penalty will be considered for purposes of mitigating the civil penalty assessed by FDA.

F.    Factors FDA Will Consider When Seeking a No-Tobacco-Sale Order

In determining whether a no-tobacco-sale order may be imposed, FDA will consider whether a retailer has taken effective steps to prevent violations of the minimum age requirements for the sale of tobacco products, as discussed above in section B.

FDA will consider the same factors in deciding whether to compromise, modify, or terminate the order.

II.    Establishing that a Tobacco Product was Commercially Marketed in the United States as of February 15, 2007

This draft guidance document provides information on how manufacturers may demonstrate that a tobacco product was commercially marketed in the United States as of February 15, 2007, i.e., that the product was commercially marketed in the United States on February 15, 2007.  This is significant because tobacco products marketed on February 15, 2007 are not subject to the premarket requirements of the FDCA and may serve as predicate tobacco products against which future tobacco products may demonstrate substantial equivalence.  Note that if the tobacco product “had been commercially marketed in the United States before February 15, 2007, but was not commercially marketed on that date, it is not a grandfathered product and may not be commercially marketed” unless the manufacturer complies with the premarket requirements described in section 910 of the FDCA.  

FDA suggests the manufacturer submit as much evidence as possible to demonstrate that the product was commercially marketed (not in test markets) as of February 15, 2007.  Such evidence could include the following:

• dated copies of advertisements;
• dated catalog pages;
• dated promotional material;
• dated trade publications;
• dated manufacturing documents;
• dated bills of lading;
• dated freight bills;
• dated waybills; and/or
• complete copies of any supporting information that demonstrate (individually or collectively) that the tobacco product was commercially marketed in the United States on February 15, 2007.

FDA will notify the manufacturer once it has reviewed the information and determined whether the product is a grandfathered product.  If FDA cannot make this determination from the information provided, it may request additional information.

By Kurt R. Karst –      

An April 21st letter penned by David Balto, a Senior Fellow at American Progress who focuses on competition policy, intellectual property law and health care, and Michael Carrier, a professor at the Rutgers University School of Law-Camden, and sent to five U.S. Senators – the same cohort of Senators who signed a March 9th letter to FDA Commissioner Hamburg concerning generic LIPITOR (atorvastatin calcium) Tablets (Sens. Tom Harkin (D-IA), Jay Rockefeller (D-WV), Charles Schumer (D-NY), Debbie Stabenow (D-MI) and Sherrod Brown (D-OH) – takes issue with the “use it or lose it” 180-day exclusivity forfeiture system established by the 2003 Medicare Modernization Act (“MMA”). 

The letter does not concern 180-day exclusivity for generic LIPITOR, which is governed by the pre-MMA version of the FDC Act, but rather uses two sentences in the letter – i.e., “In 2003, Congress amended the [FDC Act] to change provisions concerning 180-day generic drug exclusivity.  Specifically, the law was changed to a “use it or lose it” system that prevents a first filer’s exclusivity from being indefinitely “parked” and creating a bottleneck to generic competition” – to springboard into a discussion of the effectiveness of post-MMA 180-day exclusivity forfeiture, and specifically the so-called “failure-to-market” provisions at FDC Act § 505(j)(5)(D)(i)(I), under which the “later of” date of the two bookend events described at FDC Act § 505(j)(5)(D)(i)(I)(aa) and (bb) controls the date of 180-day exclusivity forfeiture. 

“We felt compelled to share our views on this matter because it is the inadequacy of this very provision that lies at the heart of what is commonly called the ‘pay for delay’ problem in which brand and first-to-file generic drug manufacturers block all generic competition through settlements in which the 180-day exclusivity is ‘parked,’” says the letter.  “If Congress is to effectively address this important public policy issue, it is imperative that the root cause of the problem be accurately diagnosed and treated.”  And what is that “root cause”?  According to Balto and Carrier:

The widely held view by many policymakers working to end the “pay for delay” problem is that “reverse payments” from the brand to the generic in these arrangements are the cause of the problem.  That is not the case.  The cause of the problem is the ability of the first generic challenger to retain exclusivity even if it settles its patent challenge, and the related lack of incentive that subsequent generic challengers have to continue the patent fight when the first filer has settled and “parked” its exclusivity.

Indeed, FDA acknowledged this issue in the Agency’s January 2008 Granisetron Letter Decision where FDA stated in a footnote that:

Inherent in the structure of the "failure to market" forfeiture provisions is the possibility that a first applicant would be able to enter into a settlement agreement with the NDA holder or patent owner in which a court does not enter a final judgment of invalidity or non-infringement (i.e., without a forfeiture event under subpart (bb) occurring), and that subsequent applicants would be unable to initiate a forfeiture with a declaratory judgment action. This inability to force a forfeiture of 180-day exclusivity could result in delays in the approval of otherwise approvable ANDAs owned by applicants that would market their generic drugs if they could but obtain approval. This potential scenario is not one for which the statute currently provides a remedy.

Despite the intent of the MMA’s failure-to-market forfeiture provisions to address the issue of parked exclusivity that could arise under the pre-MMA version of the statute, Balto and Carrier contend that the MMA’s provisions are “an anemic mechanism for uncorking markets blocked by ‘parked’ exclusivities,” stating that:

First generic challengers have rendered the “use it or lose it” provision toothless through market acceleration clauses that are standard components of settlements today.  These provisions allow the first-filer to accelerate its entry into the marketplace ahead of the later date agreed to with the brand company in its settlement should a subsequent generic challenger prevail in the courts, thus guaranteeing the first-filer that it will never be overtaken by another generic who successfully fought to open the market earlier, no matter how late the first filer agreed to delay its maker entry.  Subsequent generic challengers have no incentive to continue the patent fight under these circumstances, which again are typically present in settlements first-filers reach today. [(italics in original)]

Moreover, “the ‘use it or lose it’ system is also easily subverted due to the MMA’s failure to fully correct the declaratory judgment (DJ) problem,” says the letter, leading Balto and Carrier to conclude that “the MMA’s DJ provision is nothing more than a paper tiger.”  The so-called “DJ problem,” according to Balto and Carrier:

stems from the MMA’s requirement that subsequent generic filers must prevail through the appellate court level on the same set of patents that the first-filer has filed against qualifying it for exclusivity in order for the first-filer to be put in the “use it or lose it” position of having to launch its product or forfeit its exclusivity. Thus, to preserve bottlenecks created by settlements in which the first-filer parks its exclusivity, brand companies either do not sue subsequent generic filers at all, or sue them on some but not all patents. This forces subsequent generic challengers to pursue DJs in order to litigate the patents they haven’t been sued on but must win a judgment against in order to put the first-filer in the “use it or lose it” position. If subsequent generic filers cannot win the needed judgment(s), they cannot achieve the very action that the “use it or lose it” system hinges upon, ensuring the market will remain blocked by the “parked” exclusivity.

Balto and Carrier contend that the DJ environment has improved since the U.S. Supreme Court’s January 2007 decision in Medimmune, Inc. v. Genentech, Inc., in which the Court ruled that a dispute must be “definite and concrete” and “real and substantial” to support the exercise of a district court’s subject matter jurisdiction, but go on to state that:

generic challengers are by no means guaranteed to get DJs today when brand companies do not sue.  There are numerous post-MedImmune cases in which subsequent generic filers have been denied DJs.  Moreover, even if generics do get DJs, there is no guarantee that a subsequent filer who is willing to pursue the case to conclusion can achieve a court victory quickly enough to open the market anyway.  This process leaves subsequent filers at the mercy of brand companies whose sole objective is to sustain the bottleneck for as long as possible.  The inadequate nature of the MMA’s DJ provision ensures that the legal process will take so long that the clock simply runs out on subsequent generic filers fighting to open the market earlier than the date agreed to by the first filer in its “parked” exclusivity settlement.

Balto and Carrier do not discuss in the letter the ways in which the issues they raise can or should be addressed by Congress.  Instead, they note articles (see e.g., here and here) they have published on these issues and offer their assistance to the Senators. 

We note that in 2009 and 2010 legislation was introduced that appears to have been intended to  address, at least in part, issues raised in the Balto/Carrier letter.  Specifically, the Drug Price Competition Act (see our previous post here) would have amended the definition of “first applicant” at FDC Act § 505(j)(5)(B)(iv)(II)(bb) with respect to 180-day exclusivity eligibility so that certain subsequent ANDA applicants could trigger and also be eligible for such exclusivity.  We are not aware of any current efforts to resurrect this legislation.

By Ricardo Carvajal - 

The Atlantic’s second annual Food Summit in Washington, DC brought together speakers and attendees with divergent views on questions of how to ensure sustainability of the food supply, improve the availability and affordability of foods, and address the problem of obesity.  On one point, there was general agreement – consumers should have access to the information they need to make informed decisions about their diet.  Among the speakers was Sam Kass, Assistant Chef at the White House and prominent administration spokesperson on nutrition policy, who confirmed that the administration intends to continue its evaluation of front-of-package nutrition labeling.  FDA recently announced a proposed study designed to cast light on how consumers perceive and use such information.

With respect to the Food Safety Modernization Act, Deputy Commissioner for Foods Michael Taylor noted that the new law calls for some 50 deliverables in the form of regulations, guidance documents, and reports on strict timetables that FDA will be unable to meet.  FDA is therefore giving priority to standard setting (rulemakings on hazard analysis and risk-based preventive controls, produce safety, and intentional adulteration), use of its new compliance tools (administrative detention and suspension of facility registration), further developing its partnership with the states, and improving oversight of imports.

By Kurt R. Karst –     

A recent report from Leerink Swann LLC analyst Howard Liang, Ph.D. suggests that what appears to be a recent increase in the number of Refuse-to-File (“RTF”) letters issued by FDA to NDA and BLA sponsors – some of which are large, experienced biotech companies – might signal both a greater willingness from FDA to issue such decisions, and therefore a higher filing threshold, and that filing decisions are no longer non-events.  

FDA’s regulations at 21 C.F.R. § 314.101 (drugs) and 21 C.F.R. § 601.2 (biologics) provide the bases for the Agency to RTF an application – generally because an application does not, on its face, contain information required under the FDC Act, under the PHS Act, or in FDA’s implementing regulations.  (Note that NDA/BLA deficiencies that serve as the basis for an RTF action are distinct from filing review issues, which pertain only to applications that have been filed.)  Over the years, FDA has issued guidance (here and here) on the Agency’s RTF policies, and has established a Clinical Hold/RTF Committee that since about 2008 is supposed to meet approximately 6 times a year. 

According to Dr. Liang’s analysis of 28 publicly known RTF actions since 1998 – 13 of which have been issued since 2009 and several of which have been issued to large, experienced companies – “[w]hile it is not possible to firmly conclude that the pace of RTFs has increased statistically due to a relatively small sample size and lack of disclosure of all RTFs, the fact that even the most experienced companies receive RTFs suggests a change at the FDA.”  (It is likely that FDA has, in fact, issued more than 28 RTF decisions since 1998, as FDA acknowledged in 2006 that although infrequent, about 5 RTFs had been issued per year.  RTF decisions are difficult to track as FDA does not disclose them; however, FDA has proposed as part of the Agency’s Transparency Initiative that “FDA should disclose the fact that the Agency has issued a refuse-to-file or complete response letter in response to an original NDA, BLA, or an efficacy supplement for an NDA or BLA at the time the refuse-to-file or complete response letter is issued, and should, at the same time, disclose the refuse-to-file or complete response letter, which contains the reasons for issuing the letter.”)  The breakdown of the types of issues that led FDA to issue the 28 RTF actions discussed in Dr. Liang’s analysis is provided below.

 
Source: Leerink Swann LLC “RTFs Suggest FDA Filing Decisions May Have Become More Meaningful Events,” April 25, 2011.  Reprinted with permission.

According to Dr. Liang, the apparent increase in RTF actions suggests a lower threshold for RTFs and “could be due to the agency's enforcement mentality under the new Commissioner.”  In addition, “the wave of RTFs may also be related to the recent FDA implementation of good review practices in an initiative called ‘21st Century Review’, says Dr. Liang.  “After a pilot program started in 2008, this process is being implemented to all BLAs and NDAs in FY2011,” says the analyst report.  According to FDA, the “21st Century Review Initiative,” which is based on the Agency’s Good Review Practices, “is a set of performance standards [CDER] follows when doing drug reviews that involve multiple offices” the goal of which “is to make the drug review process more organized and integrated, and ensure all decision makers are heard.” 

In addition to the issues identified by Dr. Liang in his report as contributing to more RTF actions, it is certainly possible that pressure put on FDA officials to meet PDUFA performance goals is causing some reviewers to more liberally use the RTF procedures to better manage the review queue.  It is also possible that the increase in RTF actions has been spurred by the apparent resurgence of FDA’s Clinical Hold/Refusal-to-File Committee, which is intended to, among other things, share divisional experiences as a means of teaching and learning.

Hat tip Pharmalot.

Hyman, Phelps & McNamara, P.C.’s Jeffrey K. Shapiro will be giving the state of the industry address at Q1 Productions’ 2nd Annual Clinical & Regulatory Strategies for Combination Products, which is slated to take place in Baltimore, Maryland from July 11-12, 2011.  The potential benefit of combination products is significant for companies looking to provide cutting edge healthcare solutions and maintain a competitive edge.  These complex products have been cause for much regulatory discussion and interpretation since their inception and have thus been surrounded by uncertainty.  The conference will bring together not only industry representatives that have successfully navigated FDA’s combination product approval processes, but will also bring the Agency to the table to discuss and clarify processes and procedures for obtaining regulatory approval for these challenging products.

Topics to be covered at the conference include:

• State of the industry address: recognizing the past, present and future of combination products
• Exploration of various FDA approval pathways available for combination products
• Comparison of drug vs. device vs. combination approval routes
• Question & answer period with FDA executives, roundtable discussion
• Understanding timelines for data submission and approvals
• Development of strong working relationships with the FDA and internal teams
• Trial design strategies that ensure clinical data will support regulatory clearance
• Securing optimal data from clinical sites and labs based on regulatory path
• Establishing safety and efficacy of combination products
• Case study presentations focusing on various types of combination products
• Utilization of clinical data to support reimbursement goals
• The use of combination products in furthering personalized medicine
• Differences in approval routes for products containing a cleared product
• Opportunities in comparing similar products and establishing precedents
• Post-market concerns in adverse event reporting and surveillance
• International regulatory considerations and clearance routes
• Strategies in conducting international combination product clinical studies
• Manufacturing and quality assurance considerations for combined products
• Creating meaningful partnerships to support combination product commercialization
• Understanding and utilizing guidance documents released by the FDA
• Deciphering and complying with current good manufacturing practices

Mr. Shapiro’s presentation will focus on overcoming clinical and regulatory hurdles for combination products.  In particular, Jeff’s presentation will focus on:

• A thorough definition of combination products
• Historically important combination products & impact on regulations
• Current state of the combination products industry
• Methods for furthering commercialization
• Strategies for clinical & regulatory teams to get products to market

Additional information about the conference, including registration information, is available here.

By Ricardo Carvajal –

The Senate has adopted legislation that would strengthen criminal penalties "for any individual or corporation that knowingly endangers American lives by contaminating the food supply by distributing misbranded or tainted food products" (see Sen. Leahy's press release here).  The legislation provides for fines and imprisonment for up to ten years for any person that commits certain prohibited acts "with respect to any food… knowingly and intentionally to defraud or mislead… and… with conscious or reckless disregard of a risk of death or serious bodily injury."  The bill will now be taken up by the House.  As we noted in a prior posting, this year's version of the legislation raises the bar for prosecutors.  That should enhance its chances of becoming law.

By John A. Gilbert, Jr. & Peter M. Jaensch –

In a press conference at the National Press Club on April 19, 2011, the Administration presented its action plan (“Plan”) to address concerns about the increase in prescription drug abuse.  The Plan is entitled: “Epidemic: Responding to America’s Prescription Drug Abuse Crisis.”  Representing the Administration were White House Director of National Drug Control Policy Gil Kerlikowske, FDA Commissioner Margaret A. Hamburg, Assistant Secretary for Health and Human Services Howard Koh, and DEA Administrator Michele M. Leonhart.  (In a separate post we discuss FDA's final Risk Evaluation and Mitigation Strategy the Agency will require for all extended-release opioid medications, which FDA announced when the Administration presented its Plan.)

The Plan focuses primarily on measures to combat the abuse of prescription opioid analgesics.  The Plan calls for coordinated efforts by federal and state authorities in four key areas: Education and Training; Tracking and Monitoring; Proper Medication Disposal; and Enforcement.  Among these would be changes to the federal Controlled Substances  Act (“CSA”) and possibly state controlled substances laws, requiring the support of Congress and state legislatures.

A principal feature of the Plan is a proposed new requirement that prescribers “be trained on responsible opioid prescribing practices” as a prerequisite to registration with the DEA. Given that a DEA registration is required for practitioners to prescribe controlled substances to their patients, practitioners would need to meet this requirement to be permitted to prescribe controlled drugs.   The Plan does not provide details concerning this proposed training, stating only that such “training would include assessing and addressing signs of abuse and/or dependence.”  Such action would require a legislative amendment to the CSA, as the Plan openly acknowledges.  In questioning at the announcement of the Plan, Administrator Leonhart appeared to anticipate Congressional cooperation would be forthcoming and not controversial.

The Plan also calls on those states that have not implemented Prescription Drug Monitoring Programs ("PDMPs") to do so.  Currently 35 states have such plans.  In addition, the Plan calls for efforts going beyond most currently existing state PDMPs by encouraging an exchange of information between state plans.  Such information-sharing would arguably permit state and federal authorities to prevent drug seekers from circumventing existing limits by doctor-shopping and filling prescriptions across state lines.

The Plan also anticipates DEA administrative actions around drug disposal and e-prescribing. In the short-term, such activities primarily involve increased frequency of events at which DEA and possibly other federal and state agencies will collect unused controlled substances from end-users for disposal.  The CSA contemplates a closed system of controlled drug distribution, thus the return of controlled substances by patients to a DEA registrant, such as a pharmacy, has been prohibited under DEA regulations, with limited exceptions.  In the long term, DEA has stated that this issue would be addressed through promulgation of new regulations on disposal of controlled substances dispensed to end-users.  The Plan further contemplates issuance by DEA of a long-awaited final rule on the e-prescribing of controlled substances.

By William T. Koustas –

On Tuesday, April 19, 2011, after years of debate and several public meetings, FDA released the final Risk Evaluation and Mitigation Strategy ("REMS") it will require for all extended-release opioid medications.  The final REMS was issued as part of the White House’s multi-agency plan to reduce prescription drug abuse.  FDA has been working on a class-wide opioid REMS since at least February 2009, when it invited sponsors of extended-release opioid products to a private meeting.  Seventeen months later, in July 2010, FDA released its draft of a REMS for extended-release opioid products. 

In a letter to sponsors of extended-release opioid products, FDA states that it has “become aware of substantial numbers of postmarketing reports of abuse, misuse, addiction and overdose resulting in fatalities associated with [extended-release] opioid drugs.”  Letter from Bob A. Rappaport, M.D., Post-Approval REMS Notification, April 2011.  FDA considers this “new safety information,” which allows it to require sponsors to implement REMS under section 505-1 of the Federal Food, Drug, and Cosmetic Act. 

The REMS consists of a Medication Guide, elements to assure safe use ("ETASU"), and a timetable for submission of assessments.  The ETASU includes an education program for prescribers and materials that the prescribers can use to educate patients regarding the safe use, storage, and disposal of extended-release opioids.  Part of this program appears to include educating prescribers about the potential use of a “Patient Provider Agreement.”  The education program should be conducted through a continuing medical education provider and include information on opioid prescribing, product specific information, and patient counseling.  Prescribers must also obtain proof that they have successfully completed the education program.  The patient education materials must include, among other things, a Medication Guide and information on how to properly take an opioid, report adverse effects, and store opioids.  The materials released by FDA also mention a  “Patient Treatment Agreement,” although its use by the prescriber appears to be optional.

The timetable for submission of assessments is at least six months, 12 months, and annually after the REMS is approved.  Assessments should include the following:  the number of prescribers having completed the education program; an independent audit of the quality of the education materials used to train prescribers; an evaluation of patient and prescriber awareness of the risks associated with extended-release opioids; a surveillance plan to monitor misuse and abuse of opioids, including surveillance in various risk groups and settings; and evaluations of drug utilization and prescribing behaviors.  The FDA recommends that the sponsors of extended-release opioids cooperate to establish a single system for monitoring these assessments across all extended-release opioid products.

Sponsors must submit a proposed REMS based on the requirements described above within 120 days of the date of the notification letter.  Interestingly, FDA notes that prescriber education is not mandatory under the REMS, but FDA is working with other federal agencies and Congress to make it mandatory by linking prescriber education to training required by the Drug Enforcement Administration.  FDA expects the REMS to become effective by early 2012. 

By Kurt R. Karst –      

A recent amendment to the America Invents Act (H.R. 1249) introduced by Representative John Conyers (D-MI) and passed by voice vote during a markup of the bill last week by the
House Committee on the Judiciary would give The Medicines Company (“MDCO”) some legislative assurance of a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering the company’s ANGIOMAX (bivalirudin) as the the drama in the decade-old fight over a PTE continues to unfold in court. 

As we reported earlier this year, in February the U.S. Court of Appeals for the Federal Circuit denied MDCO’s Motion to Dismiss or, in the Alternative, to Bifurcate and Stay in Part APP Pharmaceuticals, LLC’s (“APP’s”) appeal related to Judge Claude M. Hilton’s August 3, 2010 decision in which he ordered the U.S. Patent and Trademark Office (“PTO”) to consider timely filed MDCO’s PTE application for the ‘404 patent under a next business day interpretation of the PTE statute.  (As folks might recall, FDA approved ANGIOMAX at 5:18 PM on Friday, December 15, 2000, and MDCO submitted its PTE application to the PTO on February 14, 2001 – 62 days after NDA approval, including the December 15, 2000 date of approval.  Under the PTE statute at 35 U.S.C. § 156(d)(1), the submission of a PTE application must occur “within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use.”)  The Federal Circuit’s February decision was precipitated by Judge Hilton’s September 13, 2010 decision denying APP’s Motion to Intervene in the litigation without addressing standing (on the basis that APP should have sought intervention earlier, and that allowing intervention at that point would unfairly prejudice MDCO).  APP appealed the decision to the Federal Circuit challenging not only the district court’s September 13th intervention decision, but also the underlying merits decision.  ANDA sponsor PLIVA recently filed an amicus brief in the Federal Circuit case in support of APP. 

Now back to the legislative front . . . .

Rep. Conyers’s amendment to H.R. 1249 would amend 35 U.S.C. § 156(d)(1) to add at the end of that section the following flush sentence:

For purposes of determining the date on which a product receives permission under the second sentence of this paragraph, if such permission is transmitted after 4:30 P.M., Eastern Time, on a business day, or is transmitted on a day that is not a business day, the product shall be deemed to receive permission on the next business dy.  For purposes of the preceding sentence, the term "business day" means any Monday, Tuesday, Wednesday, Thursday or Friday, excluding any legal holiday under section 6103 of title 5.

The “applicability” section of the amendment states that language above “shall apply to any application for extension of a patent term under section 156 of title 35, United States Code, that is pending on, that is filed after, or as to which a decision regarding the application is subject to judicial review on, the date of enactment of this Act.”  The language seems to match up pretty well with the current situation surrounding a PTE for the ‘404 patent.

Rep. Conyers’s amendment to H.R. 1249 – language that is not in the Senate-passed version of the bill, S. 23 – is not the first attempt to amend the PTE statute to accommodate the ‘404 patent; nor is it the first time that Rep. Conyers has been involved in what has come to be known as “The Dog Ate My Homework Act.”  In Securities and Exchange Commission filings made as early as March 2003, MDCO said that the company was “exploring an alternative to extend the term of the patent.”  Legislation was introduced in Congress in 2006, 2007, 2008, 2009, and 2010 (see our previous posts here, here, here, and here) reflecting the changing circumstances of the ‘404 patent PTE saga.  In June 2008, Rep. Conyers urged the House to pass the Responsive Government Act of 2008, which would have amended 35 U.S.C. § 156 to permit the PTO to accept late PTE submissions . . . for a fee ($65,000,000 for MDCO).

Although some industry support for H.R. 1249 seems to be fading – the Biotechnology Industry Organization issued a statement last week opposing House floor consideration of the bill due to a non-PTE issue – a legislative fix to MDCO’s ‘404 patent issue still appears to be alive and could ultimately be included in a final, enacted version of the America Invents Act. We’ll keep you posted.    

By Wes Siegner & Cassandra A. Soltis –

There has been a buzz in the trade press and industry over when a company is required under the Federal Food, Drug, and Cosmetic Act ("FDC Act") to submit to the Food and Drug Administration ("FDA") a 75-day premarket notification for a new dietary ingredient ("NDI").  Although parts of section 413 of the FDC Act are certainly confusing, the law is clear that an NDI does not need to be notified if it is “present in the food supply as an article used for food in a form in which the food has not been chemically altered.”  FDC Act § 413(a)(1).  Contrary to what has been reported in the press, to qualify for this alternative to the notification requirement, it is not necessary that the NDI be present and marketed in the food supply as an article used for food prior to October 15, 1994.  Presence in the food supply at any time, in any part of the world, is sufficient under the terms of § 413(a)(1).

Section 413 of the FDC Act defines an NDI as “a dietary ingredient that was not marketed in the United States before October 15, 1994 and does not include any dietary ingredient which was marketed in the United States before October 15, 1994” (emphasis added).  In other words, dietary ingredients that are first marketed in the United States on or after October 15, 1994 are, by definition, new dietary ingredients. 

A new dietary ingredient may be marketed immediately—that is, without FDA notification—if it is “present in the food supply as an article used for food in a form in which the food has not been chemically altered.”  FDC Act § 413(a)(1).  If there is no such evidence, however, the new dietary ingredient may still be marketed provided that a 75-day premarket notification is submitted to FDA and the notification contains, among other things, evidence that the dietary supplement containing the new dietary ingredient will “reasonably be expected to be safe.”  FDC Act § 413(a)(2).  In contrast, dietary ingredients marketed in the United States before October 15, 1994 are generally referred to in industry as “old dietary ingredients.”  Old dietary ingredients may be immediately marketed in dietary supplements; there is no notification required. 

Unlike § 413(c), which specifies that to be an old dietary ingredient, an ingredient must have been marketed in the United States prior to October 15, 1994, § 413(a) makes no such specification; the text “present in the food supply” is not qualified and, therefore, applies to any country’s food supply.  Thus, for example, if oat extract is eaten in Scotland (and assuming oat extract is not an old dietary ingredient), then oat extract is “present in the food supply”—the Scottish food supply—and is an “article used for food in a form in which the food has not been chemically altered.”  FDC Act § 413(a)(1).  Therefore, no NDI notification would need to be submitted. 

By Kurt R. Karst –      

On April 15th, Judge Ellen S. Huvelle of the U.S. District Court for the District of Columbia granted FDA’s Motion to Dismiss a Complaint filed last September by ViroPharma Incorporated (“ViroPharma”) in connection with the approval of ANDAs for generic versions of the company’s antibiotic drug of last resort, VANCOCIN (vancomycin HCl) Capsules.  The Washington Legal Foundation, in an amicus brief, joined ViroPharma in its opposition to FDA’s Motion to Dismiss.  ANDA sponsor Akorn, Inc. (represented by Hyman, Phelps & McNamara, P.C.) filed an amicus brief supporting FDA.

As we previously reported, ViroPharma’s Complaint alleges that FDA violated the Administrative Procedure Act (“APA”) when the Agency failed to engage in notice-and-comment rulemaking “before effectively amending its [ANDA] regulations to permit a waiver of the in vivo bioequivalence requirement based on 21 C.F.R. § 320.24 even when none of the waiver criteria of 21 C.F .R. § 320.22 are satisfied.” ViroPharma requested declaratory relief from the court, including “that the plain reading of FDA’s regulations requires an ANDA applicant seeking a waiver of the in vivo bioequivalence testing requirement to first meet one of the criteria set forth in 21 C.F.R. § 320.22,” and that a May 2008 FDA decision concerning generic PRECOSE (acarbose) – that 21 C.F.R. § 320.24 provides an independent basis for waiving the in vivo testing requirement even when none of the criteria of 21 C.F.R. § 320.22 is satisfied – constitutes an amendment to FDA’s ANDA bioequivalence regulations.

In her 11-page opinion, Judge Huvelle ruled that ViroPharma lacks standing.  Will Judge Huvelle’s decision help to clear the way for FDA approval of ANDAs for generic VANCOCIN for which there are, according to ViroPharma, 11 pending applications?  And will FDA now wrap-up consideration of ViroPharma’s citizen petition (detailed in Akorn’s amicus brief) and issue a response?  We patiently await answers to these questions.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Linda S. Carter will join the Firm as a Regulatory Scientist on April 19th.  Linda, who will primarily assist HP&M’s drug development group, brings significant experience and expertise in shaping regulatory policies, particularly Comparative Effectiveness Research, Personalized Medicine, and Evidence-Based Medicine. 

“I have had the pleasure to have worked alongside of Linda while we were both at FDA and have always been impressed with her sophisticated understanding of the FDA drug review system.  We are thrilled to welcome Linda to our HP&M family in order to even better enhance our services to our drug sponsor clients, and through them, to patients,” said Frank J. Sasinowski, Director.

From 1984-2002, Linda worked for FDA, during which time she served as Associate Director of Regulatory Affairs in the Office of Drug Evaluation I in the Center for Drugs Evaluation and Research, and as Regulatory Policy Advisor in the Office of Review Management (now the Office of New Drugs), CDER.  During her tenure at FDA, Linda received many awards, including the FDA Award of Merit and the Commissioner’s Special Citation. 

Prior to joining HP&M, Linda served in several pharmaceutical industry positions, including as Senior Director, Global Regulatory Policy and Intelligence, Janssen Pharmaceutical Companies of Johnson & Johnson, Executive Director, FDA Liaison, Drug Regulatory Affairs, Novartis Pharmaceuticals Corporation, and Director, Global Regulatory Affairs, Legislative Policy and Regulatory Liaison, Pharmacia Corporation. 

By Nisha P. Shah –

On April 13, 2011, FDA issued a proposed rule that would expand the scope of clinical investigator disqualification.  76 Fed. Reg. 20575, Apr. 13, 2011.   The proposed changes are in response to a September 2009 report by the Government Accountability Office (“GAO”) on FDA’s Oversight of Clinical Investigators, which recommended that FDA extend the disqualification to include ineligibility to receive any FDA-regulated investigational products, regardless of what type of FDA-regulated product was being investigated by the clinical investigator when the serious misconduct occurred.  Comments to the proposed rule are due on July 12, 2011. 

Under the draft rule, a clinical investigator, including a sponsor-investigator, disqualified pursuant to 21 C.F.R. Parts 312 (drugs and biologics), 511 (animal drugs), or 812 (devices) will be ineligible to receive “any test article.”  Specifically, the investigator will be disqualified from conducting any investigation that supports an application for a research or marketing permit for FDA-regulated products, including “drugs, biologics, devices, new animal drugs, foods, including dietary supplements, that bear a nutrient content claim or a health claim, infant formulas, food and color additives, and tobacco products.”

Several changes are intended to harmonize the drug, biologic, animal drug, and medical device clinical investigator disqualification regulations.  For instance, similar to the device regulations, FDA is proposing to add to 21 C.F.R. Parts 312 (drugs and biologics) and 511 (animal drugs) a requirement that the applicable FDA Center notify the investigator in writing of the alleged violations when the Center has information indicating that a clinical investigator has “repeatedly or deliberately” failed to comply with the relevant requirements or has “repeatedly or deliberately” submitted to FDA or to the sponsor of the investigation false information in any required report.  For purposes of the disqualification rules, the Agency is also clarifying that an investigator includes a sponsor-investigator. 

The proposed rule also will add a notification to the reviewing institutional review board (“IRB”) about the investigator’s disqualification, in addition to the current notification requirements to the investigator and sponsor.  The notification to all parties will explain the basis for FDA’s determination.  For example, the notification to the sponsor will list the investigator’s violations and include instructions concerning ongoing studies and any approved products containing the investigator’s data. 

Another change is to add that when the Agency “determines that an investigation may not be considered part of a research or marketing application, or a notification or petition submission, this determination does not relieve the sponsor of any obligation under any other applicable regulation to submit to FDA the results of the investigation.”  Further, FDA is proposing to harmonize the regulations and clarify that if the Commissioner determines, after the unreliable data submitted by the investigator are removed from the application, that the continued approval of the FDA-regulated product cannot be justified, “the Commissioner will proceed to withdraw” approval or clearance of the product in accordance with applicable provisions of the Federal Food, Drug & Cosmetic Act (FFDCA).  Finally, to harmonize the regulations, FDA is proposing that an ineligible investigator may be reinstated when the investigator has presented adequate assurances to the Agency that the investigator will conduct any clinical investigation in compliance with the applicable regulations.

By John A. Gilbert & Karla L. Palmer –

On Wednesday, April 13, 2011, the Drug Enforcement Administration (“DEA”) published an Interim Final Rule with a request for comments on the “Self-Certification and Employee Training of Mail-Order Distributors of Scheduled Listed Chemical Products.”  See 76 Fed. Reg. 20,518 (Apr. 13, 2011).  The Interim Rule implements the Combat Methamphetamine Enhancement Act of 2010 (“CMEA”), which President Obama signed into law on October 12, 2010, and we blogged about here.

Although retail distributors of these products have been subject to self certification and training requirements since 2006, the 2010 law establishes new requirements for mail-order distributors of scheduled listed chemical products (“SLCPs”), which are defined in the Controlled Substances Act (“CSA”) as products containing ephedrine, pseudoephedrine or phenylpropanolamine, and are marketed in the United States as non-prescription drugs, see 21 U.S.C. § 802(45). 

The new federal law requires mail-order distributors to self-certify to DEA in order sell SLCPs at retail if those retail sales are intended for personal use.  The DEA defines a “mail-order distributor” as a person who makes sales at retail of SLCPs for personal use, and uses the U.S. postal service or a private or commercial carrier to deliver the product to the customer.  The mail-order distributor’s required self-certification must include a statement that the distributor understands the regulatory requirements, and that its employees will receive the appropriate training prior to self-certification. 

After April 10, 2011, which is the date of the implementation of the CMEA, a mail-order distributor cannot sell SLCPs at retail unless it has self-certified through DEA’s website (and paid a $21.00 fee).  The self-certification requires the distributor to confirm the following: (1) The distributor understands that under federal law it can sell no more than 3.6 grams of SLCPs per day, or 7.5 grams in a thirty-day period, to each customer (versus a 9 gram monthly limit for face-to face sales); (2) the distributor’s employees have undergone DEA-required training prior to self-certification; and (3) the distributor is maintaining employee training records.  The distributor must submit a self-certification for each place of business where it sells the products at retail, which, for a mail-order distributor means, “at each location that prepares or packages products for distribution to customers, and each location where employees accept payment for such sales.”  Id. at 20,520.  The interim rule sets forth (in table form) a summary of requirements for mail-order sellers of SCLPs now in effect since the enactment of the CMEA.  Id. at 20,521  

The required content of the employee training has been developed by DEA and is available at its website, (http://www.deadiversion.usdoj.gov).  DEA states that employers “must use the content of this training in the training of their employees” who sell SLCPs.  An employer may supplement the required DEA training with its own content as well.  Id. at 20,520.  Starting on or after April 10, 2011, each employee of a mail order distributor who is responsible for delivering SLCPs directly to purchasers, or “who deals directly with purchasers by obtaining payment for the [SLCPs]” must undergo the training, and must sign an acknowledgement that he or she has received training prior to selling SLCPs. The record must also be kept in the employee’s personnel file. 

The interim rule implementing the law further provides that when a mail-order distributor files its initial self-certification, the DEA will assign it to one of twelve groups.  The expiration date of the self-certification for all regulated persons within any one group will be “the last day of the month designated for that group.”  The first certification period will run for a period of not less than 12 to not more than 23 months from the date of self-certification.  After this initial certification period expires, distributors must update their regulated persons must update their self-certification on an annual basis.  Id. at 20,521.

The interim rule’s preamble notes that “a mail-order distributor that knowingly or willfully self-certifies to facts that are not true is subject to fines and imprisonment by virtue of 18 U.S.C. § 1001.”  Id. 20,520. In addition, it is unlawful for mail-order distributors to “negligently fail to self-certify” under 21 U.S.C. § 830 (by an amendment to 21 U.S.C. § 842(a)(10)).

The interim rule is effective April 13, 2011.  Note, however, that the law requiring self-certification became effective on April 10, 2011 (180 days after its enactment on October 10, 2010).  DEA is soliciting comments on the interim rule, due on June 13, 2011.  The DEA found “good cause” to exempt this rule from notice and comment rulemaking that is normally required under the Administrative Procedure Act, because DEA asserts that the “requirements addressed by the [CMEA] in this rulemaking are self-implementing and changes in this rulemaking provide conforming amendments to make the language of the regulations consistent with that of the law.”  Id. at 20,519.

By Jennifer D. Newberger –

After more than fifteen years of related cases in the larger matter of The First Amendment v. Dietary Supplement Health Claims, FDA mostly won one.  And its winning card?  Knowing that the courts will not, and cannot, independently assess whether the scientific evidence provided to FDA to support a health claim for a dietary supplement constitutes “credible evidence.”  So, FDA drafted Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims (Jan. 2009), in which the Agency laid out the types of studies it believed may provide credible evidence of a health claim – including the way those studies should have been conducted and the data that should have been collected –and those that will not provide credible evidence.  Then, all a court has to do is ask if FDA followed the guidance document, without considering whether the standards the Agency put forth in the guidance document are a reasonable means of assessing credible evidence.

This appears to be the theory upon which the decision was reached in the case of Alliance for Natural Health US v. Sebelius (“Alliance II”).  In this case, plaintiffs challenged FDA’s decision declining to approve several health claims concerning the relationship between vitamins C and E and the risk for certain types of cancer.  Plaintiffs had submitted seventeen qualified health claims linking vitamins C and E with a reduction in the risk of certain types of cancer.  FDA denied thirteen of the claims entirely and permitted four others to be made as qualified claims with modified language.  In Alliance II, plaintiffs challenged FDA’s ruling on six of these claims – four that were denied outright, and two that FDA agreed to permit as qualified claims with modified language.

As a preliminary matter, the court stated that FDA need not conduct an empirical study on the efficacy of a disclaimer before an outright banning of a claim if there is either no evidence to support the claim, or the evidence in support of the claim is qualitatively weaker than evidence against the claim.  Such claims would qualify as unprotected commercial speech and are therefore not protected under the Central Hudson analysis.  However, empirical evidence of the inefficacy of disclaimers is required for FDA to ban a health claim that is based on some credible evidence.

Enter the guidance document.  At its core, the opinion indicated that if FDA properly applied the process outlined in the guidance document, and, based on that process, determined that no credible evidence existed to support the claim, or the evidence in support of the claim was qualitatively weaker than that against it, FDA’s decision would stand.  The court found this to be the case for each of the four claims that FDA banned outright, and therefore upheld FDA’s denial of these health claims.  (These claims were:  (1) Vitamin C may reduce the risk of lung cancer. The scientific evidence supporting this claim is convincing, but not conclusive. (2) Vitamin C may reduce the risk of colon cancer. The scientific evidence supporting this claim is persuasive, but not conclusive. (3) Vitamin E may reduce the risk of lung cancer. The scientific evidence for this claim is convincing, but not conclusive. (4) Vitamin E may reduce the risk of gastric cancer. The scientific evidence for this claim is persuasive, but not conclusive.)

The reason that FDA only “sort of” won this one is because the court remanded to FDA the two claims that FDA was willing to allow with additional modifications.  The court stated that the modifications “replaced plaintiffs’ claim[s] entirely” and were not sufficiently precise, concluding:  “Where the evidence supporting a claim is inconclusive, the First Amendment permits the claim to be made; the FDA cannot require a disclaimer that simply swallows the claim.” In other words, if FDA allowed a qualified health claim, the qualification cannot be so limiting as to essentially erase the relationship between a substance and the specified disease or health-related condition.

So where does this leave us?  By drafting the guidance document, FDA regained some of the control that it lost over the years regarding health claims and allowable disclaimers.  It has laid out the studies that it considers to constitute credible evidence, and no court is likely to question those determinations.  If a dietary supplement manufacturer intends to support a health claim with a study on FDA’s black list, it does so at its own risk.  But, if FDA approves a qualified health claim, it cannot modify the substance/condition relationship out of existence.  Only one thing is certain — this is not the last we will hear of The First Amendment v. Dietary Supplement Health Claims.