By Jeffrey K. Shapiro –

In our continuing quest to enlighten, we are launching today an occasional series that will examine significant or interesting warning letters involving medical device companies.

As you probably know, FDA issues warning letters to allege violations of the Federal Food, Drug, and Cosmetic Act and/or implementing regulations.  A warning letter is a statement of FDA’s enforcement position and a threat to pursue legal remedies if the target does not comply.  Usually, the alleged violation does not break new ground.  But, on occasion, FDA issues a warning letter that reveals a new or little known enforcement position.  This type of warning letter will be our critical focus.

Case in point:  A recent warning letter issued by the Philadephia District to a ventilator company appears to create a new standard for reporting malfunctions in life sustaining or life supporting devices or implantable devices.

As background, a malfunction complaint is reportable to FDA if a recurrence would be likely to cause or contribute to a death or serious injury.  See 21 C.F.R. § 803.50(a)(2).  In this case, there were complaints of ventilator malfunction that were not reported that FDA apparently believes should have been reported.  This led FDA to issue a Form 483 observation.  The warning letter followed.

The warning letter does not describe the malfunction events at issue.  The story gets interesting, however, when FDA assesses the firm’s response to the Form 483 observation.  Apparently, the firm had revised its reportability criteria to limit reportability to “ventilator failure modes that result in a loss of therapy.”  This limitation seems perfectly reasonable.  If a malfunction is not capable of causing a loss of therapy, almost by definition it is unlikely to cause or contribute to a serious injury or death.  Therefore, such malfunctions do not trigger the regulatory requirement for reportability.

Yet, FDA rejected the proposed limitation.  The agency relies upon the preamble to the medical device adverse event reporting (“MDR”) regulation.  See 60 Fed. Reg. 63,578, 63,585 (Dec. 11, 1995) (comment 12).  This comment expresses FDA’s interpretive view that a malfunction involving a life sustaining or life supporting device is reportable.

This citation is not adequate to support FDA’s position.  In context, the preamble statement seems merely intended to establish an enforcement presumption that loss of therapy in a life sustaining or life supporting device is likely to cause a serious injury or death.  The preamble does not appear to intend that literally every possible malfunction in such a device will be reportable even if the basic regulatory requirements for reportability are absent.  (Even if that were FDA’s intent, the agency legally cannot alter the basic terms of a regulation via a preamble statement.)

For example, if a red light bulb in an “on” switch indicator in a ventilator is off because internal wiring has gone bad, but a white bulb next to it still works and the user can tell that the device is “on,” there would be no interruption in treatment due to this malfunction and no death or serious injury could occur.  Therefore, this malfunction is not reportable under the MDR regulation.  Under the approach taken in FDA’s warning letter, however, it would appear that this malfunction would need to be reported.

FDA’s final statement in the letter (on this topic) states:  “[Y]our firm should submit an MDR for complaints referencing ventilator failures.”  This statement introduces a new ambiguity by using the term “failures” rather than “malfunctions.”  it appears that FDA is using these terms interchangeably, even though they really are not synonymous.  In any event, in light of the warning letter’s earlier rejection of a policy limiting reportability to malfunctions resulting in a loss of therapy, FDA’s position appears to be that all ventilator malfunctions are reportable without further analysis as to whether they meet the reporting criteria in the MDR regulation.  If so, FDA’s position extends well beyond the plain language of the MDR regulation.

It is hard to know whether this warning letter is simply a “one off” or a harbinger.  Under the previous administration, Chief Counsel’s office was required to review the legal sufficiency and consistency with agency policy of all warning letters.  Now that this review is restricted to warning letters that present significant or novel legal issues, it is not clear whether this warning letter received legal review. 

What is clear is that the reasoning of this warning letter is not limited to ventilators.  It would appear to be applicable to any device deemed life sustaining or life supporting, e.g., insulin infusion pumps, dialysis machines, cardio pulmonary bypass pumps, critical care diagnostic monitors, automated external defibrillators, insulin infusion pumps, and the like.  In light of this warning letter, manufacturers of all such devices will need to keep a wary eye on FDA’s enforcement of the MDR regulation. 

The International Conference on Drug Development (“ICD2”), formerly known as the International Industrial Pharmacy Conference, continues its annual tradition of offering an informal forum for the exchange of ideas concerning the drug discovery and development process.  The 2012 conference, which is presented by The University of Texas at Austin College of Pharmacy, is scheduled for February 27-29, 2012 at the Barton Creek Conference Center in Austin, Texas.  The 2012 conference theme is “Fostering Innovation and Translational Research in Support of Public Health and Economic Growth.”  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will present at the conference during a session titled “Legal Considerations to Establish Biosimilarity and Therapeutic Interchangeability.”

The ICD2 conference is known for bringing together national and international scientists from academia, the pharmaceutical industry, the biotechnology industry, and regulatory agencies for the opportunity to learn about and discuss new initiatives for finding a better way to develop new drugs and improve the quality of existing drug products.   Information about the 2012 conference, including registration information, is available here.  A copy of the conference agenda is available here.

By Kurt R. Karst –      

Last week, the Government Accountability Office (“GAO”) released a report, titled “Food and Drug Administration: Better Coordination Could Enhance Efforts to Address Economic Adulteration and Protect the Public Health,” in which the GAO examines FDA’s approaches to detecting and preventing so-called “economic adulteration” of food and medical products, and the challenges FDA faces in detecting and preventing such adulteration.  The report responds to requests from Representatives Henry Waxman (D-CA), Frank Pallone (D-NJ), and John Dingell (D-MI) that the GAO review how FDA oversees the safety of products to prevent and respond to economic adulteration.  The requests followed two high-profile cases of economic adulteration involving melamine and melamine-related compounds in pet foods and oversulfated chondroitin sulfate in the blood thinner heparin – in both cases, the products were imported from China.

Economic adulteration (also known as “economically motivated adulteration”) is defined in the report to mean “the fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production, i.e., for economic gain.”  Economic adulteration includes, for example, “dilution of products with increased quantities of an already-present substance (e.g., increasing inactive ingredients of a drug with a resulting reduction in strength of the finished product, or watering down of juice) to the extent that such dilution poses a known or possible health risk to consumers, as well as the addition or substitution of substances in order to mask dilution.”  (The definition of “economic adulteration” used in the GAO report is the same definition FDA proposed in April 2009 as a working definition for “economically motivated adulteration” – see 74 Fed. Reg. 15,498 (Apr. 6, 2009).)  Economic adulteration, a form of “intentional adulteration” whose primary purpose is financial gain, differs from other types of adulteration – both intentional adulteration, whose primary purpose is to cause harm (e.g., bioterrorism or sabotage), and “unintentional adulteration” (e.g., adulteration for failure to follow good manufacturing practices) – says GAO in the report.  The FDC Act does not make a distinction between intentional and unintentional adulteration, but rather prohibits the introduction of adulterated food, drugs, and medical devices into interstate commerce.  Similarly, “FDA primarily approaches economic adulteration as part of its broader efforts to combat adulteration in general, such as efforts to ensure the safety of imported products.”

FDA officials and stakeholders GAO interviewed in preparing the report noted several key challenges to detecting and preventing economic adulteration, including increased globalization, an increase in supply chain complexity, and difficulties with gathering information from industry (due to concerns about sharing proprietary information).  To enhance FDA’s efforts to combat economic adulteration, GAO recommends that Commissioner Hamburg take three actions: (1) officially adopt a working definition of “economic adulteration,” because “[w]ithout such a definition, when FDA detects adulteration, it is more difficult for the agency to make a distinction between economic adulteration and other forms of adulteration to guide the agency’s thinking about how to be more proactive about this issue;” (2) “provide written guidance to agency centers and offices on the means of addressing economic adulteration;” and (3) “enhance communication and coordination of agency efforts on economic adulteration,” because “[w]ithout such communication and coordination, in these times of economic uncertainty, FDA may not be making the best use of its scarce resources.”

FDA notes in the Agency’s response to the GAO report that FDA recently established the Working Group on Economically Motivated Adulteration (“WEMA”), which is comprised of staff from all FDA centers, the Office of Regulatory Affairs, and Office of the Commissioner.  WEMA, which held its first meeting on September 23, 2011, and will use the Agency’s proposed working definition of economically motivated adulteration to identify topics of broad Agency interest, “seeks to encourage information sharing across FDA on issues relevant to economically motivated adulteration.”

In his recent article appearing in FDLI Update, Hyman, Phelps & McNamara, P.C. Of Counsel, and former diversion investigator for the Drug Enforcement Administration (“DEA”), Larry K. Houck, explains the scope of DEA pre-registration and cyclic inspections as a step-by-step guide to actions and procedures registrants should take to prepare for and manage such inspections.  Citing, among other things, a recent notice (see our previous post here) stating that DEA is conducting more frequent scheduled investigations, as well as increasing the depth of review, Mr. Houck says that “there are certain actions and procedures that registrants can and should follow to prepare for and manage the inspection – before, during and afterwards.”

By Kurt R. Karst –      

Almost a year after having notified Genentech of a proposal to withdraw the approval of Avastin® (bevacizumab) for use with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer, and almost five months after holding a hearing (Docket No. FDA-2010-N-06211) on the topic, FDA, on November 18th, announced FDA Commissioner Margaret Hamburg’s decision to withdraw the approval.  FDA approved Avastin® under BLA No. 125085 on February 22, 2008 for the breast cancer use under the Agency’s “accelerated approval” regulations.  Avastin® was initially approved on February 26, 2004 as a first-line treatment in combination with intravenous 5-fluorocil-based chemotherapy in patients with metastatic carcinoma of the colon and rectum, and has since been approved for other uses.  None of those uses are affected by FDA’s November 18th decision. 

In December 1992, FDA promulgated final regulations under which the Agency will accelerate the approval of certain new drugs and biologics for serious or life-threatening illnesses, and when such products provide a meaningful therapeutic benefit to patients over existing treatments.  These accelerated approval regulations are located in Subpart H (21 C.F.R. Part 314) of FDA’s drug regulations, and in Subpart E (21 C.F.R. Part 601) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based on a demonstrated effect on a surrogate endpoint reasonably likely to predict clinical benefit and a sponsor’s commitment to complete with due diligence the required postmarketing studies to confirm the product’s clinical benefits.  A surrogate endpoint is an alternative measurement of the symptoms of a disease or condition that is substituted for measurements of observable clinical symptoms. 

Importantly, FDA may withdraw the approval of an application approved under the accelerated approval regulations if, for example, “[a] postmarketing clinical study fails to verify clinical benefit,” “[o]ther evidence demonstrates that [a] product is not shown to be safe or effective under its conditions of use,” or if a sponsor “fails to perform the required postmarketing study with due diligence.”  FDC Act § 506 – Fast Track Products – was enacted in 1997 as part of the FDA Modernization Act and is generally considered to have codified FDA’s accelerated approval regulations.  Like FDA’s accelerated approval regulations, FDC Act § 506 provides that FDA “may withdraw approval of a fast track product using expedited procedures,” if, for example, “a post-approval study of the fast track product fails to verify clinical benefit of the product,” or “other evidence demonstrates that the fast track product is not safe or effective under the conditions of use.” 

FDA’s February 2008 approval of Avastin® was based on a single study – the E2100 study – in which metastatic breast cancer patients showed an improvement of 5.5 months of median Progression Free Survival (“PFS”), the surrogate endpoint, but that did not demonstrate an overall survival benefit or improvement in quality of life.  The required postmarketing studies to confirm the benefit of Avastin® for the breast cancer indication – named AVADO and RIBBON1 – had already begun at the time of approval.  In both studies, PFS was the primary endpoint.  The results of the AVADO and RIBBON1 studies were submitted to FDA in November 2009.  FDA determined that the results of the studies did not confirm that the increase in PFS was as substantial as the E2100 study supporting the accelerated approval of Avastin® had suggested – i.e., the studies did not, according to FDA, verify clinical benefit – and the Agency proposed to withdraw the breast cancer indication. 

Genentech promptly requested a hearing on the proposed withdrawal.  FDA and Genentech disputed the effectiveness information for the Avastin® breast cancer indication and the appropriate risk-benefit analysis to be applied in this case.  At the conclusion of the hearing, the advisory committee unanimously voted that the AVADO and RIBBON1 studies failed to verify clinical benefit, that the available evidence on Avastin® demonstrates that the drug has not been shown to be effective for the breast cancer indication, that the available evidence on Avastin® do not demonstrate that it is safe for the breast cancer indication and that Avastin® has not been shown to present a clinical benefit that justifies the risks associated with the drug for the breast cancer indication, and that the FDA Commissioner should not continue the approval of Avastin® for the breast cancer indication while Genentech designs and conducts additional studies intended to verify the product’s clinical benefit if the Commissioner agrees with certain grounds for withdrawal.

FDA Commissioner Hamburg states in her 69-page decision that after having carefully reviewed the record, the conditions for withdrawal have been met, and that “the currently available data do not support continued accelerated approval of this drug for this indication.”  The results of the AVADO and RIBBON1 studies, says Commissioner Hamburg, “substantially changed the profile of [Avastin®],” and “have not verified the clinical benefit shown in E2100.            

The Avastin® withdrawal is not the first instance in which a product granted accelerated approval has been withdrawn from the market – either because a postmarketing study failed to verify clinical benefit, or because of a sponsor’s failure to complete a required postmarketing study with due diligence – although it is the first instance in which the hearing procedures have been completed and FDA has made a withdrawal decision.  As we previously reported, Pfizer voluntarily withdrew (at least insofar as a voluntary withdrawal is truly voluntary when FDA requests it) MYLOTARG (gemtuzumab ozogamicin for Injection) from the market after a required postmarketing study failed to demonstrate clinical benefit.  In addition, in August 2010, FDA issued a hearing notice and proposal withdraw approval of all marketing applications for the accelerated approval drug Midodrine HCl, which FDA first approved in September 1996 under the brand name PROAMATINE to treat orthostatic hypotension (see our previous post here).  Since that time, a hearing has been requested, but FDA appears to have delayed scheduling a hearing.  Instead, FDA opened a public docket (FDA-2010-N-0637) “to provide a forum to facilitate communication regarding the conduct of clinical trials needed to verify and describe the clinical benefit of midodrine hydrochloride.” 

Additional Reading:

• Genentech Press Release
• Genentech Avastin® Website
• Senator David Vitter (R-LA) Comments on FDA Avastin Decision
• National Breast Cancer Coalition Statement
• Mississippi Lawmakers Knock FDA Decision

By Kurt R. Karst –      

Less than a month before the U.S. Supreme Court is scheduled to hear Oral Argument in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, Docket No. No. 10-844 (see here and here), concerning whether the patent delisting counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I), as added by the Medicare Modernization Act, may be used to correct or delete an Orange Book-listed Patent Use Code (“PUC”), the U.S. District Court for the District of New Jersey granted a Motion to Dismiss a similar counterclaim in Hoffmann-La Roche Inc. v. Orchid Chemicals & Pharmaceuticals Ltd., a patent infringement lawsuit concerning generic BONIVA (ibandronate sodium) Tablets, 150 mg (“BONIVA Once-Monthly”).

BONIVA Once-Monthly, approved under NDA No. 021455, is a bisphosphonate indicated for the treatment and prevention of postmenopausal osteoporosis.  The drug is currently listed in the Orange Book with five patents, including U.S. Patent Nos. 7,718,634 (“the ‘634 patent”) and 7,410,957 (“the ‘957 patent”).  Both the ‘634 and ‘957 patents are listed in the Orange Book as method-of-use patents and expire on May 6, 2023.  The ‘634 patent, which issued on May 18, 2010, is listed with a “U-642” PUC, defined as “TREATMENT AND PREVENTION OF OSTEOPOROSIS,” and the ‘957 patent, which issued on August 12, 2008, is listed with a “U-887” PUC, defined as “TREATMENT AND PREVENTION OF OSTEOPOROSIS.” 

Orchid Healthcare, an unincorporated division of Orchid Chemicals and & Pharmaceuticals Ltd. (“Orchid”), submitted ANDA No. 078998 to FDA on or about May 16, 2007 seeking approval to market a generic version of BONIVA Once-Monthly, and containing a certification to the then-listed Orange Book patents for NDA No. 021455.  After having amended ANDA No. 078998 with Paragraph IV certifications to the ‘634 and ‘957 patents, Hoffmann-La Roche, Inc. (“Roche”) sued Orchid for patent infringement.  In response to Roche’s First Amended Complaint, Orchid included in its Answer, among other things, a counterclaim pursuant to FDC Act § 505(j)(5)(C)(ii)(I) requesting that the court issue an order requiring Roche to correct the PUCs for the ‘634 and ‘957 patents.  According to Orchid, “Roche’s use codes do not accurately describe the patented methods of use found in the claims of the 634 and 957 patents, in that they state that the 634 and 957 patent claims cover prevention of osteoporosis,” and “Roche must correct the use code for the 634 patent . . .  from ‘U-642: treatment and prevention of osteoporosis’ to ‘treatment of osteoporosis,’ and correct the use code for the 957 patent . . . from ‘U-887: treatment and prevention of osteoporosis’ to ‘treatment of osteoporosis.’”

Of course, hanging over Orchid’s counterclaim was the Federal Circuit’s 2010 decision in Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd., 601 F.3d 1359 (Fed. Cir. 2010), in which the Court reversed and vacated a 2009 decision from the U.S. District Court for the Eastern District of Michigan (Southern Division).  The district court ruled and issued an Order and Injunction requiring Novo Nordisk to change an Orange Book-listed PUC for a patent concerning PRANDIN (repaglinide) Tablets as a result of Caraco’s FDC Act §505(j)(5)(C)(ii)(I) counterclaim.  The Federal Circuit ruled that Caraco “does not have a statutory basis to assert a counterclaim requesting” a court to enter an order to change a PUC.  First, the Federal Circuit ruled that “the Hatch-Waxman Act authorizes a counterclaim only if the listed patent does not claim any approved methods of using the listed drug.”  Second, “the terms of the counterclaim provision do not authorize an order compelling the patent holder to change its use code narrative,” just the patent number and expiration date of an Orange Book-listed patent.  As noted above, the Federal Circuit’s decision is before the Supreme Court. 

Orchid says in its counterclaim that it believes the Federal Circuit’s “ruling is incorrect and that a cause of action for equitable relief exists . . . .”  Roche, however, says otherwise it its Motion to Dismiss: “[U]nder Caraco, the specific patent-listing issue for which the counterclaim was created does not apply here.  Since, there is no statutory basis for the new counterclaim as the Federal Circuit has stated in Caraco, Orchid’s Third Counterclaim should be dismissed pursuant to Fed. R. Civ. P. 12(b)(6), for failure to state a claim upon which relief can be granted.”  Orchid attempted to bolster its case in the company’s opposition to Roche’s Motion to Dismiss, stating that “[g]iven the substantial possibility that the law in this area will change before the present case is concluded, Roche’s motion to dismiss should be denied, without prejudice to renewal after the Supreme Court decision in Caraco.”   But Roche fired back that Orchid’s counterclaim is “dead in the water.”  “The highly speculative possibility that the Supreme Court might overturn years of established precedent in implied private right of action cases in a way that would give Orchid some grounds for relief does not justify burdening this Court or Plaintiffs with additional discovery and delay as the case is prepared for trial early next year,” argued Roche. 

Judge Stanley R. Chesler quickly dispensed with Orchid’s PUC counterclaim, saying that it “may be decided easily.”  Orchid’s sole argument in opposition to Roche’s Motion to Dismiss, writes Judge Chesler “is that a case is pending before the Supreme Court which might change existing law, and so this Court should abstain from deciding this motion now.  This Court construes this position as a concession that the third counterclaim is not valid under existing law.”  Accordingly, Judge Chesler granted Roche’s Motion to Dismiss Orchid’s third counterclaim.

By Ricardo Carvajal –

Late last month, a district court issued a ruling of interest in a Lanham Act case brought by sugar producers and trade associations against corn refiners and the Corn Refiners Association ("CRA") over their marketing of high fructose corn syrup ("HFCS").  The suit alleges that CRA’s claims that “HFCS is corn sugar,” “HFCS is natural,” and “sugar is sugar” constitute false advertising because HFCS is not naturally occurring and has effects on the body that differ from those of table sugar. 

In denying Defendants’ motion to dismiss as to Defendant CRA, the court rejected CRA’s contention that the challenged claims are not advertising, but are instead part of an “education campaign.”  The court noted that statements are not insulated from action under the Lanham Act by virtue of relating to a public health issue, and concluded that the challenged statements were promotional in nature:

As a trade organization made up of corn refiners, an economic motive exists, and the statements refer specifically to [HFCS].  The statements themselves also clearly are promoting corn syrup to food and beverage purchasers. 

However, the court granted Defendants’ motion to dismiss as to the individual corn refiners.  The court rejected Plaintiffs argument that CRA’s conduct should be imputed to the refiners because CRA is an agent of the refiners, all of whom are CRA members and financed CRA’s campaign:

Plaintiffs’ allegations as to the relationship between CRA and its members are conclusory and do not establish the authority to control that is required to show an agency relationship.  Hence, the Court cannot impute CRA’s actions to the remaining defendants.  Furthermore, Plaintiff’s allegations do not establish a false advertising claim against the individual member companies, as the First Amended Complaint lacks any allegations of the Member Defendants engaging in any advertising.

Although CRA has submitted a citizen petition to FDA seeking to rename HFCS as “corn sugar,” the court refused to apply the doctrine of primary jurisdiction.  That doctrine “allows a court to stay or dismiss an action without prejudice pending resolution by a government agency of an issue within its special competence.”  The court noted that the suit raises issues that would not be resolved by a decision on the citizen petition, and that there is no precedent for applying the doctrine in a case involving a challenge to an advertising campaign. 

By Jennifer D. Newberger –

On Tuesday, November 15th, Senator Al Franken (D-MN) announced the introduction of S. 1865, the “Patient Access to Medical Innovation Act.”  The bill is intended to accomplish two goals:  first, to allow manufacturers of products granted a humanitarian device exemption ("HDE") to profit from development of devices used in both adult and pediatric populations and, second, to ease conflict of interest restrictions on FDA advisory committee members.

Manufacturers may obtain an exemption from the effectiveness requirements for a device if (1) the device is “designed to treat or diagnose a disease or conditions that affects fewer than 4,000 individuals in the United States,” (2) the device would not be available to a person with the disease or condition unless FDA granted the exemption, and there is no comparable device available to treat or diagnose the condition, and (3) “the device will not expose patients to an unreasonable or significant risk of illness or injury and the probable benefit to health from the use of the device outweighs the risk of injury or illness from its use.”  FDC Act § 520(m)(2). 

Senator Franken’s bill retains these requirements for obtaining an HDE.  What it changes is the manufacturer’s ability to profit from sale of an HDE device.  Currently, the law prohibits a manufacturer from selling the device “for an amount that exceeds the costs of research and development, fabrication, and distribution of the device,” unless the device “is intended for the treatment or diagnosis of a disease or condition that occurs in pediatric patients or in a pediatric subpopulation, and such device is labeled for use in pediatric patients or in a pediatric subpopulation in which the disease or condition occurs.”  FDC Act §§ 520(m)(3), 520(m)(6)(A)(i)(I).  Senator Franken’s proposal would allow manufacturers to profit from the sale of any device granted an HDE, regardless of the intended patient population. 

Senator Franken’s bill also includes language that would make the legislation retroactive.  This means that manufacturers who currently market a product under an HDE, and who are unable to profit from the sale of such device, will be able to profit after the legislation is enacted, even if they obtained the HDE prior to its enactment.

In addition to changes to the HDE legislation, Senator Franken’s bill proposes changes to FDC Act Section 712, Conflicts of Interest.  Currently, section 712 limits the number of conflict-of-interest waivers that FDA may provide to experts that it would like to serve on its advisory committee.  The result of this restriction has been that FDA is often unable to obtain industry’s most qualified experts to serve.  The language in Senator Franken’s bill would require FDA to “ensure that each [waiver] considers the scope and magnitude of the financial interest at issue with the public health need for the expertise of the member on the advisory committee.”  This is intended to allow FDA to access a broader range of experts who would be unable to serve under the current legislation, and balance the potential conflict-of-interest against the need for participation by experts in a particular field.  Such expert consultation can play a critical role in bringing products to market.  If Congress enacts Senator Franken’s legislation, hopefully FDA will take advantage of the newly available expertise.

By Kurt R. Karst –      

On November 16th, Senators Jeff Bingaman (D-NM), David Vitter (R-LA), Sherrod Brown (D-OH), and Jeff Merkley (D-OR) announced the introduction of the Fair And Immediate Release of Generic Drugs Act, or the “FAIR GENERxICS Act,” a draft version of which is available here. 

The bill would make significant changes to the Hatch-Waxman Amendments, as amended by the Medicare Modernization Act, with respect to 180-day exclusivity under FDC Act § 505(j), as well as to the patent laws at 35 U.S.C. § 271(e), and is aimed at addressing the perceived ill-effects on generic competition of patent settlement agreements between drug companies (or what opponents refer to as “pay-for-delay” or “reverse payment” agreements).  According to the bill’s sponsors, the bill is intended to address “the root cause of anti-competitive pay-for-delay settlements between brand and generic pharmaceutical manufacturers: the unintended, structural flaw in the Hatch-Waxman Act that allows ‘parked’ exclusivities to block generic competition.”

As with most things Hatch-Waxman, the bill is complex.  In a future post we may dissect the various provisions of the bill, which include broadening the FDC Act’s definition of “first applicant” and the interplay with patent settlement agreements.  According to a summary of the FAIR GENERxICS Act:

The legislation would prevent “parked exclusivities” from delaying full, fair, and early generic competition by:

• Granting the right to share exclusivity to any generic filer who wins a patent challenge in the district court or is not sued for patent infringement by the brand company.
• Maximizing the incentive for all generic challengers to fight to bring products to market at the earliest possible time by holding generic settlers to the deferred entry date agreed to in their settlements.
• Creating more clarity regarding litigation risk for pioneer drug companies and generic companies by requiring pioneer companies to make a litigation decision within the 45 day window provided for in the Hatch-Waxman Act.

As a result, say the bill’s sponsors, “companies who prevail in their patent challenges and immediately come to market may be the sole beneficiary of the 180 day exclusivity period.  In addition, companies will understand litigation risk before launching generic products.” (Italics in original.)

It is worth noting that the FAIR GENERxICS Act bears some resemblance to the Drug Price Competition Act of 2009, which was introduced in the U.S. Senate by Sen. Bill Nelson (D-FL) as S. 1315, and in the House of Representatives by Rep. Alcee Hastings (D-FL) as H.R. 3777.  We previously reported on the bill here.  The Drug Price Competition Act of 2009 died with the adjournment of the last Congress, but not before  Rep. Hastings, in December 2009, proposed and then withdrew from consideration his bill as an amendment to the House Health Care Reform Bill.

By Kurt R. Karst –      

In a lawsuit filed in the U.S. District Court for the District of Columbia, Florida-based Hill Dermaceuticals, Inc. (“Hill”) is seeking declaratory and injunctive relief after FDA approved, on October 17, 2011, three ANDAs submitted by Identi Pharmaceuticals Inc. (“Identi”) – ANDA Nos. 091306, 201759, and 201764 – for AT-rated generic versions of Hill’s peanut-oil containing fluocinolone acetonide drug products Derma-Smoothe/FS Topical Oil, 0.01% (Scalp Oil and Body Oil) and Derm-Otic Oil Ear Drops, 0.01%, which are approved under NDA No. 019452 to treat certain moderate to severe skin conditions, such as eczema and atopic dermatitis.  Copies of the Complaint and Motion for a Preliminary Injunction are available here and here. 

The lawsuit comes more than two years after FDA partially granted and denied a citizen petition submitted by Hill in September 2004 (Docket No. FDA-2004-P-0215) requesting that FDA, in light of the “novel and innovative application and delivery systems” of Derma-Smoothe, withhold approval of any ANDA unless certain requirements are met concerning active ingredients, conditions of use, labeling, bioequivalence, and chemistry, manufacturing and controls.  Among other things in the petition decision, FDA, in response to Hill’s requests that the Agency require ANDA sponsors to set an upper limit for the amount of peanut protein that can be present in the vehicle and to demonstrate that their peanut oil meets this specification by using a test that is “validated and capable of quantifying very low levels of peanut protein,” stated that “[g]iven the gap between the quantity of orally administered peanut proteins required to cause an allergic reaction and the level of peanut proteins left in fully refined peanut oil, it is reasonable to conclude that the USP NF refining process reduces peanut protein to acceptable levels for the indications in question.”  Hill also requested that FDA categorically reject any request from an ANDA sponsor for a waiver of in vivo bioequivalence testing (i.e., “biowaiver”) for a generic Derma-Smoothe drug product.  FDA denied this request, stating that the Agency could grant a biowaiver because Derma-Smoothe “is a solution for purposes of 21 C.F.R. § 320.22(b)(3).”

FDA decided Hill’s citizen petition more than a year after the D.C. District Court denied Hill’s motion for a stay to prevent the approval of any ANDAs for generic Derma-Smoothe until FDA issues a substantive response to Hill’s September 2004 citizen petition.  At that time, the court stated that Hill “would have an opportunity to seek emergency relief from this Court once the FDA denied its citizen petition and improperly approved an ANDA.” 

Hill’s five-count Complaint alleges that FDA’s approval of the Identi ANDAs violates various provisions of the FDC Act and the Administrative Procedure Act (“APA”).  For starters, Hill alleges that contrary to the statutory requirement at FDC Act § 505(j)(2)(A)(v) that the labeling for a generic drug be “the same” as the labeling approved for the brand-name, reference listed drug relied on for approval, “the generic forms of fluocinolone acetonide that FDA has approved will almost certainly include labeling that is substantially different from the labeling used on Hill’s products.  In particular, the generic labeling cannot be the same as the labeling on Hill’s products because Identi’s products have not been subjected to the same tests that FDA has required Hill to perform to protect against serious risks associated with peanut allergies.”  And even if the Hill and Identi drug products do have the same labeling, says Hill, “then the generic drug is misbranded” under the FDC Act.  According to Hill:

[I]f the labeling for Identi’s products includes the same representation as the FDA-approved labeling for Hill’s products – namely, “that the, product is routinely tested for peanut proteins through amino acid analysis; the quantity of amino acids is below 0.5 parts per million (PPM)” – that would not be a truthful statement.  In addition, because the labeling does not provide accurate information about the quantity of residual peanut protein and suggests that Identi’s products have been tested in the same manner as Hill’s products, the labeling omits material facts and lacks adequate information for use.  Accordingly, because the labeling for Identi’s products are false and misleading and otherwise do not comply with the statutory requirements, the purported generic drugs are misbranded and may not be sold or marketed.

Moving on to the APA, Hill alleges that FDA violated the law by not treating like cases alike and by imposing arbitrary and unequal burdens on similarly situated parties.  “FDA has violated these settled principles of reasoned decision-making by, on one hand, compelling Hill to invest millions in developing and performing a proprietary test to determine and control the quantity of residual peanut proteins in its products on an ongoing basis and, then, on the other hand, not requiring generic manufacturers to satisfy the same onerous and important testing requirements,” says Hill in its Motion for a Preliminary Injunction.

Finally, Hill alleges that FDA violated the FDC Act in approving Identi’s ANDAs without adequate testing data:

[T]he FDCA requires applicants seeking to obtain approval through the ANDA process to demonstrate that the purported generic product is bioequivalent to the approved.  Identi cannot satisfy that requirement because its products have not undergone adequate testing. . . .  Nor do Identi’s products satisfy the regulatory criteria for waiving the requirement that Identi establish in vivo bioequivalence.  The products manufactured by Hill are topical oils and do not qualify as “solutions” subject to the limited biowaiver exception under 21 C.F.R. § 320.22(b)(3)(i).  Similarly, the products do not fall within the catch-all provision for products in a “similar other [solubilized] form.”  [(Citations omitted)]

Hill is seeking from the DC District Court declaratory and injunctive relief, including the entry of a preliminary and permanent injunction directing FDA to withdraw or suspend the Identi ANDA approvals, require Identi to conduct in vivo bioequivalence testing and to use the “same labeling” before approving such ANDAs, and to take any action necessary “to prevent the marketing and distribution of purported generic products that are not bioequivalent to, and do not use the same labeling as,” the Derma-Smoothe product line. 

By Carmelina G. Allis –

A persistent industry complaint is that CDRH too often changes data requirements in the middle of a review, or requires data for a new device that was not required for predicate devices.

It appears that CDRH has taken a step toward addressing this complaint.  A new SOP issued by FDA’s Center for Devices and Radiological Health (“CDRH”) tries to define the responsibilities of management when CDRH review staff has identified the need to make changes in data requirements from what was requested in other premarket submissions or previous communications with a manufacturer.  “[W]hen staff become[] aware of new information that may alter the information and data required for premarket review [for a generic category of devices], they should receive concurrence from the appropriate management level before taking any action.”

Concurrence from the branch chief should be obtained for data requests that apply to a single device based on specific issues applicable to that particular device, or that are deemed necessary to support a new indication or new technology that is different from the predicate.  If the data request is for clinical studies, then the branch chief should take the matter to the division level for concurrence.  In addition, division level sign-off should be obtained for situations where animal testing is imposed as a new requirement, or non-clinical data are required because of new information obtained by the agency about the device type (e.g., device failures).  Division sign-off should also be required for “minor” changes to a clinical study, such as minor adjustments to an endpoint, and for changes that impact devices in other branches within the same Division.

Concurrence from the CDRH Office of Device Evaluation would be required for situations where the changes to data requirements would affect multiple branches and/or divisions, where the request would diverge from statements in a guidance document or pre-submission with the sponsor, or the request would impose major changes to an ongoing clinical study (e.g., requiring a new clinical study, changes from a single arm to a randomized study, etc.).  Concurrence from CDRH’s Center Science Council would be required for circumstances where the data requirements are to change significantly from what was previously requested, such as asking for clinical data when such studies had not been requested in the past.

The SOP clearly emphasizes the importance of obtaining written concurrence (e.g., via email) from the appropriate management level prior to implementing the change in data requests.

It is apparent from this SOP that manufacturers will not be included in the decision process – that is, the decision to change data requirements will be implemented if the appropriate manager concurs with the change, but nowhere does the SOP require that the decision-making process weigh in the manufacturer’s opinion on the matter.  Prior public notice, such as in the form of guidance or rulemaking, will be pursued as deemed necessary, such as for changes in data requirements applied across a class of products.

Obviously, the impact of this new SOP remains to be seen, but it is a step in the right direction.

By Riëtte van Laack –

On November 8, 2011, Senator Durbin and Representative Waxman requested that the U.S. Government Accountability Office ("GAO") determine how the adverse event reporting ("AER") for dietary supplements system is working.  Since December 22, 2007, pursuant to the Dietary Supplement and Nonprescription Drug Consumer Protection Act, manufacturers, packers, and distributors of dietary supplements in the United States have been required to report information about serious AERs to FDA.  Congress requested that GAO collect information about the AERs reported thus far, e.g., number of AERs, dietary supplements associated with AERs, nature of AERs and who submits AERs.  In addition, GAO is to report on FDA’s efforts to ensure compliance with the law requiring serious AER reporting and whether, and to what extent, FDA has implemented the recommendations GAO made in its 2009 report.

By Kurt R. Karst –  

Politico recently published an opinion piece authored by Federal Trade Commission (“FTC”) Chairman Jon Leibowitz, who is up for reappointment for a second term on the Commission, in which he stated he wanted to throw in his “two cents” on how Congress (and specifically the Joint Select Committee on Deficit Reduction – a.k.a. the “Super Committee”) can work to reduce the deficit “by billions of dollars, put billions more back in consumers’ pockets and cut health care costs for businesses that create new jobs – all without any new taxes or cuts in government programs.”  How?  Yes, you guessed it – by curbing patent settlement agreements (or what opponents refer to as “pay-for-delay” or “reverse payment” agreements).  The opinion piece came out shortly after the FTC the announced the release of its annual summary of agreements filed with the Commission during Fiscal Year 2011 saying that “pharmaceutical companies continued a recent anticompetitive trend of paying potential generic rivals to delay the introduction of lower-cost prescription drug alternatives for American consumers.”  (See our previous post here.)

The Congressional Budget Office (“CBO”) recently estimated that the enactment of the Preserve Access to Affordable Generics Act (S. 27) “would reduce unified budget deficits by approximately $1.4 billion over the 2012-2016 period and by nearly $4.8 billion over the 2012-2021 period.”  In January 2010, the CBO initially estimated that an essentially identical version of the Preserve Access to Affordable Generics Act considered by the last Congress (S. 369) “would reduce unified budget deficits by approximately $0.8 billion over the 2010-2014 period and by roughly $2.0 billion over the 2010-2019 period.”   That estimate was updated to reflect the passage of the Affordable Care Act.

Chairman Leibowitz’s Politico piece drew sharp criticism from another FTC Commissioner, J. Thomas Rosch.  In a response published by Politico, Commissioner Rosch stated that he does not think the Preserve Access to Affordable Generics Act should be tacked onto any piece of legislation, but rather, should stand or fall on its own merits.  Moreover, “[a]ny projected savings [from the legislation] are inherently speculative,” wrote Commissioner Rosch. 

Commissioner Rosch also took the opportunity to once again express his disagreement with the “clear and convincing” evidence standard in the Preserve Access to Affordable Generics Act.  The bill would, among other things, amend the FTC Act to permit the FTC to “initiate a proceeding to enforce the provisions of [new Sec. 28] against the parties to any agreement resolving or settling, on a final or interim basis, a patent infringement claim, in connection with the sale of a drug product.”  Such agreements, if challenged, would be presumptively anticompetitive and unlawful unless it can be demonstrated “by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.”  According to Commissioner Rosch, “[t]his heightened standard of proof has not been required in other types of settlements.  Indeed, the parties arguably should bear only the burden of producing some evidence justifying their settlement, and the commission arguably should always bear the burden of proving that the settlement is anticompetitive.”  His comments echo those he made during a speech earlier this year at the Sixth Annual In-House Counsel Forum on Pharmaceutical Antitrust, and that are shared by some Members of Congress (see our previous post here).

Hyman, Phelps & McNamara, PC, the nation’s largest boutique food and drug regulatory law firm, is seeking a recent law school graduate or junior attorney with prior experience in the pharmaceutical or biotech industries in either clinical or regulatory affairs.  Excellent academic credentials and strong writing skills are required.  Scientific or technical background would be desirable.  Compensation is competitive and commensurate with experience.  HPM is an equal opportunity employer.

Please send your curriculum vitae, transcript, and a writing sample to Jeffrey N. Wasserstein (jnw@hpm.com). 

By Kurt R. Karst –   

On November 15th, the U.S. Court of Appeals for the Federal Circuit will hear oral argument in Medicines Co. V. Kappos et al., Case No. 2010-1534, perhaps starting (or ending) another chapter in the saga over a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering The Medicines Company’s (“MDCO’s”) ANGIOMAX (bivalirudin).

As we previously reported, Section 37 of the Leahy-Smith America Invents Act (“AIA”) (Pub. Law No. 112-029), titled “Calculation of 60-Day Period for Application of Patent Term Extension” and referred to by some as “The Dog Ate My Homework Act” or the “Medco fix,” amended the PTE statute at 35 U.S.C. § 156(d), and was intended to legislatively resolve MDCO’s PTE battle.  Section 37 effectively codify Judge Claude M. Hilton’s August 3, 2010 decision in The Medicines Company v. Kappos, 731 F. Supp. 2d 470 (E.D. Va. 2010), in which Judge Hilton ordered the 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.)

We previously reported that shortly after the enactment of the AIA, MDCO sent a letter to the U.S. Court of Appeals for the Federal Circuit notifying the Court of the enactment of Section 37 and asserting that it resolves the merits of the ongoing ‘404 patent PTE litigation with ANDA sponsor APP Pharmaceuticals, LLC (“APP”).  APP vigorously disagreed that Section 37 resolved the case, however, and argued that Section 37 cannot constitutionally be applied and that Section 37 does not take effect for one year after the AIA‘s enactment (i.e., September 16, 2012).  The Federal Circuit ordered MDCO and APP to simultaneously file supplemental briefs addressing the effect of Section 37 of the AIA on the disposition of the case.  Those briefs were filed last month – along with the brief from a surprise intervenor – and the arguments they contain will be the focus of the November 15th oral argument.

APP argues in its briefs (here and here) that there are two reasons why AIA Section 37 does not save MDCO’s PTE request for the ‘404 patent, but rather confirms that the PTE application was untimely, and that as such, the Federal Circuit should reverse Judge Hilton’s decision and deem the ‘404 patent to have expired as of March 23, 2010:

(1) Section 37 will not go into effect until [September 16, 2012].  That is what Section 35 – the AIA’s default effective-date provision – plainly provides.  While Section 37 defines the set of PTE applications to which it will apply once it takes effect, nothing in Section 37 alters the September 16, 2012 effective date. Section 37’s silence is in stark contrast to AIA provisions not covered by Section 35’s default provision, all of which expressly indicate that they are changing the effective date.

(2) [R]egardless of when Section 37 takes effect, it could not constitutionally be applied to MDCO’s PTE.  Because MDCO’s PTE request was untimely when made, [the ‘404] patent expired [on March 23, 2010].  Under the Patent Act, any term extension granted by the PTO as a result of MDCO’s untimely request is invalid and void.  Because Congress did not enact the AIA until well over a year after the ’404 patent expired, Section 37 could not revive the patent.  The Constitution’s Copyright and Patent Clause prohibits Congress providing patent protection for subject matter that already has passed into the public domain.

MDCO, of course, has a slightly different take in its briefs (here and here) on the interpretation and applicability of the AIA and Section 37.  MDCO argues that AIA Section 37 codifies Judge Hilton’s next business day interpretation of the PTE statute and confirms that the ‘404 patent PTE application was timely.  “Section 37 expressly directs that it ‘shall apply’ to any PTE application – like MDCO’s – that ‘is pending on’ or ‘as to which a decision regarding the application is subject to judicial review on’ the ‘date of the enactment of this Act.’”  APP’s contention that AIA Section 37 does not govern the case before the Federal Circuit “ignores the provision’s plain text – not to mention its history and purpose – and asks the Court to adopt an interpretation that defies common sense,” says MDCO.  Equally insubstantial, argues MDO, is APP’s constitutional Claim: “APP’s argument turns on the untenable fiction that the [‘404 patent] entered the public domain even though it never expired.  Even if the patent had expired, moreover, APP’s argument would still be foreclosed by Supreme Court precedent” (italics in original).

Although the Government long ago bowed out of the case, it has entered as an intervenor and submitted a brief to defend the constitutionality of AIA Section 37.  First, says the Government, “Section 37’s next-business-day rule for computing the time for extension applications applies to any application that is ‘pending on,’ or as to which ‘a decision regarding the application is subject to judicial review on,’ the date of the AIA’s enactment,” and the PTE application for the ‘404 patent was “pending on” the date of the AIA’s enactment, because the PTO, “having lost in district court, was engaged in calculating the correct length of MDCO’s extension.”  Moreover, says the government “‘a decision regarding the application’ was ‘subject to judicial review” on the date of enactment (and still is).”  “Congress’s explicit direction to apply the next-business-day rule to pending applications, and to decisions subject to judicial review, places section 37 outside the ambit of the general effective-date provision in section 35, which applies ‘[e]xcept as otherwise provided in this Act.’”

With respect to the constitutionality of AIA Section 37, the Government maintains that “[n]othing in the Patent Clause of Article I precludes Congress from making section 37’s next-business-day rule applicable to MDCO’s pending extension request. . . .  [B]y virtue of interim extensions, MDCO’s ’404 patent has never expired, and MDCO’s drug has never entered the public domain.”  Regardless, says the Government, “the application of section 37 to this case does nothing more than give MDCO the same patent term that it would have been entitled to by filing a timely application.” 

While the Government contends that “[t]he existence of general legislative power to extend the term of patents after their expiration is confirmed by Supreme Court precedent and historical practice going back over 200 years,” and that “the constitutionality of section 37 is already clear,” the Government nevertheless suggests that the Federal Circuit may defer resolution of the Patent Clause challenge pending the Supreme Court’s decision in Golan v. Holder, Case No. 10-545, which was argued on October 5, 2011, and which presents a related issue of whether the Copyright Clause of the United States Constitution (Article I, § 8, cl. 8) prohibits Congress from taking works out of the public domain. 

What surprise twist might happen next in a more than decade-long PTE battle that has been full of surprises?  Will there be another attempt to change the PTE law or perhaps prevent the PTO from using funds to implement AIA Section 37?  Stay tuned.