By Carrie S. Martin –

On October 25, 2010, FDA issued a draft guidance entitled “Qualification Process for Drug Development Tools.”   This draft guidance describes a new qualification process for drug development tools (“DDTs”), which  include, among other things, biomarkers and patient reported outcome instruments.  The qualification of a DDT will ensure that it can be used reliably in multiple drug development programs, rather than in just one drug-specific program.  A qualified DDT will be publicly disclosed, and is therefore particularly suited to consortia and other collaborative efforts to study the use of DDTs that can be made available for use by all drug developers.  FDA expects that DDTs will help speed up, not only the drug development process, but also FDA review, because FDA may apply the DDT for the qualified use without the need to reconfirm its utility in each new application.  The Center for Drug Evaluation and Research (“CDER”) is currently involved in several initiatives to develop DDTs and this draft guidance furthers those efforts.  These programs arise from FDA’s “Critical Path Initiative,”  an ongoing effort to identify ways to enhance and improve the efficiency of the drug development process. 
 
The draft guidance lays out a two-stage process for a qualification determination.  Stage 1, the consultation and advice stage, begins with a DDT sponsor submitting a letter of intent (“LOI”) requesting that CDER evaluate the potential use of particular DDT.  If CDER grants the request, the Division will ask for a more detailed briefing package.  In addition, the Agency will form a Qualification Review Team (“QRT”) to provide ongoing advice to the submitter, beginning with an initial meeting to discuss the DDT, including its use, supportive data, and any additional data necessary for qualification.  After the submitter has collected the recommended data, CDER will review the data and determine whether the DDT is ready for review.

In Stage 2, the qualification review stage, the submitter submits a qualification package to CDER that contains analyses of any supporting studies.  CDER will then evaluate the information submitted, and may hold a public discussion as necessary.  Finally, CDER will issue a Statement of Qualification if it determines that the DDT is “qualified.”  The determination will be issued as a draft guidance and posted on FDA’s website for comment.  Once the Agency evaluates the comments, it will publish the final guidance in the same manner.

Although this draft guidance is an important first step in establishing a regulatory framework to qualify biomarkers and other DDTs, several limitations are noteworthy.  First, the draft guidance only describes the procedure of how CDER will qualify a DDT; it does not address the level of evidence needed to qualify it.  Second, the procedures outlined do not apply to a DDT developed for a company’s propriety use.  Instead, FDA suggests that information on such DDTs should be submitted to the IND, NDA, or BLA.  Third, the draft guidance does not contain any timelines as to when CDER would respond to an LOI, make a qualification decision, or schedule meetings with the DDT sponsors.  Industry may want to consider commenting on these “gaps” in their comments to the docket.

Comments to the draft guidance must be submitted by January 24, 2011 in order to ensure consideration. 

By Peter M. Jaensch –

Over the last seven months, officials at FDA, including the FDA Commissioner, Margaret Hamburg, MD, and the Deputy Chief Counsel for Litigation, Eric Blumberg, have been promising to resume use of the individual criminal liability doctrine known as the Park Doctrine (also known as the Responsible Corporate Officer Doctrine).  If this occurs, it would increase the stakes for alleged violations of the Federal Food, Drug, and Cosmetic Act.  Because FDA appears to believe that fines, penalties, and other money payments have not deterred certain conduct, it  now seems to believe that individual criminal liability for corporate officers will be a better deterrent.  We have earlier written several pieces on this subject (here, here, and here among others).

On October 26, 2010, the Washington Legal Foundation (“WLF”) sent a letter to FDA.  WLF calls on FDA to abandon its plans to seek criminal sanctions under Park for company executives for promotional activities in instances where the executives never participated in, encouraged, or had knowledge of the alleged violations.

By Jennifer B. Davis –

Earlier this week, the Government Accountability Office (“GAO”) publicly released its September 2010 Report to the House Committee on Oversight and Government Reform concerning Drug Safety, titled “DRUG SAFETY – FDA Has Conducted More Foreign Inspections and Begun to Improve Its Information on Foreign Establishments, but More Progress Is Needed.”  The latest in GAO’s “High-Risk Series” of reports, the report sharply criticizes FDA for persistent shortcomings in its oversight and inspection of foreign drug establishments – functions essential in GAO’s view to “safeguarding the nation’s drug supply in today’s global marketplace.” 

The report details the findings of a GAO performance audit initiated in November 2009 at the House Committee’s request to evaluate FDA’s progress in: (1) conducting more foreign drug inspections; and (2) strengthening the data it uses to oversee and manage the foreign drug establishment inspection program.  Both recommendations were included in two previous GAO reports issued in 1998 and 2008 (here and here).  The latest, September 2010 report faults FDA for failing to implement GAO’s prior, specific recommendations and for otherwise failing effectively to address the “long-standing challenges” in its foreign drug inspection program, which, GAO emphasizes, “are not new, as [its] prior work shows.”  The report concludes that “it is urgent that FDA implement GAO’s prior recommendations to better protect public health.”
 
In particular, GAO’s audit found that while FDA committed significantly more resources to foreign drug inspections in 2009 ($41 million compared to $10 million in 2007 and $12 million in 2008), and, largely through a cadre of inspectors dedicated to foreign inspections, increased the overall number of foreign drug inspections conducted in fiscal year 2009 (424 compared to 333 in 2007 and 324 in 2008), that number nevertheless represented only 11 percent of the foreign drug establishments that FDA had identified as being subject to inspection.  In contrast, during the same time period, FDA conducted 1,015 domestic drug establishment inspections, representing roughly 40 percent of domestic drug establishments.  GAO additionally found that most foreign drug establishment inspections conducted in 2009 were pre-approval inspections focused on the manufacturing process for a drug product not yet in the U.S. market, as compared to comprehensive, good manufacturing practice inspections checking on the conditions of manufacture for drug products already in U.S. commerce.  The report criticizes the agency’s “pre-approval” approach to selecting foreign establishments for inspection as inconsistent with GAO’s 2008 recommendation that “FDA inspect, at a comparable frequency, those establishments that are identified as having the greatest public health risk potential if they experience a manufacturing defect, regardless of whether they are a foreign or domestic establishment.”  According to the report, the majority of foreign establishments in FDA’s inventory, almost half of which are located in China and India, may never have been inspected.

With regard to the data that FDA uses to manage the foreign establishment inspection program, GAO found that the agency continues to rely on sometimes inaccurate or incorrect information from multiple databases to annually compile an inventory of foreign drug establishments subject to inspection, and does not maintain a separate listing of such establishments.  While GAO acknowledges that FDA has taken initiatives to improve its information on foreign establishments – e.g., switching from a paper-based to an electronic registration and listing database; requesting that establishments voluntarily provide a unique Dun and Bradstreet Data Universal number to improve tracking; and collaborating with foreign regulatory authorities on the exchange of inspection information, it concludes that “these steps appear to involve long-term efforts . . . in their early stages and it is unclear if these efforts will prove successful.  In the meantime, FDA’s data systems continue to contain inaccurate information on foreign establishments, compromising the agency’s oversight of the nation’s drug supply.”

More notable, perhaps, than the report’s particular findings with regard to FDA oversight of foreign drug establishments, is GAO’s expression of its much broader concern about the adequacy of FDA’s medical product oversight in general.  GAO states in the report that “[d]ue in part to the concerns raised in our September 2008 report, in January 2009, we added FDA’s oversight of medical products – drugs, biologics, and medical devices – to our High-Risk Series, citing FDA’s ability to ensure the quality of medical products manufactured overseas as an area of particular concern.  Our subsequent reports have reinforced these designations of FDA as an agency in need of broad-based transformation by identifying additional concerns with FDA’s ability to manage its growing responsibilities and plans for modernizing the agency’s information technology capabilities.” 

In comments on the GAO report, FDA’s parent agency, the Department of Health and Human Services (“HHS”), states that it “agrees that more progress is needed in order to meet the challenge of safeguarding the nation’s drug supply in today’s global marketplace,” and identifies several initiatives undertaken by FDA to more effectively secure the drug supply chain, including FDA’s enhanced global presence and international collaboration and capacity.  Despite some progress, however, HHS notes that “[t]he sheer number of foreign facilities, the complexity of the drug supply chain, and the rapidly changing use of suppliers all pose formidable obstacles to implementing GAO’s recommendation that FDA conduct foreign inspections at a rate comparable to domestic inspections.”  How formidable?  Well, according to HHS, “FDA has estimated that if it were to conduct Good Manufacturing Practices (GMP) surveillance inspections at a rate comparable to domestic GMP surveillance inspections, the inspection frequency for both, under current resources, would be, at most, about once every 7 years.”

By Ricardo Carvajal –

FDA announced that its Pediatric Advisory Committee will meet on December 6 to “obtain and discuss information and data that will provide the Agency with a better understanding of current practices, and potential benefits and risks associated with the donation and banking of human milk.”  The Agency is opening a docket – FDA-2010-N-0553 - for the submission of public comments, which are due by January 6, 2011.

On Thursday, United Therapeutics Corporation (“UTC”), a biotechnology company focused on the development and commercialization of unique products to address the unmet medical needs of patients with chronic and life-threatening conditions, unveiled a plaque honoring HP&M Director Frank Sasinowski for his contributions to UTC’s development of its REMODULIN (trepostinil) therapy for the rare, serious condition, pulmonary hypertension (View this photo).  Others on that wall include Sir John Robert Vane, 1982 Nobel laureate for medicine and creator of this prostacyclin analog.  Mr. Sasinowsi has been devoted to aiding in the development of orphan drugs since his days at FDA when he was key to implementing the Orphan Drug Act of 1983, including his work that led to the 1984 and 1985 amendments that gave this law its life.  Mr. Sasinowski is Chair of the board of NORD, the National Oganization for Rare Disorders, which represents the 25 million americans with rare disorders.

By Kurt R. Karst –      

Company submissions to the Securities and Exchange Commission (“SEC”) can be a valuable source of information.  Consider, for example, a recent quarterly report from Celgene Corporation, which states with respect to Risk Evaluation and Mitigation Strategies (“REMS”) that:

In the fourth quarter of 2009, we received a civil inquiry and demand from the [Federal Trade Commission (“FTC”)].  The FTC requested documents and other information relating to requests by generic companies to purchase our patented REVLIMID® and THALOMID® brand drugs in order to evaluate whether there is reason to believe that we have engaged in unfair methods of competition.

The FTC inquiry, which is presumably broader than just Celgene, could very well be related to a June 2009 citizen petition in which the petitioner requested, among other things, that FDA “[r]efer to the FTC any complaints received from generic drug manufacturers alleging that the sponsor of a listed drug subject to an approved restricted distribution REMS has used such REMS in an anti-competitive manner to delay or block generic competition.”

Then there’s a recent quarterly report that Caraco Pharmaceutical Laboratories, Ltd. (“Caraco”), a subsidiary of Sun Pharmaceutical Industries Limited, submitted to the SEC raising an inquiry made to FDA about an interesting 180-day exclusivity forfeiture issue with respect to generic PRANDIN (repaglinide) Tablets.  According to the Caraco quarterly report:

The Company believes that it is the first to file an ANDA with a Paragraph IV certification for this drug product and it intends to defend this action vigorously to capitalize on the potential for obtaining 180 days exclusivity available for this product.  On May 26th, 2010, the Company received correspondence from the FDA forwarding a letter sent by Sandoz Inc. to the FDA challenging the Company’s 180 day exclusivity based on when the Company received tentative approval for its product.  The Company responded to the FDA on June 17, 2010.  On June 28th, 2010, Sandoz Inc. replied to the Company’s correspondence.  The Company issued a further letter to the FDA stating its position regarding the 180 day exclusivity on July 9, 2010.  The Company believes it received tentative approval timely, and that it has the potential to obtain 180 day exclusivity for this product.  It intends to defend that position vigorously.

Hmmmmm . . . . so what could this all mean?  We’ve previously discussed how different date calculation interpretations can lead to some interesting results.  The statements above seem to revolve around a similar issue. 

According to FDA’s Paragraph IV Patent Certification List, the first ANDA (presumably Caraco’s ANDA No. 77-571) for generic PRANDIN was submitted to FDA on February 10, 2005.  FDA granted tentative approval to Caraco for this application on August 10, 2007 – the date that is the 30-month anniversary from the date of submission of ANDA No. 77-571, depending on how you calculate 30 months (i.e., when do you begin and end counting).

Under FDC Act § 505(j)(5)(D)(i)(IV), which is one of the six 180-day exclusivity forfeiture provisions added to the FDC Act by the 2003 Medicare Modernization Act, 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed. [(Emphasis added)]

(And for completeness, the 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)).) 

So what does it mean to obtain tentative ANDA approval “within” 30 months after ANDA submission?  Does it mean that tentative approval is granted before the 30-month ANDA submission anniversary date or on the 30-month date (again, depending on when you begin and end counting)?  This would appear to be the issue in the ping-pong correspondence between Sandoz and Caraco.  The resolution of this issue will certainly be of intense interest to the generic drug industry, because FDA often grants tentative ANDA approval on the 30-month anniversary from the date of submission of an application. 

What does not appear to be at issue between Sandoz and Caraco is another issue that could come up in the future as a result of the recent decision concerning a Patent Term Extension (“PTE”) for a patent covering ANGIOMAX (bivalirudin).  In that case, Judge Claude Hilton of the U.S. District Court for the Eastern District of Virginia (Alexandria Division) ruled that a “next business day” interpretation of the PTE statute is reasonable, such that an after-hours approval of an NDA would not start the 60-day PTE application clock until the next business day.  In the case of generic PRANDIN, FDA’s tentative approval letter for ANDA No. 77-571 is date-stamped “8/10/2007 03:02:16 PM,” so it is not an after-hours tentative approval decision.  Nevertheless, it is not unusual for FDA to make such after-hours decisions, and it would not be surprising if someday someone were to argue that a “next business day” interpretation should be applied to FDC Act § 505(j)(5)(D)(i)(IV), such that tentative approval was not timely obtained.

By Peter M. Jaensch & John R. Fleder –

A company has “current Good Manufacturing Practice” (“cGMP”) issues.  FDA learns about the issues and engages in dialogue with the company regarding the purported violations.  No big deal and no news story!  Add in a terminated employee who files a whistleblower law suit against the company, and we have a case that will undoubtedly send shock waves throughout the pharmaceutical industry.

In a much ballyhooed public announcement, the Department of Justice announced on October 26, 2010 that GlaxoSmithKline (“GSK”) will pay $750 million to resolve civil and criminal liability in connection with operations by its subsidiary, SB Pharmco Puerto Rico, Inc., of a manufacturing facility in Cidra, Puerto Rico. The settlement and plea agreements address both the federal civil claims brought initially as a qui tam action under the Federal False Claims Act, and a criminal action for violations of the Federal Food, Drug, and Cosmetic Act.

According to the criminal Information, between 2001 and 2005, the Cidra facility manufactured several GSK drugs: Kytril, a sterile, injectible anti-nausea medication, Avandamet, “a combination Type II diabetes drug,” Bactroban, “a topical anti-infection ointment,” and Paxil CR, which is a controlled release antidepressant.  The manufacturing of these products was allegedly subject to massive failures in terms of complying with cGMP requirements, including the alleged contamination of bulk products and water supplies, physical defects in products and improper procedure changes, and other issues. Despite purportedly being aware of these errors, GSK continued to ship these products to market.

The parallel civil case, U.S. ex rel. Cheryl Eckard v. GlaxoSmithKline, et al., was brought six years ago by a former GSK employee under the federal False Claims Act.  The suit alleged that GSK had caused to be submitted claims for payment for these drug products to the TRICARE program, the Federal Employees Health Benefits Program (“FEHBP”), the Department of Veterans’ Affairs, and state Medicaid programs. The suit alleged that GSK knowingly sold and distributed flawed tablets, contaminated products, and products which diverged in purity and strength from their NDA-approved values. The plaintiff (Relator) was previously employed by GSK to address quality issues at the Cidra plant following an FDA inspection that had discovered some, but not all of the issues that were involved in the civil and criminal cases. She claimed that GSK had ignored her reports on quality issues, and GSK allegedly fired her after which she reported the problems to FDA.

In settlements (here, here, and here) of the civil and criminal cases, GSK agreed to pay $750 million, plus interest.  GSK’s subsidiary, SB Pharmco Puerto Rico, Inc., will plead guilty to one count of having introduced for delivery into interstate commerce various quantities of adulterated drugs in violation of 21 U.S.C. §§ 331(a), 333(a)(2), and 351(a)(2)(B).  Of the $750 million, $140 million is a criminal fine and $10 million is a forfeiture.  The $600 million resolution of the civil case is being paid to: the United States ($436,440,000.00);  Medicaid Participating States ($163,560,000.00); and the Relator (approximately $97 million plus interest).

One might think that this settlement bought GSK “global peace” with regard to the problems that led to the settlement.  Not so! Although the settlement releases GSK from further liability under the False Claims Act for the underlying conduct, it leaves open the possibility that the government agencies may seek to exclude GSK from participation in Medicare, Medicaid, TRICARE and FEHBP.   Moreover the agreements leave open the possibility that current and/or former GSK employees could be criminally prosecuted for the problems involved in the cases.

There is no doubt that this settlement raises serious warning signs for companies regulated by FDA.  First, it demonstrates that the federal government is ready and willing to bring felony charges against companies that engage in cGMP violations.  Second, it demonstrates that the government may seek to obtain huge fines relating to these violations in the context of a criminal case.  Last, the case sends a message to employees throughout all companies which cause government agencies to reimburse for sales of the companies’ products that are regulated by FDA: You too may get rich by filing a whistleblower case which alerts the government to what many may deem to be routine regulatory violations.

Companies generally pay close attention to visits to their facilities by FDA when the agency raises concerns about a company’s operations.  However, most companies do not face day to day or even frequent scrutiny by FDA.  Now it is clear that companies must pay close attention to concerns raised by their own employees, or risk facing the same type of suit that GSK faced.  For more information on dealing with potential whistleblowers see our recent article on this subject.

By Kurt R. Karst –      

Some Senate Democrats have joined their Republican colleagues in voicing opposition to the inclusion of the “Preserve Access to Affordable Generics Act” (S. 369) in the Fiscal Year 2011 Financial Services and General Government Appropriations Bill (S. 3677).  As we previously reported, in late July, the U.S. Senate Committee on Appropriations approved the inclusion of the “Preserve Access to Affordable Generics Act” in the report (Senate Report No. 111-238; pages 144-148 & 150-151) accompanying S. 3677.  The legislation would make patent settlements (or what opponents call “pay-for-delay” or “reverse payment” agreements) presumptively anticompetitive and unlawful if challenged by the Federal Trade Commission (“FTC”), unless it can be demonstrated “by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.” 

The brief October 21, 2010 letter to Senate Majority Leader Harry Reid (D-NV) and Appropriations Committee Chairman Daniel Inouye (D-HI) is signed by Sens. Arlen Specter (D-PA), Robert Casey (D-PA), Frank Lautenberg (D-NJ), Tom Carper (D-DE), and Kay Hagan (D-NC) and states:

We write to request that the provisions of S. 369 not be included in any appropriations bill this Congress.  S. 369 is an anti-trust bill and outside the purview of the Appropriations Committee.  Furthermore, we have substantive concerns with the content of these provisions, and feel that they can only be properly resolved though the regular order in the Senate.  S. 369 was favorably reported by the Judiciary Committee on October 15,2009, and is awaiting time on the Senate floor, where its provisions can be fully and fairly debated. 

The inclusion of S. 369 in an appropriations bill contradicts both the spirit and the letter of the Senate rules.  Therefore, we ask you to ensure that appropriations bills in the 111th Congress not include S. 369.

The letter follows a September 17, 2010 letter from Sens. Jeff Sessions (R-AL), Tom Coburn, (R-OK), John Cornyn (R-TX), and John Thune (R-SD)) to Senate Republican leaders.  As we previously reported, that letter expressed “vigorous objection” to the inclusion of the “Preserve Access to Affordable Generics Act” in S. 3677 and states that “the reported bill gives excessive power over such settlements to the FTC – a power that the FTC has shown itself in the past to be unable to exercise in a responsible or economically rational manner – and that the bill would do serious violence to the Hatch-Waxman process for the market entry of generic drugs.”

The Senate will presumably take up S. 3677 when it returns from recess after the November 2nd mid-term elections.

By Dara Katcher Levy –

How many lawsuits will it take before FDA starts exercising better judgment on imports?  On October 25, 2010, Amphastar Pharmaceuticals Inc. (“Amphastar”) filed suit against FDA seeking declaratory judgment and injunctive relief with regard to FDA’s detention of two entries of semi-purified heparin.  According to the Complaint, the entries, proposed for import in May 2010 in the Los Angeles District, were intended for use in the manufacture of starting material for the development of active pharmaceutical ingredient – the subject of a pending Abbreviated New Drug Application for generic LOVENOX (enoxaparin).  The material, heparin (which is used in the manufacture of enoxaparin), from an Amphastar-owned facility in China, was intended to qualify the manufacturer as an alternate source of raw material, and was intended for laboratory testing purposes only, not for use in humans or animals.

Both entries of material were tested by FDA in June 2010 and released in July 2010.  FDA rescinded both releases a week later, and two weeks after the recission of the releases, alleged the products were misbranded due to the manufacturer not being a registered facility.  This allegation was apparently incorrect, as the Chinese facility was a registered establishment.  After FDA was notified of this, the Agency then alleged the product lacked adequate directions for use, notwithstanding the fact that the material was not intended for use in humans, was for laboratory testing purposes only, and even if it were a drug for human use, would be subject to the exemption from adequate directions for use for bulk drugs intended for further processing pursuant to 21 C.F.R. § 201.122(c).

The products remain detained despite Amphastar notifying FDA of these issues.  Although the first shipment passed FDA testing, FDA still has not completed testing of the second shipment.  FDA notified Amphastar on October 18, 2010 that testing would not be completed until November 17, 2010 – approximately 5 months after FDA initially sampled the product.

Although FDA has broad discretion over imports, it is expected that FDA’s allegations of violations have some merit, and that they be made in a timely manner.  It appears that FDA is using the misbranding allegations as “place-holders” until FDA completes testing of the second shipment.  For FDA to take five months to test the shipment is extraordinary, and even more so given that the product is not intended for human use.  It will be interesting to see FDA’s response to this Complaint.

By Riëtte van Laack –

Direct Marketing Concepts, Inc. (“DMC”) and other companies and individuals marketed Coral Calcium and Supreme Greens by producing and distributing infomercials claiming that these products were an effective cure against many diseases including heart disease, cancer, lupus, etc.  The district court granted summary judgment against the Defendants, holding that the infomercials were misleading as a matter of law, and ordered the defendants to pay $50 million.

Defendants appealed, challenging the legal and factual bases for the District Court's ruling, including its calculation of "damages."  On October 21, 2010, the United States Court of Appeals for the First Circuit concluded that the Federal Trade Commission ("FTC") had shown that the Defendants had not established that they had adequate substantiation for the claims at issue.  The FTC relied on four expert declarations that asserted that a reasonable basis for the relevant claims would be double-blind, placebo-controlled human studies, but  Defendants did not meet this standard.  The Court ruled that without a reasonable basis for the claims, Defendants' advertising was deceptive as a matter of law.  The Court stated: "To be sure, there may be other scientific evidence that could be sufficient, and we may assume for these purposes that a double-blind study is not necessarily required.  But the government established that some scientific evidence is required for substantiation."

The Court also rejected a "puffery" defense, concluding that the claims at issue went far beyond puffery.  The Court also rejected Defendants' argument that they had presented adequate disclaimers in the ads. 

The Court further affirmed the liability of an owner and corporate officer of two of the companies, because it found that  the record contained ample evidence that the officer had the capacity to make decisions about the advertising ("he could have nipped the offending infomercials in the bud"), and he knew that the claims lacked substantiation.

The Court also affirmed that the gross sales volume of the products at question was deemed the appropriate measure for calculating "damages" to be awarded against the Defendants.

By Kurt R. Karst –      

FDA’s recent decision to grant an April 27, 2010 citizen petition submitted on behalf of Genzyme Corporation (“Genzyme”) concerning the Agency’s ability to approve Cobrek Pharmaceuticals, Inc.’s (“Cobrek’s”) pending ANDA for a generic version of HECTOROL (doxercalciferol) Injection sheds some light on the circumstances in which a second 30-month stay (or “superseding stay” as FDA terms it in this case) could arise as a result of a Paragraph IV certification to an Orange Book-listed patent – regardless of whether the patent was listed prior to or after the December 8, 2003 enactment of the Medicare Modernization Act (“MMA”), which generally limits ANDA applicants to a single 30-month stay of ANDA approval.  Genzyme’s petition requested that FDA not approve Cobrek’s ANDA No. 90-040 until the expiration of a second 30-month stay, or 30 months from November 24, 2009, when Genzyme received a second notice of a Paragraph IV certification from Cobrek regarding U.S. Patent No. 5,602,116 (“the ‘116 patent”), a method-of-use patent covering HECTOROL.  The initial 30-month stay reportedly expired in early July 2010.

FDA approved HECTOROL (2 mcg/mL, 2 mL) in an ampule presentation under NDA No. 21-027 in April 2000 for the treatment for secondary hyperparathyroidism in patients with end stage renal disease.  The ‘116 patent, as well as other patents, were submitted to FDA for Orange Book listing.  In December 2008, FDA approved an NDA supplement for HECTOROL for a new injectable formulation (and packaging configuration) in a vial presentation.  (The old ampule product is no longer being manufactured, and in July 2010, FDA determined in response to a citizen petition – FDA-2009-P-0088 – that the ampule presentation was not withdrawn from the market for safety or effectiveness reasons, thereby clearing the way for ANDA approval, and that the ampule and vial formulations would be considered therapeutic equivalents.)  Pursuant to 21 C.F.R. § 314.53(d)(2)(i), Genzyme resubmitted the ‘116 patent to FDA for Orange Book listing for the new vial product formulation, as well as U.S. Patent No. 7,148,211 (“the ‘211 patent”), a formulation (drug product) patent.

Cobrek submitted ANDA No. 90-040 to FDA on October 13, 2007 containing a Paragraph IV certification to the ‘116 patent (based solely on invalidity), among other patents.  (According to FDA’s Paragraph IV Certification List, the first ANDA containing a Paragraph IV certification to an Orange Book-listed patent for HECTOROL, 2 mcg/mL, 2 mL ampules, was submitted to FDA on October 15, 2007, thus seemingly making Cobrek’s submission subject to the MMA, although the possibility of an “MMA straddle” situation exists.)  Genzyme timely asserted the ‘116 patent in infringement litigation and triggered a 30-month stay of approval on Cobrek’s ANDA.  While ANDA No. 90-040 was under review, and after FDA approved the new HECTOROL vial formulation in December 2008 and the ‘211 patent was timely listed in the Orange Book, Cobrek amended its application to include a Paragraph IV certification to the ‘211 patent.  Genzyme did not sue Cobrek for patent infringement because the company “believed that Cobrek’s ampule formulation for which it was seeking approval at the time would not infringe the ‘211 patent claims.”

All seemed in order until FDA informed Cobrek that the Agency could not approve ANDA No. 90-040 because the ampule formulation was not quantitatively and qualitatively (“Q1/Q2”) the same as the new HECTOROL vial drug product.  Instead, FDA recommended that Cobrek reformulate to a Q1/Q2 formulation.  Cobrek reformulated its drug product and amended its application in 2009, but without new patent certifications.  FDA refused to accept the ANDA amendment without new certifications to both the ‘116 and ‘211 patents, but did give the company the option to request whether the old HECTOROL formulation had been withdrawn for safety or effectiveness reasons (which, as mentioned above, FDA recently ruled on) and continue on without new certifications.  Cobrek decided not to take that path, and instead continued on with its reformulated drug product and in late November 2009 certified to the ‘116 and ‘211 patents.  In January 2010, Genzyme sued for patent infringement with respect to both patents. 

About three months after initiating patent infringement litigation, Genzyme submitted a citizen petition to FDA arguing that the FDC Act “requires a separate 30-month-stay analysis for ‘each certification’ to a patent that claims the drug at issue[, and that in] this case, analysis of a second certification to the ‘116 patent requires a second 30-month stay.”  Genzyme also argued that FDA should grant the company’s request for a second 30-month stay regardless of whether the post-MMA version of the FDC Act applies, and further, that the MMA’s provisions generally prohibiting more than a single 30-month stay are inapplicable in this case because the ‘116 patent was listed in the Orange Book for HECTOROL prior to August 18, 2003 and prior to the submission of ANDA No. 90-040. 

As FDA explains in a draft October 2004 guidance document interpreting the MMA’s provisions:

The relevant provisions of the MMA apply to patents submitted to FDA on or after August 18, 2003.  For ANDAs and 505(b)(2) applications with paragraph IV certifications to a patent submitted to FDA on or after August 18, 2003, the MMA provides that a 30-month stay may be available for litigation related to that patent only if the patent was submitted to FDA before the date that the ANDA or 505(b)(2) application (excluding an amendment or supplement) was submitted.  In other words, the MMA precludes 30-month stays for later listed patents, that is, those patents submitted to FDA on or after the date the ANDA or 505(b)(2) application was submitted. Because of this limitation, in most cases, ANDAs and 505(b)(2) applications will be subject to no more than one 30-month stay.

FDA also notes in the draft guidance, however, that:

Multiple 30-month stays . . . still may be possible in certain cases.  For instance, an ANDA or 505(b)(2) application may contain a paragraph IV certification to a patent at the time of first submission that gives rise to one 30-month stay.  If the same application also contains a paragraph III certification to a different patent that was submitted to FDA (1) on or after August 18, 2003, and (2) before the ANDA or 505(b)(2) application was submitted, and the applicant subsequently converts this certification to a paragraph IV certification, a second 30-month stay could be possible.  This is because the new paragraph IV certification is subject to the MMA and references a patent submitted to FDA before the applicant’s ANDA was submitted.

Cobrek, argued in the company’s comments submitted to FDA in response to the Genzyme petition that the MMA applies in this case “because patent information on the ‘116 patent was submitted a second time with respect to the amendment covering the reformulation of this drug on December 26, 2008, after the August 18,2003 effective date of the MMA with respect to submission of patent information.”  Thus, according to Cobrek, only a single 30-month stay applies in this case.

Although FDA notes in the Agency’s petition response that “[d]etermination of whether or not the MMA applies thus depends on whether one concludes that the operative submission of patent information was [pre- or post-MMA],” such a determination is not, according to FDA, necessary “[b]ecause we conclude that the relief requested in your petition must be granted” regardless of whether or not the MMA applies.  Specifically, FDA ruled that:

Genzyme is entitled to a 30-month stay stemming from Cobrek’s paragraph IV certification made in connection with the reformulated product and Genzyme’s resulting patent infringement. . . .  Once Cobrek made the paragraph IV certification, and Genzyme subsequently sued Cobrek for infringing the ‘116 patent, the statutory requirements for a 30-month stay with respect to this paragraph IV certification were met, as the information concerning the ‘116 patent was submitted to FDA before either the original submission of the ANDA to FDA in October 2007, or the submission of the ANDA amendment in 2009.  We reach this conclusion regardless of whether the MMA applies to the facts at hand.

Although Cobrek argues in the company’s comments to FDA that Cobrek should not have been required to submit a second Paragraph IV certification in connection with the its new formulation amendment (and should be permitted to withdraw that certification), FDA declined to comment on this point, stating that such an argument is not appropriate for a petition comment and that the time for Cobrek to make that argument had passed.  That would have been an interesting to point to argue.  FDA has long been of the opinion that ANDA drug product formulation changes made in an amendment to a pending application (or a supplement to an approved application) require a new certification, but has never (to our knowledge) been challenged on the issue.  FDA stated this policy at least as far back as an October 1986 “dear applicant” letter, and most recently (to our knowledge) in the preamble to the Agency’s 1999 proposed rule that was later withdrawn. 

By Ricardo Carvajal –

The Committee on Examination of Front-of-Package Nutrition Rating Systems and Symbols (part of the Food and Nutrition Board at the Institute of Medicine of the National Academies) recently released a report on the first phase of its study of front-of-package ("FOP") nutrition rating systems and symbols.  In the first phase of its Congressionally mandated study, the Committee analyzed existing FOP systems.  In the second phase due to be completed in 2011, the Committee will focus on consumer understanding and use of FOP systems. 

The Committee’s report analyzes 20 of the many FOP systems currently used in the U.S. and abroad, and places them into three categories: (1) Nutrient-Specific Systems (those that display “the amount per serving of select nutrients from the Nutrition Facts panel or use symbols based on claim criteria”); (2) Summary Indicator Systems (those that “use a single symbol, icon, or score to provide summary information about the nutrient content of a product”); and (3) Food Group Information Systems (those that “use symbols that are awarded to a food product based on the presence of a food group or food ingredient”).  The report analyzes the different systems’ respective strengths and limitations, and provides examples of how different systems can yield different results for the same types of foods – an observation that is certain to be cited in support of any future proposal to create a single standardized system.  The report also declines to identify any options for setting criteria for certain types of systems (i.e., Summary Indicator Systems based on algorithms, and Food Group Information Systems), thereby suggesting that those systems are unlikely to form the basis for any future proposal for a single standardized system.

Of particular concern to industry, the report identifies calories, saturated fat, trans fat, and sodium as the most important nutrients to include in an FOP system, on the ground that these nutrients “are most strongly associated with the diet-related health risks affecting the greatest number of Americans.”  At the same time, the report questions the utility of including nutrients that industry has sought to highlight in some FOP systems, such as vitamins and minerals, in part based on “concerns about encouraging overfortification or the addition of these nutrients to food systems in which the nutrient is unstable or not biologically available.”  The report also questions the utility of including fiber, in part based on concerns that “fortification may also encourage consumers to eat foods that have had fiber added rather than increasing their consumption of naturally-occurring, plant-based foods that are high in dietary fiber, as recommended by the 2010 Dietary Guidelines Advisory Committee.” 

Consumers have shown increasing interest in nutrition and health information generally, and food marketers have responded by crafting FOP systems to help convey that information in a way that differentiates their products in a crowded marketplace.  In light of these trends, the course charted by the Committee could well run through rough seas.

By Jeffrey K. Shapiro –

FDA’s Center for Devices and Radiological Health is conducting a usability study of the establishment registration and device listing database. The objective is to make the database easier to use. They are looking for feedback from those who regularly use the database. During the evaluation, participants will be asked to use the database and provide feedback. Participation can be in person in Washington, D.C. or online. Contact Kristina Schall at kristina.schall@opinionstrategies.com to sign up.

By Susan J. Matthees –

Two consumers, a resident of Florida and a resident of New Jersey, have filed a putative class action against Basic Research LLC, Carter-Reed Company, LLC, Dennis Gay, Daniel Mowrey, and Mitchell Friedlander, alleging that Defendants made false and deceptive claims about Relacore and Relacore Extra, two dietary supplement products sold by Basic Research and Carter-Reed and marketed according to plans allegedly designed by Defendants Mowrey, Friedlander, and Gay.  Plaintiffs allege they are entitled to damages for Defendants’ alleged violations of the Racketeer Influenced and Corrupt Organizations Act (“RICO”), Florida’s Deceptive and Unfair Trade Practices Act, and New Jersey’s Consumer Fraud Act, and under the theory of unjust enrichment. 

Relacore was advertised on television and the internet with the claims such as “Helps prevent stress-related abdominal fat,” “formulated to help:  reduce stress, reduce mild anxiety, improve mood, fight mid-day fatigue, [and] increase energy.”  Both plaintiffs claim that they purchased Relacore and used the product as directed to reduce abdominal fat, but ultimately stopped using the product because it did not work as labeled and advertised.  One plaintiff also purchased and used as directed Relacore Extra, which made similar claims to reduce stress-related abdominal fat, and found that the product did not work as advertised.  Plaintiffs allege that Defendants “knew or should have known” that the products “do not prevent or reduce stress-related abdominal fat, do not reduce stress and anxiety, and do not elevate mood and emergency” and that there was no scientific validation of the claims made for the products. 

In addition, Plaintiffs allege that Defendants Basic Research, Gay, Mowrey, and Friedlander violated a Federal Trade Commission (“FTC”) Consent Order by marketing Relacore and Relacore Extra.  Defendants agreed to the FTC Consent Order in 2006 for claims made for a different weight loss product.  That Order prohibits them from making any claims about health or weight loss without “competent and reliable scientific evidence” to substantiate the claims. 

The case was filed in the southern district of Florida on October 11.

By Kurt R. Karst –      

Earlier this month, President Obama signed into law S. 1674, the Improving Access to Clinical Trials Act (Pub. L. No. 111-255).  The bill, introduced in the Senate by Senator Ron Wyden (D-OR) in September 2009, amends the Social Security Act (42 U.S.C. 1382b & 42 U.S.C. 1396a) to provide for an exclusion under the Supplemental Security Income (“SSI”) program and Medicaid for certain compensation of individuals who participate in clinical trials for rare diseases or conditions.

According to the bill’s findings, “[w]ith a small number of potential trial participants and the possible loss of [SSI] and Medicaid benefits for many who wish to participate, clinical trial research for rare diseases and conditions becomes exceptionally difficult and may hinder research on new treatments and potential cures for these rare diseases and conditions.”  Senator Wyden’s bill, however:

would give people who are eligible for [SSI] and Medicaid the same access to clinical trials as those who are more financially fortunate. . . .  Currently, SSI and Medicaid eligible individuals who want to participate in a clinical trial have to worry about whether or not they will see a loss or a reduction in their benefits for their participation in a clinical trial if the trial offers any sort of research compensation to participants as part of its approved Internal Review Board study design.  This legislation would make it so benefits that these individuals receive from clinical trials are not counted against those who are seeking SSI or Medicaid benefits or those who are already eligible for these benefits.

Specifically, for SSI income exclusion purposes, the new law excludes “the first $2,000 received during a calendar year by such individual (or such spouse) as compensation for participation in a clinical trial involving research and testing of treatments for a rare disease or condition,” provided the clinical trial has been reviewed and approved by an appropriate institutional review board.  For Medicaid exclusion purposes, the new law provides that “[t]he first $2,000 received by an individual (who has attained 19 years of age) as compensation for participation in a clinical trial meeting the requirements of section 1612(b)(26) shall be disregarded for purposes of determining the income eligibility of such individual for medical assistance under the State plan or any waiver of such plan.”

Because, according to Sen. Wyden, there are “some legitimate concerns that research compensation may create the wrong kind of incentives for low-income people,” the new law requires the Comptroller General of the United States to conduct a study to evaluate the effects of S. 1674 on enrollment of SSI beneficiaries in clinical trials for rare diseases or conditions.  The study, which has to be conducted not later than 36 months after the efffective date of the new law, must include an analysis of:

(1) The percentage of enrollees in clinical trials for rare diseases or conditions who were SSI beneficiaries during the 3-year period prior to the effective date of this Act as compared to such percentage during the 3-year period after the effective date of this Act.

(2) The range and average amount of compensation provided to SSI beneficiaries who participated in clinical trials for rare diseases or conditions.

(3) The overall ability of SSI beneficiaries to participate in clinical trials.

(4) Any additional related matters that the Comptroller General determines appropriate.

Not later than 12 months after completion of the study, the Comptroller General must submit a report to Congress with the study results and “with recommendations for such legislation and administrative action as the Comptroller General determines appropriate.”

The new law takes effect within 180 days of enactment, or sooner if the Commissioner of Social Security promulgates final regulations to implement the new law.  S. 1674 is scheduled to sunset in five years, so that Congress can examine the Comptroller General’s report and determine whether the the program is working and should be reauthorized and/or changed. 

The enactment of the Improving Access to Clinical Trials Act is the latest development in a recent flurry of rare disease/orphan drug legislative activity.  As we previously reported (here and here), Congress is considering legislation to streamline the development and regulation of products for rare and neglected diseases and to increase incentives for the development and approval of such products.  We also note that earlier this month the Institute of Medicine issued a 350-page report to help refocus attention on accelerating rare diseases research and product development (see our previous post here), and that FDA and the Drug Information Association (in collaboration with the National Organization for Rare Disorders and Genetic Alliance) recently announced an Orphan Drug Designation Workshop scheduled for November 4-5, 2010, in Lansdowne, Virginia.