By Ricardo Carvajal –

FDA released a report summarizing the first seven months of the agency’s experience with its Reportable Food Registry (for more on recent developments pertaining to the RFR, see our prior posting here).  The data summarized by FDA show how the potential adulteration of a widely used ingredient such as hydrolyzed vegetable protein ("HVP") can trigger a deluge of RFR reports.  In March alone, FDA received 1001 reports related to the potential presence of Salmonella in foods containing HVP.  This accounts for almost half of all submissions received by the agency during the entire reporting period.  The data also confirm that less than 10% of submissions are what the agency refers to as “primary reports,” meaning “the initial report concerning a reportable food from either industry or public health officials, such as federal, state, or local regulators.”  The vast majority of submissions are so-called “subsequent reports,” meaning “a report submitted by either a supplier (upstream) or a recipient (downstream) of a food/feed (including ingredients) for which a primary report has been submitted.”  Put these facts together and it appears that the RFR is generating lots of data about the chain of distribution of potentially adulterated products.  Small wonder that the Deputy Commissioner for Foods is singing the RFR’s praise. 

The agency cautions that “it is too early to draw inferences concerning patterns of food and feed adulteration."  However, we can't resist the observation that the vast majority of the primary reports were precipitated by foodborne pathogens and undeclared allergens/intolerances – a pattern similar to what we have observed in Class I recalls. 

By Kurt R. Karst – 

Earlier today, the U.S. Court of Appeals for the Federal Circuit denied Caraco Pharmaceutical Laboratories, Ltd.’s (“Caraco”) and Sun Pharmaceutical Laboratories, Ltd.’s (“Sun”) Petition for Panel Rehearing and Rehearing en banc of an April 14, 2010 Federal Circuit decision in Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd. addressing 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”).  Interest in the case has been high, as evidenced by the amicus briefs submitted by GPhA, Mylan, Teva, Apotex, Impax, and the Consumers Federation of America.

FDC Act §505(j)(5)(C)(ii)(I) states that:

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

As we previously reported (here and here), last year the U.S. District Court for the Eastern District of Michigan (Southern Division) ruled and issued an Order and Injunction requiring Novo Nordisk, Inc. (“Novo”) to change an Orange Book-listed PUC  for a patent (U.S. Patent No. 6,677,358 (“the ’358 patent”)) on its drug product, PRANDIN (repaglinide) Tablets, as a result of Caraco’s FDC Act §505(j)(5)(C)(ii)(I) counterclaim.  Novo appealed and the Federal Circuit reversed and vacated the district court’s judgment in a 2-1 decision.

The Federal Circuit, in its April 2010 majority opinion, ruled that Caraco “does not have a statutory basis to assert a counterclaim requesting” a court to enter an order to replace Novo’s new PUC with the former PUC.  First, “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.  Judge Dyk lodged a 28-page dissent arguing that “the majority’s crabbed view of the statute sanctions an unjustified manipulation of the Orange Book,” and that FDC Act §505(j)(5)(C)(ii)(I) should be available with respect to challenging PUCs, because “all Orange Book information is ‘patent information.’”

The Federal Circuit’s July 29th Order denying Caraco’s/Sun’s rehearing petition is brief, stating, in part, that “[t]he petition for rehearing was considered by the panel that heard the appeal, and thereafter the petition for rehearing en banc, the response to the petition, and briefs amici curiae were referred to the circuit judges who are authorized to request a poll on whether to rehear the appeal en banc.  A poll was requested, taken, and failed.” 

Judges Gajarsa and Dyk, however, took the opportunity to rail against the majority’s decision, stating that:

• The majority’s opinion construes the counterclaim provision contrary to its manifest Congressional purpose.  That construction renders 21 U.S.C. § 355(j)(2)(A)(viii) (“Section viii”) carve-out statements a virtual nullity and leaves generic drug manufacturers without a remedy to challenge inaccurate Orange Book listings with respect to method of use patents.

• With the majority’s blessing, pioneering drug manufacturers now have every incentive to follow Novo’s lead and draft exceedingly broad use codes thereby insulating them-selves from generic competition and rendering Section viii a dead letter.

• Finally, the majority opinion effectively invalidates the FDA’s effort to define “patent information” for the purposes of the counterclaim provision.  This invalidation is especially troubling given Congress’s explicit approval of those regulations.  Without even requesting the views of the FDA, the majority opinion refuses to give effect to the FDA’s interpretation of an important statutory term.

As we previously noted, the number of PUCs have doubled since FDA permitted firms to design their own descriptors in 2003.  Whether the Federal Circuit’s decision will make “section viii” statements a nullity remains to be seen.  In the meantime, we would not be surprised if there is a push to get Congress to amend the FDC Act.

By Kurt R. Karst –   

Earlier this week, the U.S. District Court for the District of Columbia denied Sanofi-Aventis’s Motion for Summary Judgment and granted Cross-Motions for Summary Judgment (here and here) filed by FDA and intervenor-defendants last fall in a dispute over FDA’s approval of applications for generic versions of Sanofi’s drug ELOXATIN (oxaliplatin).  In our previous post on the litigation over generic ELOXATIN – The Oxaliplatin Controversy – a Tale of Intrigue, Secrecy, and Suspense – we reported on the various twists and turns that eventually resulted in the approvals.  The most recent decision affirms what court decision terminates a 30-month stay of ANDA (and 505(b)(2) application) approval in Paragraph IV patent infringement litigation.

When we last left you, FDA had reinstated the approvals for generic ELOXATIN after the U.S. Court of Appeals for the District of Columbia Circuit ordered the dissolution of an administrative injunction suspending the approvals.  Shortly thereafter, on September 10, 2009, the U.S Court of Appeals for the Federal Circuit vacated a judgment (which the Court had previously stayed) from the U.S. District Court for the District of New Jersey that U.S. Patent No.5,338,874 (“the ‘874 patent”) covering ELOXATIN was not  infringed by certain generic applicants.  Just a few days later, Sanofi filed a Motion for Summary Judgment in the U.S. District Court for the District of Columbia in the case it had filed against FDA in August 2009 (Sanofi-Aventis et al. v. Food & Drug Admin. et al., No. 2009-1495) arguing that a stayed judgment is not a “judgment” within the meaning of FDC Act § 505(j)(5)(B)(iii)(I)(aa) (ANDA) and FDC Act § 505(c)(3)(C)(i) (505(b)(2)) terminating the 30-month stay on approval, and that as a result of the Federal Circuit’s September 10th decision vacating the New Jersey district court’s judgment, the 30-month stay on ANDA/505(b)(2) approval was effectively reinstated.  FDA and the intervenor-defendants argued in their Cross-Motions for Summary Judgment that regardless of the Federal Circuit’s stay and subsequent vacatur of the New Jersey district court’s decision, the FDC Act required the Agency to approve the applications once the New Jersey district court entered its judgment with respect to the ‘874 patent.

In ruling on the “purely legal issue of whether a vacatur entered by an appellate court overrides the terminating effect that the entry of a district court judgment has on the thirty-month stay under the FDCA,” the D.C. district court turned its attention to the text of FDC Act § 505(j)(5)(B)(iii) and § 505(c)(3)(C):

In short, there are two ways the thirty-month stay can terminate prematurely.  The first – addressed in the entry of judgment provisions [at FDC Act §§ 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I)] – arises when the district court rules that the patent is invalid or not infringed or endorses a settlement agreement stating that the patent is invalid or not infringed prior to entering judgment.  That scenario ends with the district court; there is no provision for what happens if the district court’s judgment is appealed.  The other scenario [under FDC Act §§ 505(c)(3)(C)(ii) and (j)(5)(B)(iii)(II)(aa)] occurs when the district court determines that the patent is valid and infringed, the judgment is appealed and the court of appeals either reverses the district court judgment and determines that the patent is invalid or not infringed or endorses a settlement agreement stating that the patent is invalid or not infringed before issuing an opinion.  When viewed in context, the omission of a discussion of the appellate process in the entry of judgment provisions is glaring. Accordingly, the court takes this omission to be intentional and concludes that Congress intended the thirty-month stay to terminate upon the entry of judgment by a district court that a patent is invalid or not infringed without regard to the appellate process.

Although not implicated in the litigation, the court noted that Congress made reference to the appellate process in the ANDA 180-day exclusivity forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA).  This provision states that in a failure-to-market forfeiture analysis one event that is considered is when “a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has or can be taken.”  Thus, the court determined that “the lack of limiting language in the entry of judgment provisions – in contrast to the successive sections and the forfeiture provision – is sufficient to demonstrate Congress’s intent that the entry of judgment by the district court be the event that triggers the termination of the thirty-month stay notwithstanding any subsequent appeal or ruling by the appellate court.”

Presumably the district court’s decision will put this matter to bed, but an appeal is always possible.

By Alexander J. Varond* & Diane B. McColl –

As noted in our blogpost less than two months ago, the U.S. District Court for the District of Columbia held that FDA acted unconstitutionally in Alliance for Natural Health, US v. Sebelius when the agency limited qualified health claims (“QHCs”) concerning selenium and reduced incidence of certain cancers proposed by Wellness Lifestyles, Inc.  In part, the court held that FDA erred when it “completely eviscerated plaintiff’s claim” rather than adopting a less restrictive approach such as drafting “short, succinct, and accurate disclaimers.”  We viewed the Alliance for Natural Health (“ANH”) decision as potentially cementing in place a regime for FDA’s review of qualified health claims that is very favorable to health claim petitioners. 

Now a new challenge to FDA’s restrictive treatment of health claims in foods and dietary supplements seeks to build on ANH’s success.  In a recently filed complaint in the U.S. District Court for the District of Connecticut, Fleminger, Inc. (“Fleminger”) contests FDA’s reaction to its proposed QHC regarding green tea and the incidence of breast and prostate cancers.  The tea maker claims that by mandating the use of specific language for the QHCs, FDA violated the company’s commercial free speech rights under the First Amendment of the U.S. Constitution.

Fleminger, which sells green tea at www.teaforhealth.com, submitted its health claim petition to FDA on January 27, 2004.  The company claimed that its green tea QHC was based upon two separate studies.  In its June 30, 2005 enforcement discretion letter response, FDA acknowledged that, although the studies were “weak,” they did point to “limited credible evidence” that green tea may provide some benefit against prostate and breast cancers.  However, FDA stated that stronger, more credible studies did not show an effect of green tea on either prostate or breast cancer.  Thus, FDA decided to allow only the following heavily qualified claims:

Two studies do not show that drinking green tea reduces the risk of breast cancer in women, but one weaker, more limited study suggests that drinking green tea may reduce this risk.  Based on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of breast cancer.

One weak and limited study does not show that drinking green tea reduces the risk of prostate cancer, but another weak and limited study suggests that drinking green tea may reduce this risk.  Based, on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of prostate cancer.

Fleminger’s petition for administrative review was denied on August 19, 2008.  FDA justified its denial by stating that the two QHCs “provide the ‘precise language’ that allow Plaintiff’s qualified health claims to be ‘truthful and not misleading.’” 

Subsequently, on February 22, 2010, FDA issued a warning letter to Dr. Sin Hang Lee of Fleminger that threatened “the seizure of [Fleminger’s] illegal products and injunctions against manufacturers and distributors of those products.”  The FDA also reasserted that Fleminger was required to use  without modification, only the exact QHC language that FDA set forth in its enforcement discretion letter.

Fleminger responded by filing a complaint in the U.S. District Court for the District of Connecticut, asserting that FDA essentially required the company to “choose between speaking exactly as [FDA] wish[es], remaining silent, or risking adverse action for its own commercial speech in violation of the First Amendment.”  Furthermore, it alleges that by forcing Fleminger to use the “government’s speech or none at all,” FDA failed to use the “least restrictive means of preventing any alleged deception of consumers who choose to purchase [Plaintiff’s] green tea.” In addition, the complaint charges that FDA’s prohibition on Plaintiff’s speech was overly broad and amounted to an unconstitutional prior restraint.

A ruling in Fleminger’s favor would confirm that FDA’s ability to allow only severely restricted and narrow QHCs has been  drastically reduced.  Such a success would send yet another strong signal to the agency that FDA needs to revamp its strict approach toward food and dietary supplements QHCs.

* Law Student

By Jamie K. Wolszon & Jeffrey N. Gibbs –

FDA officials, at a July 19-20, 2010 workshop, stated that the agency intends to end the “exercise enforcement” authority over some laboratory-developed tests (“LDTs”).  Put more plainly, FDA now plans to regulate some LDTs as medical devices.  However, while FDA was clear that it plans to regulate LDTs, key FDA officials, including Center for Devices and Radiological Health (“CDRH”) director Jeffrey Shuren emphasized that the agency had not decided on the details of their regulatory scheme. 

LDTs are diagnostic tests developed and performed by a single laboratory.  They are widely used; virtually all genetic tests are LDTs, as are many tests for emerging diagnosis and for rare conditions.  Regulating these tests will raise many policy, regulatory, legal, and public health questions.

Many attendees, panelists and presenters at the meeting accepted the idea of FDA regulation of LDTs.  However, many speakers stressed that FDA must proceed carefully or the regulation of LDTs could have unintended negative consequences. 

Those potential unintended consequences include reduced innovation, delay in developing tests, fewer improvements in tests, and limiting patient access to tests.  Many speakers were particularly concerned about the effect on tests that are developed in response to new and emerging threats, and tests for rare disorders.  According to many meeting attendees, patient care could suffer and advances into personalized medicine could slow if LDT regulation is not implemented in a balanced manner.

One of the FDA speakers, Elizabeth Mansfield, Director for Personalized Medicine, Office of In Vitro Diagnostic Device Evaluation and Safety (“OIVD”) at CDRH, said that the framework for regulation of LDTs still needs to be written.  Elements that need to be outlined by the agency include: risk categorization, a phase-in period for premarket review and quality systems requirements for new LDTs; registration and listing; and inspections of laboratories.  Other speakers identified additional details that would need to be addressed.

The End of Enforcement Discretion?

Starting in 1992, FDA asserted that all LDTs are devices subject to regulation under the Federal Food, Drug, and Cosmetic Act.  Since then, the agency said it was exercising its enforcement discretion and not regulating LDTs.  Thus, the primary federal regulation of laboratories has been under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).  As a number of speakers noted, LDTs are also regulated by the states (notably New York) and other bodies (notably the College of American Pathologists) (“CAP”).

Until recently, FDA has departed from this position of enforcement discretion in relatively few instances.  For example, FDA has asserted that a test was not a true LDT and advanced its controversial and now-defunct proposal to regulate a subset of LDTs, known as In Vitro Diagnostic Multivariate Index Assays (“IVDMIAs”).  (IVDMIAs are tests where the results of multiple markers are combined to generate an “index score.”)

We previously reported that FDA announced last month that it is revisiting its years-long policy of exercising enforcement discretion over LDTs, and considering adopting a risk-based framework.  The agency announced that it was holding the July 19-20 workshop as a first step to gather comment on how to more actively regulate LDTs.

FDA officials at the meeting reiterated that they intend to regulate at least for some LDTs.  FDA is still grappling with many unanswered questions as to the details of a regulatory scheme.  As shown by the debate over the less sweeping IVDMIA proposal, extending FDA regulation to LDTs will raise many questions.  Issues discussed at the meeting include the following.

Notice and Comment Rulemaking

The agency took the position that FDA does not need to pursue notice-and-comment rulemaking to implement this policy shift.  Dr. Shuren stated that because the laws which permits FDA to regulate laboratories are already in effect; the agency merely has been exercising its enforcement discretion, and therefore can implement the new regulatory framework through guidance. 

Notice-and-comment rulemaking is a more demanding process than issuing a guidance.  For example, in notice and comment rulemaking, FDA must consider and respond to each of the primary comments.  In a guidance, the agency does not have to address comments.  Rulemaking must explicitly address other factors, such as economic impact.  When FDA proposed to regulate IVDMIAs, it also did so through guidance.

A few attendees urged the agency to proceed through notice-and-comment rulemaking.  For example, Anna Longwell, of Longwell and Associates, questioned the approach of moving forward through guidance instead of rulemaking.  Ms. Longwell said there should be a formal notice of proposed rulemaking.  If FDA does proceed to regulate LDTs through a guidance document, any legal challenge is likely to assert that FDA violated the Administrative Procedure Act by skipping the rulemaking process. 

Risk Categorization and Premarket Review

The agency must determine how it will categorize risk.  Meeting presenters and attendees provided examples of possible categorization schemes.

Examples of tests that the agency might consider high risk, according to Dr. Mansfield, include companion diagnostics, such as an LDT used to help determine whether the drug is used properly.  Other examples of high-risk tests include those where an undetected false result could seriously affect the patient; tests that diagnose cancer; and tests that manage serious diseases.

Examples of medium-risk tests provided by Dr. Mansfield include those that could lead to non-serious injury; those where it is easy to detect false results; and adjunctive tests.  Medium-risk tests also could include those where it could lead to psychosocial issues and genetic tests where the assessment is based on a phenotype and the genetic tests are merely confirmatory.  They also include those tests intended to monitor patients with a known disease. 

Examples of lowest-risk tests are those that are highly adjunctive, and for medical knowledge only and evaluation without directed management.  Examples of low-risk tests also include those that have little clinical impact.

Asked whether a test intended for use in evaluating cancer recurrence would be high-risk, Dr. Mansfield responded that currently tests that monitor the cancer of someone who already has been diagnosed generally is not high-risk, although it would depend on the specific claims made.

William Clarke, representing the American Association for Clinical Chemistry (AACC), advocated a classification scheme that includes three categories: high risk, moderate risk, and low risk.  He said that IVDMIAs should be high risk under the upcoming scheme and that high-risk tests should be subject to FDA oversight.  

Gail Vance, representing CAP, proposed that low-risk LDTs be validated and placed into service.  An accredited organization would inspect the low-risk LDTs.  For moderate-risk LDTs, the laboratory would validate the test and then give the data to an accredited party to review.  For high-risk LDTs, there would be validation and the laboratory then would give the data to FDA to review.

Other speakers offered their own ideas.  A key element of any regulatory scheme will be to appropriately and precisely define which tests are subject to FDA regulation.  Ambiguous criteria will create confusion and uncertainty.  In follow-up discussions with clinicians regarding the representative classification of well-known markers, we found that they often sharply disagreed about the correct classification.  Characterizing the risk can get even more difficult with new intended uses.   
 
Quality Systems Regulation (“QSR”)

Several presenters said it will be difficult for laboratories to comply with the QSRs.  (21 C.F.R. Part 820.)  Of particular concern is the design control requirement.  There appears to be agreement that how QSRs would be applied is an important practical issue, but there was no consensus on that topic.  One suggestion was that FDA rely on inspections by third parties conducted pursuant to CLIA.

Advisory Panel IVD Classification

Some attendees noted that the agency will have to consider how to conserve resources, including staff, as it embarks on such a massive undertaking of regulating LDTs.  Depending on what LDTs are subject to regulation, FDA could receive many new pre-Investigational Device Exemption (“IDE”) requests and marketing applications.  Moreover, because of their novelty, many of these tests will place greater demands on OIVD.  Dr. Mansfield suggested that the agency is considering using advisory panels for down classifications of current IVDs, which would free up staff.  Several meeting attendees, including Elaine Lyon at the Association for Molecular Pathology, recommended use of advisory committees for risk categorization of LDTs.

Phase-In Period for new LDTs

FDA is considering phasing in new premarket review and quality systems requirements over time to help facilitate predictability and planning, according to Dr. Mansfield.  FDA could first require compliance for high-risk tests, and later implement requirements for other tests, she suggested.

Applying New Scheme to Currently Marketed LDTs

When the agency proposed to regulate IVDMIAs, it proposed a grandfather period – albeit a comparatively short one – during which companies already marketing those tests would have a certain amount of time to submit premarket review applications.  Asked how the agency would treat tests already offered, Dr. Mansfield responded that the agency does not yet know the answer to this question.  She did state, however, that the agency has no intention of disrupting clinical testing. 

One presenter suggested that FDA grandfather in all LDTs approved by the New York State Department of Health.

Registration and Listing

FDA also seeks a way to determine a list of who offers what tests.  Dr. Mansfield noted that the National Institutes of Health is in the process of establishing a voluntary genetic testing registry.  Dr. Mansfield noted that FDA probably will need to expand registration and listing to include LDTs.  A number of speakers thought that a mandatory registry could play a constructive role.

Utilizing CLIA Inspectors
 
Dr. Mansfield also noted that the agency is considering piloting third-party accreditation for inspection of LDTs.  Currently, the CLIA scheme for regulating laboratories includes an inspectional requirement.  In addition, the CAP inspects laboratories for accreditation.  FDA could use those same CLIA or CAP inspectors to conduct inspections on FDA’s behalf. 

Rare Disorders

Attendees almost universally recognized tests for rare disorders as needing special protection under the future scheme.  Some, including William Clarke, representing the AACC, recommended exempting tests for rare disorders from the future regulatory scheme.  While it was suggested by attendees that the Humanitarian Use Device/Humanitarian Device Exemption program could help, these mechanisms can play only a limited role.  The HUD/HDE process is unavailable if the number of patients to be tested exceeds 4000 per year.

Emergencies Including Infectious Diseases

Several attendees noted that when an emerging disease arises, LDTs are often the first test to meet that previously unmet need.  Delaying the introduction of these tests could hamper public health agencies in responding in the case of an emergency. 

Steve Gutman, the former Director of OIVD, noted that the agency can process with emergency use authorizations (“EUA”) rapidly; however, some attendees appeared unconvinced that the EUA program would be sufficiently timely or responsive, particularly for less common emerging diseases.

Modifications and Personalized Medicine

Attendees also warned that an unintended consequence could be to reduce modifications made to tests and to slow advances in personalized medicine.  Once a product is cleared or approved, even relatively small modifications can trigger the need for a new submission.  Thus, the ability to rapidly incorporate new information into assays could be impeded.

Conclusion

The expansion of FDA’s device regulatory scheme to LDTs – even a small subset of LDTs – will raise significant questions.  Many speakers expressed their hope that this will be a collaborative process.  The FDA’s release of series of letters issued to laboratories on the first day of the meeting did prompt some concerns as to whether this hope would be realized fully.  Given the complexity of LDT regulation and its potential consequences – both expected and unexpected – it is critical that this wish for active collaboration be granted. 

By Kurt R. Karst –   

As we thought might happen, Sanofi-aventis U.S. L.L.C. (“Sanofi”) sued FDA over the Agency’s July 23, 2010 approval of Sandoz Inc.’s (“Sandoz’s”) ANDA No. 77-857 for a generic version of Sanofi’s blockbuster anti-coagulant drug LOVENOX (enoxaparin sodium injection).  (On the same day that FDA approved Sandoz’s ANDA, the Agency responded to a February 2003 Sanofi citizen petition concerning the approval of generic LOVENOX.)  Sanofi filed a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction the U.S. District Court for the District of Columbia late on July 26th requesting that the  court issue a declaratory judgment that FDA acted unlawfully in approving ANDA No. 77-857, as well as a temporary restraining order and preliminary injunction directing FDA to immediately suspend and withdraw approval of the Sandoz ANDA, and a permanent injunction under the same terms.

Sanofi alleges in its court papers that FDA violated the FDC Act in approving ANDA No. 77-857.  Specifically, according to Sanofi:

By approving Sandoz’s ANDA, FDA has exceeded its authority under Section 505(j) of the [FDCA], ignored its own precedent regarding approval of generic versions of drugs that have not been fully characterized, and has failed to ensure that Sandoz's drug has the same active ingredient as Lovenox, as required by the ANDA provisions of the FDCA.

Furthermore, Sanofi alleges that FDA's approval of Sandoz’s ANDA violated the Administrative Procedure Act (“APA”) and was improper under the FDC Act insofar as “FDA approved Sandoz's ANDA for a fully substitutable generic version of Lovenox notwithstanding the fact that the Agency required Sandoz to submit additional data and information demonstrating the safety and effectiveness of its product.”  According to Sanofi, FDA disregarded FDC Act § 505(j)(2)(A), which concerns the required content of an ANDA and “specifically precludes FDA from requiring the submission of such [safety and effectiveness] information.”  Moreover, requiring or considering such information as part of an ANDA “effectively allows the generic applicant to rely upon the pioneer's confidential commercial information in a manner not contemplated by the statute,” according to Sanofi. 

Sanofi also alleges that FDA violated the APA “by effectively according different treatment to similarly situated products.”  According to Sanofi, “FDA has ignored Agency precedent relating to generic versions of drugs that have not been fully characterized,” and “failed to provide a substantive reason why generic enoxaparin should be treated differently from other drugs that cannot be fully characterized.”  Sanofi detailed a body of precedent in the company’s 2003 citizen petition (and in supplements to that petition) that the company believes should have supported FDA fully granting the company’s petition. 

Finally, Sanofi alleges that FDA has also dismissed, “without any rational justification or analysis, a wealth of scientific evidence establishing that small variations in the manufacturing process used to create low molecular weight heparins (LMWHs) such as Lovenox can result in significant changes to the structure and pharmacological properties of generic versions of the drug,” and that “[b]y allowing generic applicants to deviate from the manufacturing process used by [Sanofi] to produce Lovenox, FDA has failed to ensure that generic versions of enoxaparin have the same active ingredient and the same safety and effectiveness profile as Lovenox, as required by the ANDA provisions of the FDCA.”

We will continue to update our loyal FDA Law Blog readers on this interesting (and not unexpected) lawsuit.  A hearing on Sanofi's motion is currently scheduled for August 17, 2010 at 10:30AM.

By Ricardo Carvajal –

As we discussed in a prior posting, Section 4205 of the Patient Protection and Affordable Care Act requires the display of certain nutrition information by chain restaurants and retail food establishments with 20 or more locations doing business under the same name and offering for sale substantially the same menu.  In return, such larger chain restaurants are relieved of having to comply with state or local requirements that are not identical to the new federal requirements.  Smaller chain restaurants (meaning those with one to 19 locations) were left a choice: voluntarily register with FDA and submit to federal requirements as implemented by FDA through forthcoming regulations, or be subject to state requirements.  Now FDA has published a Federal Register notice announcing how smaller chain restaurants can voluntarily register with FDA effective immediatel.  Given the speed with which menu labeling requirements are changing at the state and local level, we’re guessing that many smaller chain restaurants might just hold their noses and opt to fall under the federal thumb.

By Kurt R. Karst –   

On July 26, 2010, the U.S. District Court for the District of Wyoming denied a Motion for Temporary Restraining Order and Preliminary Injunction filed last week by Cody Laboratories, Inc. and Lannett Co., Inc. (collectively “Cody/Lannett”) against FDA in a case involving marketed unapproved Morphine Sulfate Solution Immediate-Release 20mg/mL products.  The 37-page opinion, which is nearly identical to the proposed Order submitted by FDA, also dismissed Cody/Lannett’s Complaint filed last week.

As we previously reported, the lawsuit stems from FDA’s March 2009 Warning Letters to Cody and Lannett (among other companies) to stop manufacturing certain unapproved narcotic drugs, including morphine sulfate oral solutions.  At that time, FDA concluded that marketed unapproved morphine sulfate products are “new drugs [under the FDCA] and not grandfathered and that manufacturing and marketing of these products without an approved application constituted a violation of the Act.”  In subsequent communications with Cody/Lannett, FDA stated that the Agency would exercise enforcement discretion with regard to the shipment and distribution of Cody’s/Lannett’s unapproved Morphine Sulfate Solution Immediate-Release 20mg/mL drug products until July 24, 2010, which is 180 days after FDA approved an NDA for the drug product.  Meanwhile, Lannett submitted its own NDA to FDA for Morphine Sulfate Solution Immediate-Release 20mg/mL in late February 2010.  That NDA is still under review by FDA.

Cody/Lannett argued in their lawsuit that FDA should be enjoined from taking enforcement action after July 24, 2010 if such enforcement action is based on FDA’s contention that Morphine Sulfate Solution Immediate-Release 20mg/mL is an unapproved “new drug,” and that the court should issue a declaratory judgment that FDA violated the Administrative Procedure Act (“APA”) in determining that the product is a “new drug.”  Cody/Lannett also alleged that FDA violated the APA by not treating Cody/Lannett fairly in the NDA process.

In denying the injunctive and declaratory relief requested by Cody/Lannett, the court relied on the U.S. Supreme Court’s decision in Ewing v. Mytinger & Casselberry, Inc., 339 U.S. 594 (1950).  Ewing and its progeny “established that courts lack jurisdiction to enjoin FDA from initiating enforcement proceedings under the FDCA.”  Specifically, the Supreme Court held in Ewing that “district courts do not have jurisdiction to review an FDA determination to initiate an enforcement action under the FDCA, finding that ‘[j]udicial review of this preliminary phase of the administrative procedure does not fit the statutory scheme nor serve the policy of the FDCA.’”  Applying the Ewing decision to the current case, the district court ruled:

[T]he Supreme Court in Ewing has foreclosed the possibility that an injunction, like the one plaintiffs seek here, can be granted to halt FDA enforcement actions.  Because plaintiffs are attempting to enjoin an anticipated enforcement action, the well-settled precedent applies with all the more force.  Such relief would be without foundation and a wholly inappropriate interference with FDA’s charge to protect the public health.  FDA’s ability to enforce its statutory mandate would be frustrated if, prior to even determining that initiation of an enforcement action was warranted, a lawsuit could be brought against the Agency.  Because the relief sought by plaintiffs is clearly foreclosed by Ewing and its progeny, plaintiffs’ complaint must be dismissed.

Moreover, with respect to Cody/Lannett’s claim to grandfather status for their marketed unapproved Morphine Sulfate Solution Immediate-Release 20mg/mL products, the court commented:

By their very nature, plaintiffs’ claims cannot be evaluated as a question of pure law.  An enforcement action brought on behalf of FDA by the United States Department of Justice, alleging that Plaintiffs' drug may not be legally marketed because its composition and the conditions of use reflected in its labeling have changed since 1938, would provide the appropriate forum to resolve the factual basis for plaintiffs' dispute.

Alternatively, plaintiffs could can [sic] file a citizen petition at any time seeking FDA's views as to the claimed grandfather status of their drug, and FDA's response to such a petition constitutes final agency action subject to immediate judicial review under the APA. Plaintiffs failed to exhaust this much-utilized procedure under which they could have obtained FDA's view on an administrative record.

If this Court were to become involved in this matter now, it would need to apply the criteria in FDA's regulations to plaintiffs' drug and undertake an evaluation to determine whether plaintiffs' have produced sufficient evidence in support of their claim that their drug meets the requirements of the 1938 grandfather clause and is not a "new drug." [(citations omitted)]

The court further ruled that Cody/Lannett’s claim is not ripe for adjudication, because the companies seek to “enjoin a possible future FDA enforcement action to remove their unapproved morphine sulfate oral solution from the market.”  Cody/Lannett relied on FDA’s Warning Letter as evidence of imminent and inevitable Agency enforcement action.  Consistent with other court decisions (including the recent decision in Regenerative Sciences, Inc. v. FDA, although not cited by the court), however, the district court ruled that “the issuance of a warning letter by FDA does not constitute final agency action ripe for judicial review. . . .”

Even if FDA were to take enforcement action based on the fact that Cody/Lannett’s product is an illegally marketed unapproved new drug, the court ruled that the plaintiffs’ only defense – that their drug is grandfathered under the FDC Act’s 1938 grandfather clause – would fail:

Unless the evidence produced by plaintiffs establishes that there have been no changes whatsoever in the formulation, dosage form, potency, route of administration, indication for use, or intended patient population for their 20 mg/ml morphine sulfate oral solution since 1938, plaintiffs' drug does not qualify for the 1938 grandfather clause exemption. . . .  Plaintiffs admit that they have only been marketing their drug for the past five years and have failed to produce any pre-1938 labeling for their drug.  Thus, it is impossible for plaintiffs to demonstrate that their drug's "labeling contained the same representations concerning the conditions of its use" in 1938 that it presently contains. [(citations omitted)]

Finally, the district court disagreed with Cody/Lannett’s allegations that FDA acted unfairly in violation of the APA in considering Lannett’s NDA for Morphine Sulfate Solution Immediate-Release 20mg/mL.  “FDA did nothing more than follow its well established policies for the designation of certain NDAs for priority review,” according to the court.  “Because FDA gave everyone the same notice at the same time and encouraged all to apply, and now intends to do exactly what it said 15 months ago it would do, FDA's actions are not unreasonable.”

It is unclear whether Cody/Lannett will appeal the decision.  If the decision stands, FDA will likely use it as “Exhibit A” if any company expresses its intent to challenge FDA in court over the Agency’s Unapproved Drugs Initiative enforcement plans.

By Kurt R. Karst –

Earlier today, FDA issued its long-awaited response (45 pages) to a February 2003 citizen petition submitted to the Agency on behalf of Aventis Pharmaceuticals, Inc. (“Aventis”) concerning the approval of generic versions of the company’s anti-coagulant drug LOVENOX (enoxaparin sodium injection).  FDA approved LOVENOX in March 1993 under NDA No. 20-164.

Aventis requested that FDA not approve an ANDA for generic LOVENOX unless certain conditions are met – specifically, (1) “until enoxaparin has been fully characterized . . . unless the manufacturing process used to create the generic drug product is determined to be equivalent to Aventis’s manufacturing process for enoxaparin or the application is supported by proof of equivalent safety and effectiveness demonstrated through clinical trials;” and (2) “unless the generic product contains a 1,6 anhydro ring structure at the reducing ends of between 15 percent and 25 percent of its poly(oligo)saccharide chains.”  FDA granted Aventis’s petition with respect to item (2), and denied the petition in all other respects.  At the same time, FDA approved Sandoz Inc.’s ANDA (which presumably contains a 1,6 anhydro ring structure in the proper position and which will presumably be “AB” rated to LOVENOX in the Orange Book).  Sandoz is not a first-filer, and therefore, will not be awarded 180-day exclusivity.  As FDA explains in the Sandoz approval letter, 180-day exclusivity for generic LOVENOX, which is governed by the pre-Medicare Modernization Act version of FDC Act § 505(j), was triggered by a court decision and has since expired. 

Briefly, FDA explained in its petition response that the FDC Act:

does not require ANDA applicants to (1) completely characterize all the different polysaccharides of enoxaparin by isolating, purifying, and sequencing each of its unique polysaccharide chains and determining their relative abundance, (2) use the same manufacturing process as that used for the RLD, or (3) conduct clinical studies to demonstrate equivalent safety and effectiveness. 

For an ANDA applicant to demonstrate sameness of its active ingredient as compared to LOVENOX, the Agency considers five criteria (i.e., standards for identity): (1) equivalence of physicochemical properties; (2) equivalence of heparin source material and mode of depolyierization; (3) equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species; (4) equivalence in biological and biochemical assays; and (5) equivalence of in vivo pharacodynamic profile.  According to FDA, a robust showing on all five of these factors by a generic applicant would demonstrate that the molecular diversity of the generic is equivalent to that of enoxaparin, including with respect to the 1,6 anhydro ring structure. 

FDA’s petition response may have implications on other complex drug products for which ANDAs are pending at FDA.  While FDA claims that the Agency’s approach to determining enoxaparin sameness is consistent with the Agency’s previous ANDA approval decisions for heterogeneous polysaccharides, such as heparin and hetastarch, we would not be surprised if FDA is sued over its petition response and ANDA approval.

ADDITIONAL READING:

• FDA, Generic Enoxaparin Questions and Answers

• FDA, Establishing Active Ingredient Sameness for a Generic Enoxaparin Sodium, a Low Molecular Weight Heparin

By Kurt R. Karst –   

Earlier this week, Cody Laboratories, Inc. and Lannett Co., Inc. (collectively “Cody/Lannett”) filed a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction in the U.S. District Court for the District of Wyoming requesting that the court enjoin FDA from taking any enforcement action with respect to their marketed unapproved Morphine Sulfate Solution Immediate-Release 20mg/mL products.  The lawsuit is (to our knowledge) the first challenge arising from FDA’s Unapproved Drugs Initiative, which was kicked off in June 2006 with the publication of the Agency’s Compliance Policy Guide (“CPG”).  FDA’s CPG articulates the Agency’s risk-based enforcement approach to taking enforcement action with respect to the manufacture and distribution of marketed unapproved drugs.  Under that policy, FDA gives higher priority to enforcement action against unapproved drugs in certain categories, including drugs that present direct challenges to the “new drug” approval and over-the-counter drug monograph systems (e.g., when a drug is approved under an NDA and other companies market the same product without approval). (An article we authored that appeared in RAPS Focus a couple of years ago discussing the world of marketed unapproved drugs is available here.)

The Cody/Lannett lawsuit stems from FDA’s March 2009 decision to issue Warning Letters to nine companies, including Cody and Lannett, to stop manufacturing fourteen unapproved narcotic drugs, such as high concentrate morphine sulfate oral solutions, morphine sulfate immediate release tablets, hydromorphone, and oxycodone (see our previous post here).  At that time, FDA concluded that marketed unapproved morphine sulfate products are “new drugs [under the FDCA] and not grandfathered and that manufacturing and marketing of these products without an approved application constituted a violation of the Act.”

Shortly thereafter, in April 2009, FDA announced that the Agency would reverse course to allow the continued marketing and distribution of one of the drug products – Morphine Sulfate Solution Immediate-Release 20mg/mL – on an interim basis due to concerns over a drug shortage, and sent letters to the affected parties, including Cody and Lannett.  (see our previous post here)  Specifically, FDA stated that the Agency would exercise discretion not to take enforcement action “until 180 days after any firm receives approval for a morphine sulfate oral solution 20 mg/ml product.” 

FDA approved an NDA for Morphine Sulfate Solution Immediate-Release 20mg/mL on January 25, 2010.  In follow-up letters sent to Cody and Lannett (here and here) in March 2010, FDA stated that consistent with the Agency’s previous communications, FDA would exercise enforcement discretion with regard to the shipment and distribution of Cody’s/Lannett’s unapproved Morphine Sulfate Solution Immediate-Release 20mg/mL until July 24, 2010.  Meanwhile, Lannett submitted its own NDA to FDA in late February 2010.  Cody/Lannett have continued to market their unapproved morphine sulfate products, but have reportedly encountered problems in obtaining quota from the Drug Enforcement Administration for additional raw material to manufacture new product – apparently as a result of FDA’s position on this unapproved drug.

Enter the lawyers . . . .

Cody/Lannett argue in their lawsuit that FDA should be enjoined from taking enforcement action after July 24, 2010 if such enforcement action is based on FDA’s contention that Morphine Sulfate Solution Immediate-Release 20mg/mL is an unapproved “new drug,” and that the court should issue a declaratory judgment that FDA violated the Administrative Procedure Act (“APA”) in determining that the product is a “new drug.”  Specifically, Cody/Lannett argue that:

The FDA failed to develop an adequate record to support its determination that the Product is a “new drug” that does not fall within the grandfathering provisions of the FDCA. . . .  By failing to develop an adequate record for its determination that the Product is a “new drug” for purposes of the FDCA, the FDA acted arbitrarily, capriciously, contrary to law, and abused its discretion in violation of the APA in reaching such a determination.

The 1938 and 1962 grandfather clauses in the FDC Act have been construed very narrowly by FDA and the courts.  FDA believes that there are few, if any, marketed drugs that are actually entitled to grandfather status, because the drugs currently on the market likely differ from the previous versions in some respect, such as formulation, dosage form, strength, method of manufacture, route of administration, indications or intended patient population.  If a company claims that its product is grandfathered, FDA considers it the firm’s burden to prove that assertion.  FDA stated in the Agency’s 2006 CPG that it believes “it is not likely that any currently marketed prescription drug product is grandfathered or is otherwise not a new drug,” but recognizes that “it is at least theoretically possible” that such a product exists.

Cody/Lannett take aim at FDA’s 2006 CPG in their lawsuit, stating that the CPG “operated effectively to render the grandfather provisions of the FDCA inoperative,” and that the CPG “is contrary to the express terms of the statutory grandfather provisions of the FDCA, through which Congress expressed an unequivocal intent that the FDCA apply only prospectively to ‘new drugs’ and not retroactively to drugs on the market at the time of its passage.”

Cody/Lannett also allege that FDA violated the APA by not treating Cody/Lannett fairly in the NDA process.  Specifically, that FDA provided another company “greater assistance in moving through the NDA process” and by creating “substantial delays in scheduling meetings with Cody/Lannett and denying Cody/Lannett’s request for expedited treatment of its NDA.”

By Nisha P. Shah –

A U.S. District Court recently held that misrepresentation and false description of active ingredients by a manufacturer of generic prescription vitamins can be actionable under the Lanham Act.  Sciele Pharma, Inc. v. Brookstone Pharmaceuticals, LLC.  
 
Plaintiff, Sciele Pharma, Inc., develops and sells branded prescription products, including the prenatal vitamins PRENATE ELETE and PRENATE DHA.  An alleged unique feature of PRENATE is that it contains a 1 mg combination of 400 mcg of folic acid and 600 mcg of L-Methylfolate (“L-MTHF”), a bioactive form of folate that does not require additional metabolism by the body. Defendant, Brookstone Pharmaceuticals, LLC, a/k/a Acella Pharmaceuticals, LLC, develops and sells generic prescription prenatal vitamins called PNV and PNV-DHA.  Defendant’s labels and package inserts represent that PNV vitamins contains the same combination of folate as the PRENATE vitamins. 

However, plaintiff asserts in this litigation that defendant’s vitamins do not contain L-MTHF, but rather a different dietary ingredient known as D,L-MTHF.  This ingredient allegedly contains an equal mixture of the L-isomer and D-isomer of MTHF.  According to plaintiff, D,L-MTHF and L-MTHF are recognized as distinct dietary ingredients.  Plaintiff also claims that the presence of the D-isomer may be harmful to women taking the PNV vitamins. 
 
Plaintiff argues that defendant’s labels and package inserts for PNV vitamins are false and likely to deceive consumers, pharmacists, and others in the pharmaceutical distribution chain as to the content of the vitamins.  Since PNV vitamins are cheaper than PRENATE vitamins, plaintiff contends that pharmacists could decide to substitute PNV for PRENATE, despite having different active ingredients.  Plaintiff asserts claims under (1) the Lanham Act for false advertising and unfair competition, and (2) the Georgia Uniform Deceptive Practices Act.  Defendant filed a motion to dismiss on the grounds that the Federal Food, Drug, and Cosmetic Act (“FDCA”) precludes plaintiff from bringing Lanham Act claims.

The Court initially recognizes that the FDCA does not allow for a private right of action and that a tension exists between the FDCA and the Lanham Act in cases involving products regulated by FDA.  Further, the Court remarks that plaintiffs cannot use the Lanham Act as a vehicle to enforce the FDCA. 

Nevertheless, the Court looks at “the extent to which the plaintiff relies on the FDCA as the basis for its claim, or alternatively the extent to which the claim would require the Court to interpret or apply the FDCA or FDA regulations.”  Id. at *10.  According to the Court, “plaintiff credibly argues” its claim that defendant is misrepresenting the content of the PNV vitamins “can, and will, be proven without reference to the FCDA.”  Id. at *12.  In rejecting defendant’s motion, the Court concludes that “the simple fact that a Lanham Act claim touches upon an area that is within the purview of the FDCA is not a bar to proceeding,” and that “the Lanham Act prohibits exactly the type of misconduct that plaintiff alleges in its complaint: the misrepresentation and false description of the nature of the product.”  Id. at *12-13.

The Court similarly dismisses Brookstone’s second motion to dismiss on the merits of the Lanham Act claims.  Defendant argues that plaintiff’s claims cannot success because defendant complied with Georgia law on pharmaceutical substitution and that the disclaimers used with the vitamins insulate defendant from Lanham Act liability.  According to the Court, at the motion to dismiss stage, it must accept as true plaintiff’s allegations that the L-MTHF in PRENATE vitamins and the D,L-MTHF in the PNV vitamins are distinct dietary ingredients, and therefore, the two vitamins are not legally substitutable.  If plaintiff’s claims are accurate, the Court concludes that defendant’s misrepresentation is “unquestionably actionable under the Lanham Act.”  Id. at *14-15.  Moreover, the Court agrees with plaintiff’s argument that the disclaimer issue is better resolved on a motion for summary judgment or at trial. 

The Court also addresses several other motions, including the Court’s grant of plaintiff’s motion to remove the confidentiality designation to documents that (1) identify defendant’s manufacturers and suppliers, and (2) state the current formulation and/or ingredients of PNV vitamins, as both types of documents are not considered trade secrets. 

ADDITIONAL READING:

• March/April 2010 issue of FDLI Update article – The Lanham Act: Another Vehicle to Enforce the FDC Act?

By Kurt R. Karst –   

Earlier this week, Rep. Jan Schakowsky (D-IL), along with Reps. Ed Markey (D-MA) and Tammy Baldwin (D-WI), introduced H.R. 5786, the Safe Cosmetics Act of 2010.  The bill would significantly change the regulatory structure of cosmetics in the U.S., more closely aligning it with other FDA-regulated products, such as drugs, biologics, and medical devices. 

Except for color additives, there is no requirement today that a cosmetic establishment be registered with FDA or that a cosmetic ingredient be approved by, or even listed with, FDA prior to use.  Instead, FDA administers voluntary cosmetic establishment registration and ingredient filing programs (21 C.F.R. Parts 710 & 720).  Currently, FDC Act § 601(a) simply establishes a general principle that a cosmetic shall be deemed to be “adulterated” (and thus subject to regulatory action by FDA) “[i]f it bears or contains any poisonous or deleterious substance which may render it injurious to users under the conditions of use prescribed in the labeling thereof, or, under such conditions of use as are customary or usual. . . .”  FDA’s regulations prohibit or restrict the use of certain ingredients in cosmetics.  Most of these regulations appear in 21 C.F.R. part 700.  FDA would consider a cosmetic containing an ingredient in violation of any of the prohibitory regulations to be adulterated.  FDA may initiate regulatory action (including, for example, a civil seizure action in a U.S. district court, or a request for recall) whenever the Agency concludes that a particular ingredient used in a cosmetic product violates the general adulteration standard of  FDC Act § 601(a).

The Safe Cosmetics Act of 2010 would maintain current FDC Act §§ 601-603 concerning adulterated and misbranded cosmetics, but would amend the FDC Act to add a new subchapter on the regulations of cosmetics.  H.R. 5786 would, among other things:

• Require domestic and foreign establishments that manufacture, package, or distribute cosmetics to register annually with FDA, including providing FDA with contact information, a description of the establishment’s activities, gross receipts, the number of employees, and the name and address of any company that supplies a cosmetic manufacturing establishment with ingredients for its products.  FDA would be required to make its registration list publicly available, but not the registration documents.  Establishments would also be required to provide detailed product-specific information to FDA;

• Require FDA to establish a “schedule of fees . . . to provide for oversight and enforcement” of the new FDC Act subchapter on the regulation of cosmetics.  Such fees would be prorated based on an establishment’s gross receipts or sales, and would only be assessed on companies with annual gross receipts or sales of more than $1 million;

• Require, within one year after the date of enactment of the Safe Cosmetics Act of 2010, “the label on each package of cosmetics, including cosmetics distributed for retail sale and professional use, to bear a declaration of the name of each ingredient in such cosmetic in descending order of predominance.”  A similar requirement applies to Internet vendors with respect to providing ingredient information;

• Require manufacturers and distributors of cosmetics and ingredients to submit (in an electronic format) to FDA, not later than one year after the date of enactment of the Safe Cosmetics Act of 2010, “all reasonably available information in the possession or control of the manufacturer or distributor that has not previously been submitted to [FDA] regarding the physical, chemical, and toxicological properties of single or multiple chemicals listed on the cosmetic labels,” including function and uses, tests of cosmetics, and exposure and fate information;

• Require FDA to issue regulations not later than two years after the date of enactment of the Safe Cosmetics Act of 2010 that includes lists of ingredients  identified by the Agency as “prohibited ingredients,” “restricted ingredients,” or  “safe without limits” for use in cosmetics.  FDA must also develop a “priority assessment list of not less than 300 ingredients” that cannot be included on the above-referenced lists “because of a lack of authoritative information on the safety of the ingredient.”  FDA must make safety determinations for these ingredients.  

• Prohibit companies from manufacturing, importing, distributing, or marketing a cosmetic or cosmetic ingredient if the company failed to provide information to FDA as required under the bill or if the company’s products contain non-permitted ingredients;

• Require responsible parties to notify FDA if a marketed cosmetic “is adulterated or misbranded in a manner that presents a reasonable probability that the use or exposure to the cosmetic (or an ingredient or component used in any such cosmetic) will cause a threat of serious adverse health consequences or death to humans.”  FDA may request a voluntary recall of the affected products, issue an order for the company to cease distribution, and, under certain circumstances, require a recall or issue an emergency recall order;

• Give FDA the authority to require that cosmetics containing “nano-scale” materials be labeled as such;

• Mandate the reporting of adverse health effects associated with the use of a cosmetic; and

• Require FDA to publish a list of “alternative testing methods” that do not involve the use of animals to test a chemical substance and that must be used in product testing where practicable.  (As we recently reported (here and here), FDA was sued by a coalition of animal rights advocates for not substantively responding to a November 2007 citizen petition requesting that Agency require drug and device companies to submit data only from non-animal test methods whenever available.  FDA subsequently denied the citizen petiton and explained that there are currently no suitable non-animal alternatives to the testing necessary for FDA to conclude that a drug or device is safe for human use.)  

The introduction of H.R. 5786 comes just days after The Personal Care Products Council (“PCPC”) (formerly CTFA) announced that the organization had sent a letter to key health policy leaders in Congress outlining “a number of new science-based regulatory changes that we believe should be adopted in legislation that would further strengthen the effective FDA regulation of our products – including FDA reviews of cosmetic ingredients.”  The PCPC proposal includes enhanced FDA registration, a new process to set safety levels for trace constituents, a new FDA ingredient review process, new FDA oversight of Cosmetic Ingredient Review findings, and FDA-issued Good Manufacturing Practices.  Several of these proposal are included in H.R. 5786 in one form or another.

By Susan J. Matthees –

FDA recently announced that the Agency is seeking public comments on how to implement section 4205 of the Patient Protection and Affordable Care Act of 2010 (“PPACA”), which requires certain restaurants and vending machines to disclose nutrition information.  The docket opened on July 7 and will remain open for comment for 60 days. 

Under PPACA § 4205, chain restaurants and retail food establishments with 20 or more locations doing business under the same name and offering for sale substantially the same menu (“chain restaurants”) as well as  vending machine owners or operators with 20 or more vending machines must display certain nutrition information.  The law does not limit the location count to the United States, so it is not clear whether restaurants and vending machines outside the US count towards the 20 limit. Chain restaurants with drive-through menus must display calorie information next to each standard menu item.  All chain restaurants also must include on  menus  the Secretary of the Department of Health and Human Services’ (“the Secretary”) statement on suggested daily caloric intake, provide  written  nutrition information to customers upon request, state on menus that written nutrition information is available, and, for self-service foods (e.g., buffets), include  calorie disclosures next to each food.  The Secretary must pass regulations that establish how nutrition content will be disclosed for standard menu items that are offered in a variety of flavors or combinations (e.g., pizza, ice cream). 

Vending machines must bear calorie disclosures for each item offered for sale unless the Nutrition Facts panel for a food is available for the customer to view before purchasing food. 

FDA seeks input on a number of matters related to implementing the law, including:

• The types, sizes and nature of activities of chain restaurants, and size of chain vending machine operators;
• Current practices with respect to the use of menus and menu boards, including the disclosure of nutrition information on menus and menu boards;
• The disclosure of calorie content  in self-service areas and for vending machine foods;
• The calorie disclosure statement to be established by the Secretary  for addition to  chain restaurant menus;
• Methods on how to achieve nutrition disclosure for menu items offered in a variety of flavors and combinations;
• Categories that should be exempt from the disclosure requirements;
• Estimated number of chain restaurants and vending machine operators that might be affected by the law and those that might voluntarily comply;
• How to determine calorie content of foods offered by chain restaurants; and
• How to display the Nutrition Facts panels on vending machines.

The comment period closes on September 5.

By Kurt R. Karst –   

Last week, the U.S. Court of Appeals for the Federal Circuit denied Lupin Pharmaceuticals, Inc.’s (“Lupin’s”) Petition for Rehearing en banc of a May 10, 2010 panel decision in Ortho-McNeil Pharmaceutical, Inc. v. Lupin Pharmaceuticals, Inc. in which the Court affirmed a May 2009 decision from the U.S. District Court for the District of New Jersey that the Patent Term Extension (“PTE”)  granted by the U.S. Patent and Trademark Office (“PTO”) with respect to U.S. Patent No. 5,053,407 (“the ‘407 patent”) covering Ortho McNeil’s (“Ortho’s”) LEVAQUIN (levofloxacin) is valid.  The Court’s May 2010 panel decision, which was issued on the same day as the Federal Circuit’s decision landmark PTE decision in Photocure ASA v. Kappos, and the Court’s July 2010 denial of Lupin’s rehearing petition leave  standing an interesting dichotomy with respect to the treatment of single enantiomers in previously approved racemates insofar as the availability of PTEs and New Chemical Entity (“NCE”) exclusivity are concerned.

Levofloxacin is an enantiomer in the previously approved Ortho racemate drug product FLOXIN (ofloxacin).  Lupin initially challenged the ‘407 patent PTE in the context of ANDA Paragraph IV Certification patent infringement litigation on the grounds that the PTE is invalid because FDA previously approved the active ingredient levofloxacin when the Agency approved the racemate ofloxacin.  (See our previous post here.)

Under the PTE statute at 35 U.S.C. § 156(a)(5)(A), the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred.”  The term “product” is defined at 35 U.S.C. 156(f)(2) to mean, in relevant part, “the active ingredient of – a new drug, antibiotic drug, or human biological product . . . including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient” (emphasis added).  (The term “active ingredient” is defined in FDA’s regulations to mean “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure of any function of the body of man or of animals.”) 

For several years, the PTO had interpreted  the term “product” in 35 U.S.C. § 156(a)(5)(A) to mean “active moiety” (i.e., the molecule in a drug product responsible for pharmacological action, regardless of whether the active moiety is formulated as a salt, ester, or other non-covalent derivative) rather than “active ingredient” (i.e., the active ingredient physically found in the drug product, which would include any salt, ester, or other non-covalent derivative of the active ingredient physically found in the drug product).  In contrast, the Federal Circuit’s 1990 decision in Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392, 13 USPQ2d 1628 (Fed. Cir. 1990) (“Glaxo II”), construed the term “product” in 35 U.S.C. § 156(a)(5)(A) to mean “active ingredient.”  The Federal Circuit’s May 2010 decision in Photocure and Ortho-McNeil, both of which concerned the proper interpretation of 35 U.S.C. § 156(a)(5)(A), ruled that the Glaxo II decision and its “active ingredient” interpretation of the PTE statute should be applied for PTE purposes. 

In contrast, FDA has for decades, treated single enantiomers of previously approved racemates as previously approved drugs not eligible for 5-year NCE exclusivity (but eligible for three-year new clinical investigation exclusivity).  For example, FDA stated in the preamble to its 1989 proposed regulations implementing the Hatch-Waxman Amendments that “FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis.  FDA notes that a single enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity.”  FDA still adheres to this policy today, although the FDA Amendments Act of 2007 amended the FDC Act to add § 505(u), which permits the sponsor of an NDA for an enantiomer (that is contained in a previously approved racemic mixture) containing full reports of clinical investigations conducted or sponsored by the applicant to “elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug,” and thus be eligible for NCE exclusivity.

The dichotomy between the treatment of enantiomers in previously approved racemates with respect to PTE and NCE exclusivity eligibility was at the heart of Lupin’s Petition for Reconsideration.  Lupin argued that: 

The FDA and PTO abused their discretion when they applied two conflicting interpretations to the same words – “active ingredient” – in the same legislation – the “Hatch-Waxman Act.”  Thus, the district court and the panel erred in failing to consider the important legal issue: what the term “active ingredient” means and how it should be applied to enantiomers.  The Court should grant this petition for rehearing en banc to adopt and apply a consistent definition of “active ingredient” and to reverse the district court’s determination that the [PTE] was properly based on the approval of LEVAQUIN®, which contained the previously approved enantiomer, levofloxacin, as its active ingredient.

Lupin also relied on the Federal Circuit’s 2004 decision in Arnold Partnership v. Dudas to build its case.  In that case, which concerned the availability of a PTE for a combination drug, the Court ruled that “the [PTE] statute places a drug product with two active ingredients, A and B, in the same category as a drug product with a single ingredient . . . .  To extend the term of a patent claiming a composition comprising A and B, either A or B must not have been previously marketed.”  In reaching its decision in Arnold Partnership, the Court relied on FDA’s regulations to construe the term “active ingredient” as used in the PTE statute.  Applying the concept that “[w]hen the same term appears in multiple locations in the same Congressional Act, it is generally considered to have the same meaning each time,” Lupin argued (unsuccessfully) that “the term ‘active ingredient’ should be construed to have the same meaning when it appears in the [PTE] provisions of the Hatch-Waxman Act . . . and in the new product exclusivity provisions of the Hatch-Waxman Act,” such that the PTO should have considered levofloxacin to have been previously approved in ofloxacin and not granted a PTE with respect to the ‘407 patent covering LEVAQUIN.

By Kurt R. Karst –   

As the U.S. Senate Committee on Appropriations begins its markup and consideration of appropriations bills for Fiscal Year (“FY”) 2011, and in particular the Agriculture, Rural Development, FDA, and Related Agencies Appropriations bill (S. 3606), rare and neglected disease (i.e., orphan disease) advocates appear to be poised to make big gains (once again!). 

The FY 2011 Senate bill includes a $2 million increase (for a total of  $16,035,000) for FDA’s Orphan Product Development Grant program.  The FY 2010 funding for the program was about $14 million, of which approximately $10 million funded noncompeting continuation awards, and approximately $4 million of which funded 10 to 12 new awards.  The FY 2011 increase is the first since FY 2005.

The FY 2011 Senate bill also includes funding of $1 million for the new Office of the Associate Director for Rare Diseases in the Office of New Drugs in FDA’s Center for Drug Evaluation and Research (“CDER”).  FDA announced the position of Associate Director for Rare Diseases in February 2010.  This orphan drug czar “will serve as CDER’s focal point to the rare disease drug development community and assist stakeholders and developers of drug and biologic products in navigating the complex regulatory requirements for bringing safe and effective treatments to patients in need.”  The $1 million funding will be used to hire additional staff with specific expertise in facilitating the development and review of products to treat rare and neglected diseases. 

Finally, we understand that the manager’s package that will hopefully be adopted by the Appropriations Committee will include the provisions below, which are intended to build on § 740 of the Agriculture, Rural Development, FDA, and Related Agencies Appropriations Act of 2010 (Pub. L. No. 111-80) co-sponsored by Senators Sam Brownback (R-KS) and Sherrod Brown (D-OH).  As we previously reported, the Brownback/Brown amendment requires FDA to convene a committee of expert Agency employees to consider the ways FDA reviews products to treat people with rare and neglected diseases, and consider policy improvements that might help people with rare diseases get better treatments faster.

The proposed language in the manager’s package (tentatively identified as § 741 in Senate Report 111-221 accompanying S. 3606) states:

Sec. __. (a) When implementing the authority provided in paragraphs (2) and (3) of section 740(c) of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act, 2010 (Public Law 111-80) that requires the Commissioner of Food and Drugs to develop updated guidance documents and review standards for the development of safe and effective products to treat rare diseases and neglected tropical diseases, the Commissioner shall —

(1) maximize the use of accelerated approval where feasible and appropriate;

(2) work with sponsors to facilitate expanded access to investigational therapies;

(3) increase coordination and interaction with the World Health Organization, European Medicines Agency, and other international regulatory agencies;

(4) implement mechanisms for enhanced collaboration between the Food and Drug Administration and National Regulatory Authorities in developing countries;

(5) develop guidance on clinical development programs for rare diseases;

(6) develop guidance on the use of surrogate endpoints that are reasonably likely to predict clinical benefit of drugs and biological products under the regulations under subpart H of part 314 of title 21, Code of Federal Regulations and subpart E of part 601 of title 21, Code of Federal Regulations; and

(7) increase coordination among individual drug, biological product, and device review divisions across Food and Drug Administration centers to support the development of safe and effective medical products for rare and neglected diseases.

(b) The Commissioner of Food and Drugs shall submit a report to the Committee on Appropriations of the Senate and the Committee on Appropriations of the House of Representatives not later than 180 days after the report required in section 740(c)(1) of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act, 2010 (Public Law 111–80) is submitted: Provided, That the report submitted in response to this section shall describe in detail how the Food and Drug Administration is implementing subsection (a).

The latest legislative push to address rare and neglected disease issues has been spearheaded by the National Organization for Rare Disorders (“NORD”) and Dr. Emil Kakkis’s Kakkis EveryLife Foundation.  NORD has issued a press relase on the FY 2011 appropriations bill.  The NORD Board of Directors is chaired by Hyman, Phelps & McNamara, P.C. Director Frank J. Sasinowski.

There have been several events leading up to the appropriations bill language.  On June 23, 2010, the Senate Appropriations Committee held a hearing to discuss FDA’s review process for products to treat rare and neglected diseases.  That hearing was followed up by a two-day FDA public hearing on the same topic (see our previous post here).  In addition, Representatives Joseph Crowley (D-NY) and Fred Upton (R-MI) recently announced the establishment of the Rare and Neglected Diseases Caucus.