By Susan J. Matthees –  

USDA and HHS have announced the availability of the final Report of the Dietary Guidelines Advisory Committee (“DGAC”).  The agencies are required by law to jointly update and publish the Dietary Guidelines for Americans at least every 5 years, and the final Report, along with public comments to the Report, will be used by the agencies to draft the 2010 Dietary Guidelines for Americans. 

A major focus of the Report is America’s “growing” problem with weight management and the great paradox of the American diet- we are eating more than enough food, yet are not getting adequate amounts of key nutrients, such as vitamin D, calcium, and dietary fiber.  The Report recommends that the Dietary Guidelines make reducing obesity a priority, explaining that the “DGAC considers the obesity epidemic to be the single greatest threat to public health in this century.”   

The Report reiterates what many nutrition experts and health advocates, including Mrs. Obama, have been suggesting: Americans should shift their diets to more plant-based foods, such as legumes, seeds, nuts, whole grains, vegetables and fruit,  reduce intake of foods that contain added sugar and solid fat, and increase their physical activity.  The 2010 DGAC opted to discontinue the term  “discretionary calorie allowance” to explain how much extra fat and sugar should be in the American diet.  The 2005 DGAC used this term, but the 2010 DGAC found that although it is still a scientifically valid concept, it is difficult to communicate to consumers.  Instead, the 2010 DGAC recommends using numerical limits, including a recommendation that added sugar be limited to 25% of total calorie consumption. 

Weight management was not the sole focus of the Report.  The Report also recommended a reduction in sodium intake to 1,500 mg per day or less, which is a decrease from the 2005 DGAC recommendation to limit sodium intake to less than 2,300 mg.  The Report acknowledged that this could be difficult and thus recommends a gradual reduction in intake with a nod towards the Institute of Medicine’s ("IOM’s") recent roadmap to reduce sodium intake. 

The Report also reviewed the consumption of alcohol, water, potassium, protein, and carbohydrates.  The Report concluded that there was no evidence that high protein, low carbohydrate diets are better for weight loss and weight maintenance than other diets.  Although there has been increased attention to the fact that many Americans are deficient in vitamin D, the DGAC opted not to conduct its own review because the IOM is currently reviewing the DRI for vitamin D.  Finally, although the Report notes that most Americans are deficient in some nutrients, it states that daily supplementation with a multivitamin/multimineral “does not offer health benefits to healthy Americans.”  
 
Interested parties are encouraged to submit written comments until July 15, 2010.  Written comments can viewed on the same website.  There will also be a public meeting on July 8, 2010, to solicit oral comments. 

By William T. Koustas –

Regenerative Sciences, Inc. (“Regenerative”) filed a complaint in the U.S. District Court for the District of Columbia against FDA on June 22nd in order to prevent FDA from essentially closing the business.  Regenerative owns a procedure by which physicians take bone marrow and blood samples from a patient, culture the stem cells, and place them back in the patient’s damaged joint in order to repair it (“Regenexx Procedure”).  Regenerative Sciences, Inc. v. FDA, United States District Court for the District of Columbia, June 22, 2010 (“Complaint”).  The Regenexx Procedure is exclusively licensed for use at the clinic where the inventors of the procedure practice.  Complaint at 2.  However, FDA appears to consider Regenerative a drug manufacturer and the stem cells it cultures in its Regenexx Procedure to be biological drugs, and thus claiming that Regenerative is manufacturing an unapproved drug.  Complaint at 8. 

FDA conduced an inspection of Regenerative’s facility in February and March of 2009, which culminated in FDA issuing a Form 483.  Complaint at 8.  Then, FDA returned to inspect Regenerative again earlier this month and again issued another Form 483.  According to the complaint, an FDA investigator threatened that FDA would issue a warning letter, cease and desist letter, civil penalties and seek an injunction if Regenerative did not correct the deficiencies found during the inspection.  Complaint at 7.  Regenerative claims that correcting the deficiencies found in the inspection would bankrupt it.  Complaint at 3. 

Regenerative argues that the Regenexx Procedure is the practice of medicine and is beyond the scope of FDA’s regulatory authority as provided in the U.S. Food, Drug & Cosmetic Act as well as the Public Health Service Act.  Complaint at 12.  Regenerative contends that the manipulation of stem cells occurs in the normal course of a medical practice which is regulated by Colorado.  Further, Regenerative stresses that the Regenexx Procedure occurs completely within the state of Colorado and is therefore not subject to FDA’s authority because it does not engage in the interstate sale of drugs.  Complaint at 14.  Regenerative also asserts a due process argument in that FDA’s actions violate the Due Process Clause of the Fifth Amendment as it will force Regenerative to go out of business.  Complaint at 17.  The complaint requests that the Court enjoin FDA from regulating the Regenexx Procedure, issuing a cease and desist letter and from ex-parte action by FDA to prevent the use of the Regenexx Procedure.  (A related case filed in the U.S. District Court for the District of Colorado was dismissed earlier this year and has been appealed to the U.S. Court of Appeals for the Tenth Circuit.)

By Carrie S. Martin –

The Office of Inspector General (“OIG”) recently issued a report detailing the inclusion of foreign clinical trial data in New Drug Applications (“NDAs”) and Biologics License Applications (“BLAs”) and FDA’s oversight of foreign clinical trial sites.  The OIG examined all NDAs and BLAs, and related documents, submitted in Fiscal Year (“FY”) 2008 with two questions in mind: (1) how much foreign data did sponsors submit in their marketing applications; and (2) to what extent did FDA monitor and inspect these foreign clinical trials.  The answers: (1) a lot; and (2) not enough.

OIG found that 80% of approved NDAs and BLAs in FY 2008 contained data from foreign clinical trials.  Although most subjects and sites were located in Western Europe, Central and South America accounted for the highest average number of subjects per site.  Usually, only one clinical investigator oversees a clinical trial site.  OIG also determined that FDA inspected only 0.7% of foreign clinical trial sites in FY 2008.  (That being said, FDA inspected only 1.9% of U.S. sites.)  Finally, the report noted that data limitations inhibited FDA’s ability to inspect foreign sites, including, for example, the failure of sponsors to submit complete information on site locations and subject enrollment.  Some of these data omissions may be understandable:  federal law does not require an Investigational New Drug (“IND”) application for clinical trials conducted exclusively outside the U.S.  INDs serve as FDA’s primary method of collecting information on clinical trials.

OIG acknowledged the perceived benefits of foreign trials – lower clinical trial costs, larger populations from which to collect patients, and the desire to obtain foreign marketing approvals.  The downside, according to critics, is the lack of patient protection due to inadequate monitoring and the ability to “generalize” foreign data to the U.S. population.

Based on its research, OIG made three recommendations to FDA: (1) require standardized electronic clinical trial data and create an internal database from which FDA can select sites for inspection; (2) monitor trends in foreign clinical trials not conducted under INDs and take steps as necessary to encourage sponsors to file INDs; and (3) explore additional ways to expand the Agency’s oversight of foreign clinical trials, including agreements with foreign regulatory bodies and inspections of clinical trial sites in countries not previously inspected. 

FDA generally agreed with OIG’s recommendations and is seeking to address each recommendation.  For FDA’s full response, see Appendix E of the report.  OIG predicts that the reliance on foreign data will grow in coming years; this will undoubtedly increase the pressure on FDA to adopt new ways to ensure patient protection and the integrity of foreign data.

By Kurt R. Karst –   

Earlier this week, FDA announced Pfizer’s voluntarily withdrawal (at least insofar as a voluntary withdrawal is truly voluntary when FDA requests it) of MYLOTARG (gemtuzumab ozogamicin for Injection) from the market after a required postmarketing study failed to demonstrate clinical benefit.  FDA approved MYLOTARG in May 2000 under the Agency’s Subpart H (“accelerated approval”) regulations as a single agent for patients with CD33 positive Acute Myeloid Leukemia (“AML”) in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.  Pfizer announced that the company will withdraw the MYLOTARG NDA effective October 15, 2010. 

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

FDA approved MYLOTARG based on the surrogate endpoint of response rate observed in 142 patients with AML across three clinical trials and required the applicant to conduct a postmarketing study designed to determine whether adding MYLOTARG to standard chemotherapy demonstrated an improvement in overall survival time (i.e., clinical benefit) of AML patients.  The required postmarketing study was initiated in 2004, but was stopped early when no clinical benefit was observed.  In addition, according to FDA, the study was also stopped “after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone.” 

The MYLOTARG withdrawal appears to be the first instance in which a product granted accelerated approval has been withdrawn from the market – either because a postmarketing study failed to verify clinical benefit or because of a sponsor’s failure to complete a required postmarketing study with due diligence.  Although FDA could have pursued withdrawing approval of IRESSA (gefitinib) when the sponsor’s postmarketing study failed to verify clinical benefit, FDA instead approved new labeling that limits IRESSA use to patients with cancer who are currently benefiting, or have previously benefited, from IRESSA treatment. 
 

By Kurt R. Karst –   

Earlier today, the U.S. Supreme Court declined to hear appeals in two separate cases of interest to the food and drug law bar involving the False Claims Act (“FCA”) – Hopper v. Solvay Pharms, Inc., 588 F.3d 1318 (11th Cir. 2009) and United States, ex rel. Mark Eugene Duxbury v. Ortho Biotech Products, L.P., 579 F.3d 13 (1st Cir. 2009).  The decision lets stand two circuit court rulings.

In Solvay, the U.S. Court of Appeals for the Eleventh Circuit ruled that a FCA action should be dismissed when, as in this case, the Relators are unable to present any evidence that the defendant company actually caused false claims to be submitted based on an alleged off-label marketing campaign.  As we previously noted (here and here), Solvay is an important ruling in the context of FCA litigation generally, but more specifically with regard to off-label use cases.  The Eleventh Circuit’s ruling is the first decision by a United States Court of Appeals concerning off-label use in which the court ruled that a complaint was deficient where there were no claims identified by the Relator.  Many off-label FCA actions have been initiated by company sales representatives who claim first-hand knowledge about an alleged off-label sales program, but do not have first-hand knowledge about the reimbursement practices of the company (usually because  those functions are handled by others in the company).

As we previously reported (here and here), the underlying case in Duxbury asserted qui tam claims under the FCA against Ortho Biotech that were based on certain of the company’s product promotion activities, alleging promotion of off-label use, marketing the “spread” and providing “kickbacks” to providers in the form, among others, of free product samples.  The District Court dismissed all of the claims, citing multiple grounds.  On appeal, the U.S. Court of Appeals for the First Circuit reversed in part, reviving only those claims attributable to Duxbury based on kickbacks.

The United States recommended in an amicus brief that the Supreme Court decline to hear the case, in part, on the basis that a recent amendment to the FCA’s definition of the term “original source” made one question posed in the Petition for a Writ of Certiorari “not of sufficient continuing importance to warrant this Court’s review.”

By Jamie K. Wolszon –

FDA is signaling that it is considering whether to fundamentally reshape how it regulates laboratories and laboratory-developed tests ("LDTs").  LDTs, which are diagnostic tests developed and performed by a laboratory, are widely used.  For example, virtually every genetic test is an LDT.  When new diseases emerge, the initial diagnostic tests are often LDTs. 

Starting in 1992, FDA asserted that it had authority over LDTs as devices.  FDA’s position is that all LDTs are devices subject to regulation under the Federal Food, Drug, and Cosmetic Act.  The legality of FDA’s position has been disputed, but not yet been the subject of a court challenge.

FDA has adopted a policy of “enforcement discretion” over laboratories and LDTs.  However, FDA now is considering jettisoning that enforcement-discretion approach and instead adopting a new, more forceful approach to regulation for LDTs.  FDA is seeking comment on a new-risk based premarket approach at a July 19-20 public meeting.

The meeting notice is one in a series of recent signs of a more activist approach to regulating LDTs.  Less than a week before the meeting announcement, on June 10, FDA sent letters to five companies stating that their genetic diagnostic tests were unapproved, a move seen as heralding increased interest in asserting regulatory power over LDTs. 

In addition, FDA commissioner Margaret A. Hamburg and National Institutes of Health Director Francis S. Collins recently authored an article in the New England Journal of Medicine that also suggested FDA interest in a more active role in LDT oversight.  The letters, article, and meeting appear to represent a coordinated effort to extend FDA regulation over LDTs.

The July 19-20 meeting notice, published in the Federal Register on June 17, 2010, stated that for years the agency has generally exercised enforcement discretion and not enforced the regulations it claims were applicable to devices.  The notice added that the agency generally has not actively regulated LDTs. 

There have been exceptions to the hands-off approach.  Over the years, FDA has occasionally challenged a test offered by a laboratory, e.g., asserting that the test was not a true LDT.  FDA also proposed regulating as devices a single, narrowly-defined subset of LDTs, In Vitro Diagnostic Multivariate Index Assays ("IVDMIAs"), which are tests where the results of multiple markers are combined to generate an “index score.”  As previously reported, it proposed premarket review requirements for those tests in a September 7, 2006, draft guidance, and a revised draft guidance issued July 26, 2007.  It has not proposed premarket review for other subsets of LDTs.

The IVDMIA approach was widely criticized.  One of the major criticisms was that it was not risk-based.  FDA has never finalized those IVDMIA draft guidances.  According to published reports, the agency will not issue the IVDMIA guidance, but instead will focus on the more comprehensive review of LDTs.
In its meeting notice, FDA states, “[T]he agency believes it is time to reconsider its policy of enforcement discretion over LDTs.”  Expanding on its goals, FDA added, “[a]t this time, FDA believes that a risk-based application of oversight to LDTs is the appropriate approach to achieve the desired public health goals….”  After the conclusion of the public meeting and the public comment period, “FDA will move forward expeditiously to develop a draft oversight framework for public comment to provide predictability as quickly as possible.  The FDA also intends to phase in such a framework over time based on the level of risk to the test.”

Discussing the factors that brought it to the conclusion that it should abandon its years-long policy of enforcement discretion, FDA said that in the past LDTs were simple, well-characterized and understood tests for rare diseases.  Now, according to the agency, LDTs often use unregulated components, assess high-risk but common diseases, and sometimes are marketed directly to consumers.  Whether FDA’s view of LDTs is correct, will certainly be the subject of comments at the meeting.

The agenda for the meeting includes sessions on patient and clinical considerations, clinical laboratory challenges, direct-to-consumer testing, and education and outreach.  The agency has posed the following questions for the patient and clinical considerations session:

• What would patients and clinicians like to see done by the FDA with respect to LDTs?  What is ideal?  What is practical?
• How might increased FDA oversight of LDTs affect patients and clinicians?  What might be the benefits?
• What are patient expectations with regard to results obtained by an LDT?  How might increased oversight of LDTs affect these expectations?
• What is the patient’s perspective regarding tests that are non-regulated versus regulated by the FDA?
• Are physicians aware that a given diagnostic test may not have been cleared or approved by FDA?  How might this knowledge affect clinical practice?
• What are the reasons that a patient or physician might choose an LDT over an FDA cleared/approved IVD?
• What are patient’s and clinician’s expectations regarding clinical validation of LDTs?
• Examples or case studies related to LDTs.

FDA has proposed the following questions as part of the clinical laboratory challenges session:

• What are the potential benefits of increased FDA oversight of LDTs?
• What would you like to see done with respect to FDA oversight of LDTs?  What is ideal?  What is practical?
• Suggested approaches of risk stratification of LDTs
• What might be some of the specific challenges faced by clinical laboratories in meeting FDA regulations?
• How might increased oversight of LDTs affect diagnostic test innovation?
• How could increased oversight of LDTs affect diagnostics used for rare conditions?
• How might increased oversight of LDTs affect reimbursement and/or the cost of diagnostic tests for the consumer?
• What are the challenges associated with validation of LDTs for clinical laboratories?
• What will the challenges be to clinical labs with respect to diagnostic test change control under greater oversight of LDTs?
• Should the clinical and analytical validation requirements be different between FDA regulated and non-FDA regulated diagnostic tests?   

The agency has proposed the following questions for the DTC session:

• What are the major concerns associated with DTC testing?
• What is the benefit of DTC testing?  What are the risks?  What is the cost?
• Are there concerns that DTC testing could lead to consumer fraud?
• Are patients taking medical action based upon preliminary diagnostic test claims?  What are the risks and benefits? 

FDA suggests the following topics for the education and outreach session:

• What resources or educational opportunities are currently available to assist clinical laboratories in meeting FDA regulations?  What would be needed?
• What specific support will be needed by clinical laboratories from the FDA given greater LDT oversight?
• How can physicians use new genetic information? 
• Whose responsibility is it to ensure that physicians can use the information provided to them by LDTs?

Given the increasingly important role in LDTs in health care in general, and in personalized medicine in particular, the meeting is almost guaranteed to provide FDA with diverse – and strongly expressed – viewpoints.

By Wes Siegner –   

On June 14, 2010, The University of Maryland School of Law hosted the first of a series of multidisciplinary meetings being held as part of a Human Microbiome Project ELSI (Ethical, Legal, Social Implications) grant to study federal regulation of probiotics.  The team that received the grant included:

• Diane E. Hoffmann, MS, JD, Associate Dean for Academic Programs and Director, Law and Health Care Program, University of Maryland School of Law (Principal Investigator)
• Claire M. Fraser-Liggett, Ph.D, Professor of Medicine and Director, Institute for Genome Sciences,  University of Maryland School of Medicine
• Frank Palumbo, Ph.D, JD, Professor and Executive Director, University of Maryland School of Pharmacy Center on Drugs and Public Policy
• Jacques Ravel, Ph.D, Associate Professor, Institute for Genome Sciences, University of Maryland School of Medicine

Participants in the conference included members of academia and the scientific research, business, legal and federal regulatory communities.  The National Institutes of Health and the Federal Trade Commission are participating in the study, and representatives from the Food and Drug Administration attended as observers.  The agenda for the first meeting, including speakers for the first day, can be found here.

The first all-day meeting focused on achieving a broad-based understanding of the science relating to probiotics and the current federal regulatory framework into which products containing probiotics fall.  As planned, this meeting was a question-generating session.  Subsequent sessions will focus more on attempting to find consensus answers to the complex regulatory questions that surround products containing probiotics.  The next meeting is being planned for January 2011.

By Kurt R. Karst –   

With all of the FDA-related amendments being introduced for consideration to the Tax Extenders Act (H.R. 4213), including the Preserve Access to Affordable Generics Act to address patent settlement agreements and an amendment to legislatively extend a patent covering The Medicines Company’s ANGIOMAX (bivalirudin), it was a fait accompli that Sen. Bill Nelson (D-FL) would reintroduce his Drug Price Competition Act by proposing it as an amendment to the bill.  That happened on June 15th, with the submission of SA4361.

SA4361, which is viewed by some as a complement to the Preserve Access to Affordable Generics Act, appears to be identical to Sen. Nelson’s S. 1315, which was introduced last June.  Rep. Alcee Hastings (D-FL) introduced a companion bill (H.R. 3777) in the House of Representatives.  Rep. Hastings also initially proposed his bill as an amendment to the House Health Care Reform Bill last November, but then withdrew it from consideration.  In January 2010, before the election of Scott Brown (R-MA) to the Senate, the American Antitrust Institute, among several other organizations, penned a letter to Senate Majority Leader Harry Reid (D-NV) and House Speaker Nancy Pelosi (D-CA) encouraging inclusion of the Drug Price Competition Act in the final Health Care Bill, along with a per se ban on patent settlement agreement payments. 

As we previously reported (here and here), Sen. Nelson’s legislation would amend the definition of “first applicant” at FDC Act § 505(j)(5)(B)(iv)(II)(bb) with respect to 180-day exclusivity eligibility so that certain subsequent ANDA applicants could trigger and also be eligible for such exclusivity.  Specifically, under SA4361, a subsequent applicant subject to a first applicant’s 180-day exclusivity eligibility could qualify as a “first applicant,” and could obtain approval and trigger 180-day exclusivity for all first applicants if there is no timely filed patent infringement lawsuit arising from its Paragraph IV certification, or if there is a timely filed lawsuit and there is a court decision (including a district court decision) of patent invalidity or non-infringement or a “substantive determination that there is no cause of action for patent infringement or invalidity.”  Curiously, SA4361 also provides that any subsequent ANDA applicant that submits a “section viii” statement to an Orange Book-listed patent would be considered a “first applicant” eligible for 180-day exclusivity.

SA4361 and its predecessors appear to be rooted in a paper Apotex issued early last year.  In that paper, Apotex recommends that Congress work for legislation “that gives shared (if not sole) exclusivity to a generic challenger who, although not first to file a paragraph iv certification, is first to succeed in addressing the listed patents.”

By Kurt R. Karst –   

Since shortly after the enactment of the Hatch-Waxman Amendments in 1984, FDA has recognized an NDA sponsor’s ability to relinquish or selectively waive exclusivity, such as 5-year new chemical entity exclusivity and 3-year new use exclusivity, even though  the statute does not specifically permit relinquishment or waiver.  However, as FDA stated in a 2004 citizen petition response, it was not until 1997 that the Agency first considered an ANDA sponsor’s ability to relinquish or waive 180-day generic drug exclusivity.  In that 1997 case, which concerned a request from Genpharm to waive its pre-Medicare Modernization Act (“MMA”) 180-day exclusivity for Ranitidine HCl in favor of Granutec, FDA determined that a waiver was permissible.  That decision was challenged in court, see Boehringer Ingelheim Corp. v. Shalala, 993 F. Supp. 1 (D.D.C. 1997), and the D.C. District Court upheld FDA’s interpretation of the statute as permissible.  FDA subsequently proposed regulations (in 1999) to codify its interpretation, but those proposed regulations were withdrawn in 2002.  

FDA’s 2004 citizen petition response provides a comprehensive discussion of waiver and relinquishment of 180-day exclusivity.  Under FDA policy: 

an ANDA applicant who has obtained 180-day exclusivity may relinquish its exclusivity entirely or selectively waive the exclusivity in favor of a single ANDA, or multiple ANDAs, containing a paragraph IV certification.  Before the exclusivity period has been triggered, an applicant may only relinquish its exclusivity; after the exclusivity has been triggered, it may be selectively waived.

FDA stated in its petition response that “allowing eligible applicants to relinquish or waive [180-day] exclusivity enables them to exercise the exclusivity as they deem most beneficial,” and that there are four general reasons supporting waiver and relinquishment of 180-day exclusivity.  Specifically, that the practice of permitting relinquishment and waiver of 180-day exclusivity:

(1)  is based on a permissible statutory construction as acknowledged by the courts,
(2)  is consistent with the Agency’s long-standing allowance of waiver and relinquishment of other forms of market exclusivity,
(3)  promotes marketplace competition among pharmaceuticals in furtherance of the objectives of the [Hatch-Waxman Amendments], and
(4)  is consistent with FDA’s role in regulating the public health as opposed to competitive business arrangements.  

Importantly, FDA notes in its 2004 petition response that the Agency’s interpretation is limited to 180-day exclusivity subject to the pre-MMA (i.e., pre-December 8, 2003) statute:

[T]his response does not provide[] an Agency interpretation of section 505(j)(5)(B)(iv) as amended by the [MMA]. . . .  [T]he MMA made a number of changes to the statutory scheme in section 505(j) governing 180-day exclusivity, including providing tor forfeiture of the exclusivity. . . . The Agency has not yet assessed whether the changes made by the MMA should result in a different approach to waiver or relinquishment for those applications subject to the new exclusivity provisions.

Given the first applicant approach under the post-MMA statute, under which multiple first applicants can qualify for and share 180-day exclusivity (or forfeit such exclusivity), relinquishment and waiver of 180-day exclusivity is more complicated.

We are unaware of a post-MMA case in which a first applicant has relinquished 180-day exclusivity eligibility; however, FDA’s 2009 Letter Decision concerning generic versions of STARLIX (nateglinide) Tablets could provide some insight as to how FDA might ultimately address this issue in the context of multiple first applicants.  (Where there is only a single first applicant, relinquishment does not appear to complicate a 180-day exclusivity analysis.)  In the generic STARLIX case (see our previous post here), there were multiple first applicants and at least one first applicant forfeited 180-day exclusivity eligibility under FDC Act § 505(j)(5)(D)(i)(IV) (failure to obtain tentative approval in 30 months of ANDA submission).  FDA ruled that “a first applicant that forfeits exclusivity may obtain [ANDA] approval . . . and that first commercial marketing by any first applicant (including a first applicant that forfeits exclusivity) will begin the 180-day exclusivity period.”  Insofar as forfeiture is considered to be effectively the same as relinquishment, a first applicant that relinquishes its 180-day exclusivity could arguably continue to be a first applicant and not be blocked by another first applicant’s 180-day exclusivity eligibility, and also trigger other first applicants’ 180-day exclusivity. 

A selective waiver of 180-day exclusivity post-MMA (both where there is only a single first applicant and especially where there are multiple first applicants) is more complicated than relinquishment, as it confers on a subsequent applicant the most important benefit of first applicant status – 180-day exclusivity. 

We are aware of only one instance post-MMA in which FDA has permitted a selective waiver of 180-day exclusivity.  That case involved Bupropion HCl Extended-Release Tablets, 300 mg, and a single first applicant – Anchen Pharmaceuticals, Inc.  FDA approved Anchen’s ANDA No. 77-284 on December 14, 2006 and noted in the approval letter that as a first applicant the company is eligible for 180-day exclusivity.  Just a few days later, on December 15, 2006, however, FDA approved ANDA No. 77-415 for Bupropion HCl Extended-Release Tablets, 300 mg.  FDA noted in the approval letter for ANDA 77-415 that the applicant was not a first applicant but that there was a “relinquishment or selective waiver” of 180-day exclusivity by Anchen.  Although the ANDA approval letter is not clear on its face whether there was a relinquishment or waiver of 180-day exclusivity, the notation of exclusivity in the Orange Book for both applications makes clear that there was, in fact, a selective waiver and not a relinquishment.  (The Orange Book showed a period of shared 180-day exclusivity for both ANDAs.)

There is not, to our knowledge, a post-MMA case in which FDA has permitted a selective waiver of 180-day exclusivity where there are multiple first applicants.  Given the fact that FDA has permitted a waiver where there is a single first applicant, however, it seems likely that FDA, when faced with the issue, will permit a waiver when there are multiple first applicants.  But there will certainly be some ground rules. 

Being a first applicant means that you are the member of an exclusive club.  So to allow a non-member to share in the benefits of club membership, it seems possible that FDA would require all first applicants (whether 1 or 10) to agree in writing that a subsequent applicant should be accorded the benefits of club membership.  Also, it seems likely that because a subsequent applicant does not become a first applicant by virtue of all club members agreeing to a selective waiver, a first applicant will first have to trigger the 180-day exclusivity period before a waiver is made and a subsequent applicant can take advantage of the 180-day exclusivity period.    

The issue of selective waiver post-MMA is certain to crop up at some point in time, and we will be interested to see the outcome. 

By Ricardo Carvajal –

June 22 looms large on the calendar for firms subject to the requirements of the Family Smoking Prevention and Tobacco Control Act (“FSPTCA”) and FDA’s final rule curbing promotion and sale of cigarettes and smokeless tobacco to underage consumers.  In anticipation of that date, FDA has issued the following guidance documents:

• Compliance with Regulations Restricting the Sale and Distribution of Cigarettes and Smokeless Tobacco To Protect Children and Adolescents – This draft guidance document addresses questions raised by retailers with respect to their obligation under FDA’s final rule to ensure that cigarettes and smokeless tobacco are not sold to underage consumers.  It also addresses questions with respect to the obligation of retailers, distributors, and manufacturers to ensure compliance with advertising, marketing, and promotion restrictions imposed by that rule.  According to the document, FDA intends to exercise enforcement discretion with respect to certain requirements that are the subject of litigation (e.g., the limitation of labeling and advertising to black text on a white background and the restriction on the use of trade names of nontobacco products).  Violation of the final rule’s many other requirements could subject a retailer, distributor, or manufacturer to a range of civil and criminal penalties.  The final rule takes effect on June 22.

• Use of “Light,” “Mild,” “Low,” or Similar Descriptors in the Label, Labeling, or Advertising of Tobacco Products – This guidance document addresses the statutory ban on the use of the cited descriptors in labeling and advertising unless FDA authorizes such use.  Products labeled or advertised as such may not be sold after July 22 unless they were manufactured before June 22 and introduced into domestic commerce before July 22.

• Enforcement Policy Concerning Rotational Warning Plans for Smokeless Tobacco Products – This guidance document states FDA’s intent to exercise enforcement discretion with respect to the requirement that smokeless tobacco manufacturers, distributors, importers, and retailers have a rotational warning plan that has been approved by FDA, as long as they submit such a plan to the agency by July 22.  However, industry must begin rotating the warnings on June 22.

In addition, FDA has published “Harmful and Potentially Harmful Constituents” in Tobacco Products as Used in Section 904(e) of the Federal Food, Drug, and Cosmetic Act.  This draft guidance document provides FDA’s interpretation of the phrase “harmful and potentially harmful constituents.”  The FSPTCA requires that FDA publish a list of such constituents within two years of the law’s enactment.  That list will partially guide subsequent submissions by manufacturers of information on constituents in their products.  In that same vein, FDA will announce in the June 15 Federal Register that the Tobacco Product Constituents Subcommittee of the Tobacco Products Scientific Advisory Committee will meet on July 7-8 to "finalize its proposed list of harmful or potentially harmful constituents, the rational for inclusion of each substance, validated methods for measuring the constituents and the ancillary and normalization standards for the identified constituents."

By Kurt R. Karst –   

On the same day that the Senate Judiciary Committee held a hearing on “Oversight of the Enforcement of the Antitrust Laws,” at which Federal Trade Commission (“FTC”) Chairman Jon Leibowitz and U.S. Department of Justice (“DOJ”) Assistant Attorney General for the Antitrust Division Christine Varney testified (here and here) on, among other things, patent settlement agreements (what opponents call “pay-for-delay” agreements), Senators Herb Kohl (D-WI), Charles Grassley (R-IA), and Susan Collins (R-ME) proposed an amendment – SA 4332 – during the Senate’s consideration of the Tax Extenders Act (H.R. 4213) that could significantly curtail patent settlement agreements.  As we previously reported, H.R. 4213 is also being eyed as a vehicle for legislatively granting a patent term extension for U.S. Patent No. 5,196,404 covering The Medicines Company’s ANGIOMAX (bivalirudin).

SA 4332 appears to be identical to Sen. Kohl’s “Preserve Access to Affordable Generics Act” amendment, which was considered, but ultimately rejected, during debate of the Senate Health Care Reform Bill late last year.  That amendment was almost identical to the substitute amendment to S. 369, which was passed out of the Senate Judiciary Committee last year – see our previous post here. 

Like its predecessors, SA 4332 would amend the FTC Act to permit the FTC to “initiate a proceeding to enforce the provisions of [new Sec. 28] against the parties to any agreement resolving or settling, on a final or interim basis, a patent infringement claim, in connection with the sale of a drug product.”  Such agreements, if challenged, would be presumptively anticompetitive and unlawful unless it can be demonstrated “by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.”  In addition, “[e]ach person, partnership or corporation that violates or assists in the violation of [new Sec. 28] shall forfeit and pay to the United States a civil penalty of not more than 3 times the gross revenue of the NDA holder from sales of the drug product that is the subject of the patent infringement claim for the period of the violation, starting with the date of the agreement.”  A summary of SA 4332 is available here. 

Senators Orrin Hatch (R-UT), Jon Kyl (R-AZ), John Cornyn (R-TX), and Tom Coburn (R-OK) previously criticized the legal presumption rule in S. 369.  A report on S. 369 issued earlier this year states that:

the bill would amount to a de facto per se ban on covered settlements—and would entail all of the evils attendant to a per se ban . . . . For a legal-presumption rule to work, however, the parties must be afforded a forum in which they can quickly and fairly test whether they have overcome the presumption and whether the agreement is valid.  Unfortunately, under the reported bill, settlements would be made presumptively unlawful, but the bill does not create a process for quickly resolving whether the agreement is unlawful.  The issue would not be resolved until the FTC brings an action to challenge the settlement, which could be years after the settlement was entered into.  Moreover, the current bill requires the brand and generic companies to rebut the presumption that the agreement is unlawful by clear and convincing evidence.  This is a heavy burden that is not appropriate for commercial litigation and that tilts the scales in a lawsuit sharply in the government’s favor. . . . By effectively preventing the parties from settling, it is likely that this bill will discourage generic drug companies from bringing challenges to brand companies’ patents in the first place—and as a result, the bill will ultimately reduce competition and raise prices for drugs that are currently subject to invalid or low-quality patents.

The introduction of SA 4332 comes on the heels of an April 2010 decision by a 3-judge panel of the U.S. Court of Appeals for the Second Circuit in In re: Ciprofloxacin Hydrochloride Antitrust Litigation.  As we previously reported, in that case, the Court affirmed a 2005 decision by the U.S. District Court for the Eastern District of New York to grant summary judgment for defendants (i.e., manufacturers of CIPRO (ciprofloxacin HCl) or generic versions of CIPRO) in an antitrust challenge to certain patent settlement agreements, but also invited further review of the case by the full Court, noting that “because of the ‘exceptional importance’ of the antitrust implications of reverse exclusionary payment settlements of patent infringement suits,” plaintiffs-appellants should petition for rehearing en banc.  Since issuing the decision, the Court has been petitioned for a rehearing en banc.  Several interested parties have filed amicus briefs in the case urging a rehearing by the full Court, including the FTC, DOJ, American Antitrust Institute, AARP/American Medical Association/The Public Patent Foundation, Inc., 34 State Attorneys General, AFSCME, and various consumer groups. 

The FTC is also appealing to the U.S. Court of Appeals for the Eleventh Circuit an April 2010 judgment related to a February 2010 order from the U.S. District Court for the Northern District of Georgia (Atlanta Division).  As we previously reported, in that case the district court largely dismissed multidistrict litigation brought by the FTC, direct purchasers, and indirect purchasers challenging certain agreements in which Solvay Pharmaceuticals, Inc. allegedly paid generic drug companies to delay generic competition to Solvay’s drug product ANDROGEL (testosterone gel). 

By Jeffrey N. Wasserstein –

Loyal readers of the FDA Law Blog have followed (with bated breath) the saga of Vermont’s law that prohibits pharmaceutical and medical device companies from giving many items that are permitted under the PhRMA Code and AdvaMed Code.  The plot has thickened even further with the recent passage of S. 88, which became law on May 27, 2010, albeit without the governor’s signature (he objected to some of the very provisions we’ll be discussing below). 

Most notably, the bill amends the existing law to provide that samples that may be given to patients include not only prescription items, but also over-the-counter drugs, nonprescription medical devices, or items of nonprescription durable medical equipment.  Nota bene:  “Sample” was also defined to include “starter packs and coupons or other vouchers that enable an individual to receive a prescribed product free of charge or at a discounted price.”  While permissible, the kicker here is that beginning on or before April Fools’ Day 2012, companies must disclose all samples that have been disseminated in Vermont during the prior calendar year, identifying for each sample the product, recipient, number of units, and dosage.  While pharmaceutical companies already track samples for purposes of compliance with the PDMA sample tracking requirements, the Vermont requirement also applies to coupons and vouchers for free or discounted prescription products, OTC products and nonprescription devices and DME which are not currently tracked.

The Vermont law does not apply by its terms to any samples required to be reported under the Patient Protection and Affordable Care Act of 2010 (a/k/a Healthcare Reform), which we summarized here, as long as the Vermont Attorney General determines that the U.S. Department of Health and Human Services ("HHS") will collect and report state- and recipient-specific information regarding samples.  How this will play out, remains to be seen. 

On the bright side, we have seen at various booths throughout the country at professional meetings and conferences signs that say “Dogs and Vermont Physicians Need Not Apply for Coffee”.  (Ok, we exaggerate slightly, but see below.) 

The new law clarifies that the provision of coffee or other snacks or refreshments at a booth at a conference or seminar is permitted, and does not even need to be reported!  Barristas from Bennington to Newport rejoice!

Other notable changes include permitting companies to provide grants for fellowship salary support, provided the manufacturer is completely hands-off, including that the institution requesting the grant selects the fellows, the manufacturer imposes no demands or limits on the use of the funds, and (demonstrating that Vermont doesn’t quite understand why companies might want to fund such fellowships), the fellowship cannot be named for the sponsoring manufacturer.  The law also clarifies that companies may sponsor continuing medical education programs and the sponsor may, in its discretion, use such funding to provide for meals and other food at the conference.  There was some  confusion prior to this law as to the permissibility of funding for CME where the CME provider used the funding for meals.  Clarity achieved!  Fund away!

We kid because we care.  As we noted in one of our prior posts on Vermont, states are free to experiment.  At some point, the experimentation goes too far.  As noted by the Governor of Vermont in his statement explaining why he was refusing to sign the bill and was allowing it to become law without his signature, “physicians, non-profits and other organizations across Vermont have expressed significant concern about the chilling effect certain provisions could have on the ability of low-income Vermonters to receive free samples of vital prescription drugs.”  At some point, companies will weigh the cost of doing business in Vermont and decide that it isn’t worth it.  Or, they will do business and decide it’s not worth providing coupons, vouchers or samples to physicians in Vermont, thereby avoiding the hassle of reporting to the Vermont Attorney General.  That cannot be good for Vermont patients, as noted by Governor Jim Douglas.  But at least we know companies can give Vermont MDs a cup of joe at the next professional meeting.

By Kurt R. Karst –   

FDA's recent approval of an ANDA submitted by Perrigo R&D Company ("Perrigo") for a generic version of the over-the-counter drug MONISTAT 1 Combination Pack (1200 mg miconazole nitrate vaginal insert and 2% miconazole nitrate cream) contains some interesting language concerning 180-day exclusivity eligibility.  It it the latest type of post-Medicare Modernization Act ("MMA") 180-day exclusivity "punt" language adopted by FDA. 
 
As we previously reported, FDA has, on several occasions punted on the issue of post-MMA 180-day exclusivity eligibility.  Those punts have come up in the context of 180-day exclusivity forfeiture under FDC Act § 505(j)(5)(D)(i)(IV), where a company failed to obtain tentative ANDA approval within 30-months of application submission.  In each of those cases, FDA did not make a formal forfeiture determination at the time of ANDA approval and stated it would do so only if another applicant becomes eligible for approval within 180 days after exclusivity is triggered.
 
The latest punt comes under the failure-to-market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I), which provide that 180-day exclusivity is forfeited based on the "later of" two dates: (1) the earlier of 75 days after ANDA approval or 30 months after ANDA submission; and (2) 75 days after which "[t]he patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the" NDA holder (FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC)), among two other litigation-related events (FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA) & (BB)).  In March 2010, the U.S. Court of Appeals for the District of Columbia Circuit ruled in Teva Pharms USA, Inc. v. Sebelius, 595 F.3d 1303 (D.C. Cir. 2010), that Teva did no forfeit 180-day exclusivity eligibility under the failure-to-market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I), and FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC) in particular.  In doing so, the Court reasoned that the patent delisting counterclaim provision at FDC Act § 505(j)(5)(C)(ii)(I) added by the MMA must be read together with the patent delisting forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC), and that FDA's broad reading of FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC), in which the Agency interpreted the provision such that the mere request to withdraw patent information from the Orange Book is a forfeiture event under FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC), was not sustainable.  FDA has been reluctant to adopt a narrow interpretation of FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC), but has done so nevertheless. 
 
MONISTAT 1 Combination Pack is listed in the Orange Book with two patents – U.S. Patent Nos. 5,514,698 ("the '698 patent) and 6,153,635 ("the '635 patent").  Both patents are identified with a "Delist Requested" flag, which first appeared in the May 2009 Orange Book Cumulative Supplement.  According to FDA's Paragraph IV Certification List, FDA received Perrigo's ANDA containing a Paragraph IV certification to the '698 and '635 patents on December 5, 2007.  This set up a potential 180-day exclusivity forfeiture under FDC Act § 505(j)(5)(D)(i)(I) for late last week, as the "later of" date was 30 months after ANDA submission.  FDA timely approved Perrigo's ANDA, however, and stated in the approval letter that:

With respect to 180-day generic drug exclusivity for Miconazole Nitrate Vaginal Insert (1200 mg) and Miconazole Nitrate Cream (2%), Perrigo was the first ANDA applicant to submit a substantially complete ANDA for Miconazole Nitrate Vaginal Insert (1200 mg) and Miconazole Nitrate Cream (2%), with a paragraph IV certification to the patents listed above.  Therefore, with this approval, Perrigo may be eligible for 180 days of generic drug exclusivity for Miconazole Nitrate Vaginal Insert (1200 mg) and Miconazole Nitrate Cream (2%). . . .   The agency notes that a delisting request has been submitted for the '698 and '635 patents.  The agency is not making a formal determination at this time of Perrigo's eligibility for 180-day generic drug exclusivity.  It will do so only if another applicant becomes eligible for approval within 180 days after Perrigo begins commercial marketing of Miconazole Nitrate Vaginal Insert (1200 mg) and Miconazole Nitrate Cream (2%). [(emphasis added)]

Now, someone could read the emphasized language above and conclude that FDA has not fully embraced the Teva decision.  After all, there has not, to our knowledge, been a counterclaim brought under FDC Act § 505(j)(5)(C)(ii)(I) that would call Perrigo's 180-day exclusivity into question.  So why even include the "punt" language in the approval letter at all?  We think that FDA included the language in the letter to cover all of the bases.  That is, as a placeholder just in case a counterclaim is brought by another applicant under FDC Act § 505(j)(5)(C)(ii)(I). 

By Diane B. McColl & Ricardo Carvajal –

It’s here!  FDA’s Center for Veterinary Medicine (“CVM”) finally implemented a "generally recognized as safe" (“GRAS”) notification program for use of ingredients in animal feed or pet food.  We have waited for this program since 1997, when it was first proposed along with FDA's Center for Food Safety and Applied Nutrition's (“CFSAN's”) GRAS notification program for human food ingredients.  CVM's efforts to establish the program were announced more than a year ago.  In the ensuing months, producers of potential new ingredients met with CVM, trying to understand how the program might work.  Now we have a basic framework.  CVM's GRAS notification program food parallels CFSAN's GRAS notification program, which has operated successfully for more than 10 years.  As CFSAN did in the early days of its program, CVM “strongly encourages” potential notifiers to discuss their plans with the Division of Animal Feeds prior to submission.

Based on CVM’s Federal Register notice and the instructions provided on its website, it appears that CVM intends to administer its program so that it is both substantively and procedurally consistent with CFSAN’s program -  with a couple of notable exceptions.  First, if the ingredient will be fed to food-producing animals, safety of the ingredient must be shown   both for target animals consuming the ingredient and for humans consuming food derived from those animals.  Thus, for both the target animal and the human populations, a GRAS notifier must establish that the proposed use of a food ingredient is not just safe, but also generally recognized as such.  Second, CVM describes its program as a “pilot” program, and notes that resources are limited in the animal food program.  Consequently, CVM does not commit to a specific time frame for responding to notifications.  While CFSAN originally set a target of 90 days for its GRAS notifications, that target has crept up to 180 days.

As with CFSAN’s program, notifiers under CVM’s program should expect their GRAS determination claims to become publicly available on the date that the GRAS notice is received.  Pivotal safety data and information (i.e., those data without which the GRAS determination cannot stand) should already be in the public domain.  Other data and information in the GRAS notice will immediately be made available to the public, subject to exemptions in FDA’s regulations implementing the Freedom of Information Act (21 C.F.R. Part 20).

By Ricardo Carvajal –

Kellogg Company has agreed to FTC’s expansion of the settlement order that the company entered into in July 2009 regarding false claims that Frosted Mini-Wheats improve children’s attention (see our prior post here).  At issue now are “dubious health claims” that Rice Krispies supports children’s immunity.

Under the modified order, Kellogg is prohibited from making any representation in connection with the marketing of any food regarding

A. the benefits, performance, or efficacy of such product for cognitive
function, cognitive processes, or cognitive health; or

B. any other health benefit of such product

unless the representation is not misleading and is adequately substantiated.  The modified order now describes FTC’s substantiation standard in detail.  Kellogg must have:

competent and reliable scientific evidence that is sufficient in quality and quantity based on standards generally accepted in the relevant scientific fields, when considered in light of the entire body of relevant and reliable scientific evidence, to substantiate that the representation is true. . .. [C]ompetent and reliable scientific evidence means tests, analyses, research, or studies that have been conducted and evaluated in an objective manner by qualified persons and are generally accepted in the profession to yield accurate and reliable results.

As we noted in a prior posting, FTC staff have repeatedly expressed concern over the use of immunity claims in promotion for foods.  However, the claim used by Kellogg (“now helps support your child’s immunity”) strikes us as relatively timid – notwithstanding the Commission’s characterization of it as a claim to “boost” immunity.  Although FTC’s action might be partially attributable to the fact that Kellogg embarked on its immunity campaign shortly after negotiating the original settlement, it appears that the Commission is prepared to challenge any questionable immunity claim – even those that don’t explicitly reference an ability to boost immunity.