By Alan M. Kirschenbaum –

On January 5, 2010, FDA released a “Guidance for Industry on New Contrast Indication Considerations for Device and Approved Drug and Biological Products.”  The primary purpose of the Guidance is to establish a process that allows imaging device manufacturers to obtain approval of new indications for use of a device with an already marketed contrast or radiopharmaceutical imaging drug (a “new contrast indication”), where the drug is not labeled for that indication.  FDA’s publication of the Guidance fulfills one of the Agency’s performance commitments under the Medical Device User Fee Amendments of 2007.  A draft version of this guidance was issued in September 2008, and FDA held a stakeholder meeting on the draft guidance in August 2009. 

Under the Guidance, if a new imaging device modification involves the use of an approved imaging drug in a manner consistent with the latter’s approved labeling, a submission from the device sponsor alone will be sufficient in most cases, without need for a change in the drug labeling.  Conversely, if a new imaging device modification requires a use of the approved imaging drug that is not consistent with the drug’s approved labeling, submissions will be required from both the drug and device sponsors to ensure consistent labeling – a situation that precludes a device manufacturer from implementing a modification unilaterally.  The final guidance provides a number of examples illustrating when a device submission alone would, or would not, be sufficient to support a new contrast indication for the device.  It appears from the examples that FDA will be restrictive in permitting new contrast indications for imaging devices without corresponding changes in the drug labeling.  Moreover, the Guidance requires device manufacturers who seek a new contrast indication modification to submit clinical study support similar to what would be required in an NDA supplement.  In light of these barriers, the Guidance is most likely to facilitate new device modifications for use with contrast only where the drug is used consistent with the indications, dosage, and rate and route of administration in the already approved drug labeling and where the new use does not raise new questions of safety and efficacy.

By David B. Clissold –

Acting on cross motions for summary judgment, a Federal District Court in Kentucky has struck down some provisions of the Family Smoking Prevention and Tobacco Control Act (“Tobacco Act”) as unconstitutional, and upheld others.  As we had reported earlier, the plaintiffs originally argued that portions of the Act violated their free speech rights under the First Amendment; their due process rights under the Fifth Amendment; and effected an unconstitutional “taking” of property under the Fifth Amendment.  For reasons that are not clear, the plaintiffs apparently abandoned most of their Fifth Amendment claims during the course of the proceedings.  Thus, the decision primarily concerned free speech.

Unconstitutional As A Violation Of Free Speech Under The First Amendment

The Tobacco Act provides that labeling or advertising for cigarettes or smokeless tobacco must use only black text on a white background.  The court held this portion of the law unconstitutional since “images of packages of their products, simple brand symbols, and some uses of color communicate important commercial information about their products” such as who makes the product.  In addition, the Tobacco Act's “blanket ban” on all uses of color and images was too broad since it also precluded use of “innocuous images and colors – e.g., images that teach adult consumers how to use novel tobacco products, images that merely identify products and producers, and colors that communicate information about the nature of a product . . .”

The Tobacco Act prohibits any statement in labeling or through the media suggesting that the product was approved by FDA, that FDA deems the product to be safe, or that FDA endorsed the use of the product.  The court held that these prohibitions were reasonable.  However, the law also banned statements suggesting that “the product is safe or less harmful” because it was regulated or inspected by FDA or that it was in compliance with FDA regulations.  This was held to be unconstitutional since it banned “journalists, doctors, scientists, politicians, and numerous other groups and individuals” from making statements about the effect of the FDA regulation of tobacco products.

Too Early To Tell Whether Constitutional Under The First Amendment

The Tobacco Act bans all “outdoor advertising for cigarettes or smokeless tobacco, including billboards, posters, or placards, . . . within 1,000 feet of the perimeter of any public playground or playground area in a public park . . ., elementary school, or secondary school.”  However FDA must issue a regulation “in light of governing First Amendment case law,” explaining how this ban will be enforced before it can take effect.  The court held it could not examine this issue until FDA had issued the final regulation.

Constitutional Under The First Amendment

The Tobacco Act requires tobacco companies to print new government warnings for cigarette packages that occupy the top 50% of the front and rear panels of packaging and include “color graphics depicting the negative health consequences of smoking to accompany the label statements.” Similar warnings, occupying 30% of each of the two principal display panels, are required for smokeless tobacco products.  For all categories of tobacco products, the new warnings must occupy 20% of any advertisements.  The court held that such requirements were reasonable in part because Congress “relied on the international consensus reflected in the World Health Organization’s Framework Convention on Tobacco Control” and also reviewed “the use of a nearly identical warning requirement in Canada.”  The court also noted that even with the warnings, a substantial amount of area remained for use by the manufacturers.  However, the court ruled that the plaintiffs’ takings claim under the 5th Amendment needed to be brought in the Court of Federal Claims, and so the court lacked jurisdiction to decide that issue.

Manufacturers can not promote their brands through sponsorship of “athletic, musical, artistic, or other social or cultural event[s]” and FDA must reissue regulations that prohibit the sponsorship of athletic, social, and cultural events “in the brand name” of a tobacco product.  The court found because such events “glamorized” smoking and that many children were exposed to the events, the limitations on sponsorship were permitted.  The law also directs FDA to reissue regulations that prevent a tobacco manufacturer from distributing items such as caps and t-shirts that bear the name or logo of a tobacco brand.  The court agreed that it was impossible to limit the distribution of these items to adults only and noted that even if it was, the wearers would become “walking advertisements” conveying the notion “that tobacco use is widely accepted.”  Accordingly, the court held that the ban on such items was constitutional. With respect to the law's ban on free samples, gifts with purchase, and marketing tobacco products with non-tobacco products, the court held that these provisions restricted distribution, but did not implicate free speech rights.

The Tobacco Act’s Modified Risk Tobacco Products (“MRTP”) provision prohibits the labeling, or advertising of a tobacco product from suggesting that the product is less harmful than other tobacco products, and prohibits manufacturers from taking any action that would be reasonably expected to result in consumers believing that the tobacco product or its smoke may be less harmful than other tobacco products, without prior FDA approval of the product as “modified risk.” The plaintiffs had already lost a motion for a preliminary injunction in November 2009 that this law violated free speech.  None of the arguments presented subsequently were enough to change the court’s mind.

Conclusion

Both sides can claim at least partial victory under this decision, and it is not yet clear whether any of the parties will appeal any portion of the ruling.  In upholding many of the challenged provisions of the Tobacco Act, the court relied on Congressional findings and reports from the Institute of Medicine, World Health Organization, National Cancer Institute, and other organizations that focused on the effect that tobacco advertising may have on underage smoking.  The court agreed that preventing children from smoking was a “substantial” government interest, and found that most of the Tobacco Act’s provisions controlling the advertising and promotion of cigarettes and smokeless tobacco were directly related to promoting that interest.  Aside from any appeal in this case, the next significant challenge is likely to be whether FDA’s regulation to control outdoor advertising passes constitutional muster.

By Kurt R. Karst –      

Following FDA’s decision, reflected in the October 2009 Orange Book Cumulative Supplement (page A-28), to grant 5-year New Chemical Entity Exclusivity (“NCE”) for EMEND (fosaprepitant dimeglumine) Injection, the Agency has issued an exclusivity determination explaining its decision.  Fosaprepitant is a phosphamide derivative (a type of covalent derivative) and a pro-drug of the previously-approved active ingredient in EMEND (aprepitant) Capsules (NDA No. 21-549).

Under the FDC Act, FDA grants 5-year exclusivity for NCEs.  An NCE is a drug that contains no “active moiety” that has been approved by FDA in another NDA.  An “active moiety” is defined in FDA’s regulations at 21 C.F.R. § 314.108(a) to mean “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.”  In addition, FDA stated in the preamble to the Agency’s 1989 proposed regulations implementing the Hatch-Waxman Amendments that “[a] compound (other than an ester) that requires metabolic conversion to produce an already approved active moiety is considered a ‘new molecular entity,’ . . . and will be considered a new chemical entity entitled to 5 years of exclusivity. 

Thus, for purposes of determining whether a particular drug product is eligible for 5-year NCE exclusivity, FDA’s Exclusivity Summary completed for each NDA approval asks the following about the chemical structure of a drug:

Has FDA previously approved under section 505 of the Act any drug product containing the same active moiety as the drug under consideration?  Answer “yes” if the active moiety (including other esterified forms, salts, complexes, chelates or clathrates) has been previously approved, but this particular form of the active moiety, e.g., this particular ester or salt (including salts with hydrogen or coordination bonding) or other non-covalent derivative (such as a complex, chelate, or clathrate) has not been approved.  Answer “no” if the compound requires metabolic conversion (other than deesterification of an esterified form of the drug) to produce an already approved active moiety.

According to FDA’s exclusivity determination memorandum, which was added to the Summary Basis of Approval for EMEND (NDA No. 22-023):

Emend for Injection under FDA’s interpretation of 21 CFR § 314.108 should have been classified at the time of approval as an NCE. . . .  Fosaprepitant dimeglumine is a pro-drug phosphoramide derivative of aprepitant.  A phosphoramide is a compound in which one or more of the OR groups of phosphoric acid have been replaced with covalent bonds to an amino or substituted amino group.  Fosaprepitant dimeglumine is neither an ester, salt (including a salt with hydrogen or coordination bonds), nor other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule aprepitant.  It is a covalent phosphoramide derivative.  As a non-ester covalent derivative of aprepitant, under 21 CFR § 314.108, fosaprepitant dimeglumine is a new chemical entity entitled to 5 years of exclusivity.

Fosaprepitant is not the first instance in which FDA has reversed an exclusivity decision.  In October 2004, FDA informed the sponsor of VITRASE (hyaluronidase) Injection that contrary to the Agency’s earlier decision to grant 3-year exclusivity for the product, “[a]fter reviewing information and data regarding hyaluronidase drug products . . . the Agency has decided that 5-year exclusivity is appropriate because we have inadequate information to determine whether any active moiety in Vitrase is the same as any previously approved active moiety.”

By Kurt R. Karst –      

A recent Impact Report (subscription required) from the Tufts Center for the Study of Drug Development (“CSDD”), titled “Drug approvals for neglected diseases increase along with more R&D funding,” concludes that new products to treat neglected diseases (such as malaria, kinetoplastids, diarrheal diseases, roundworm, bacterial pneumonia and meningitis, and typhoid and paratyphoid fever) have received marketing approval from regulatory agencies at a steadily increasing rate in the past several years as research and development  funding for neglected diseases has dramatically increased.  The report is based on research conducted by CSDD Senior Research Fellow Joshua P Cohen.  

Among other things, CSDD found that:

• The annual rate of new product approvals for neglected diseases increased from an average of 1.8 in 1975-1999 to 2.6 in 2000-2009;

• Between 1999 and 2008, annual funding for neglected diseases rose from less than $100 million annually to more than $2.5 billion today, and today government research and development funding accounts for 69% of all neglected disease product development funding, with non-profit organizations and the drug industry contributing 21% and 10%, respectively;

• Vaccines have displaced drugs as the primary products being developed for neglected diseases, and products to treat HIV/AIDS and malaria accounted for 81% of negelected disease approvals from 2000-2009;

• Public-private partnerships for new product development accounted for 46% of all approvals to treat neglected diseases in 2000-2009, which is up from 15% in 1975-1999.

A provision included in the Agriculture, Rural Development, FDA, and Related Agencies Appropriations Act of 2010, Pub. L. No. 111-80, could also lead to a greater number of products approved to treat neglected diseases in the coming years.  As we previously reported, § 740 of the law requires FDA to establish within the Agency “a review group which shall recommend to the Commissioner of Food and Drugs appropriate preclinical, trial design, and regulatory paradigms and optimal solutions for the prevention, diagnosis, and treatment of neglected diseases of the developing world.”  FDA is also required to submit a report to Congress on the review group’s findings and recommendations, and to issue guidance and develop internal review standards based on those recommendations.

By Ricardo Carvajal & David B. Clissold –

The most recent issue of the Food and Drug Law Journal contains an article on the Family Smoking Prevention and Tobacco Control Act (“Tobacco Act”) authored by Hyman, Phelps & McNamara’s (“HPM’s”) Ricardo Carvajal, David B. Clissold, and Jeffrey K. Shapiro.  The Tobacco Act provides FDA with regulatory authority over virtually every aspect of the design, production, marketing, and advertising of tobacco products. Although the new law has its detractors, there is little question that the law’s enactment marks a dramatic shift in the relationship between the federal government and the tobacco industry.  This article provides a summary of the new law’s major provisions and highlights some of the legal issues that implementation of the law is likely to raise.  The authors gratefully acknowledge HPM’s Tom Scarlett for his review of a draft of the manuscript.

The most recent issue of the Food and Drug Law Institute's Update magazine contains an article authored by Ricardo Carvajal and David B. Clissold that focuses on the Tobacco Act's impact on retailers.  In the sectors that FDA has historically regulated, FDA has focused the bulk of its resources on ensuring that manufacturers and wholesale distributors are in compliance with the law.  FDA has generally undertaken little enforcement activity against retailers, whose conduct is typically policed by state authorities.  This could change under the Tobacco Act, which aims to restrict the availability and appeal of tobacco products to youth.

Our colleague and friend, Stephen H. McNamara passed away on December 28, 2009 of complications from cancer at the age of 66.  Steve is survived by Caroline, his wife of 43 years, and his children, Matthew (Veronica) McNamara, and Deborah  (Nicholas) Hutchins and six grandchildren. 

Steve was a member of this firm from 1984 until poor health forced his withdrawal from practice in 2003.  He was an eminent figure in the food and drug bar, admired by his clients, fellow practitioners, and opponents.  He provided valuable advice to the Congress in the development of the Dietary Supplement Health and Education Act.  In his professional endeavors he was respected for his attention to detail and for the imaginative solutions he found for knotty issues.  He was universally admired for his civility and respect for others.

Prior to joining HPM, Steve was the Senior Vice President and General Counsel for the Cosmetic, Toiletry and Fragrance Association, Inc. (now the Personal Care Products Council).  Steve was also proud of his service at the U.S. Food and Drug Administration, where he was a staff attorney, senior trial attorney, and ultimately the associate chief counsel for food.  For about a year, he served as the acting chief counsel.  He was twice recognized by the agency with the FDA Award of Merit (FDA’s highest award for service). 

Steve served as a chaplain’s assistant in the U.S. Army from 1967-1969, and was awarded the Bronze Star for meritorious service, the Purple Heart for wounds received in action in Vietnam, and the Army Commendation Medal. 

He was a graduate of the University of Virginia and the University of Virginia School of Law.

Steve was a complete and very good man, worthy of the honors accorded him and deserving of the love felt by those who knew him. We will remember how he loved his family.  We will remember him for his love and militant support of the Irish.  We will remember him as a scholar, focused on the classical world.  And his friends will always remember his love of ice cream. Steve will be greatly missed.

We extend our heartfelt sympathy to his wonderful wife, Caroline, who has supported him through such difficult times, and to his entire family.   A memorial service will be held for Steve in January 2010.

By William T. Koustas –

As FDA becomes more comfortable with the authority provided to it by the Food and Drug Administration Amendments Act of 2007 (“FDAAA”), the frequency of Risk Evaluation and Mitigation Strategies (“REMS”) being applied to an entire class of drugs is increasing.  (See our REMS Tracker.)  The most notable example of this is the class-wide REMS for extended-release opioid drugs, where FDA may impose onerous new requirements on the manufacturers, prescribers, dispensers and consumers of such products.  In light of these developments, a recent article in the December issue of the Regulatory Affairs Professionals Society’s Regulatory Focus publication authored by Hyman, Phelps & McNamara’s William T. Koustas, titled “Trends in FDA’s Use of Class-wide REMS,” explores the current state of class-wide REMS through interesting and relevant examples.  Understanding FDA’s current implementation of class-wide REMS may be the best means of preparing for the future use of REMS.  

By Alan M. Kirschenbaum, Kurt R. Karst & J.P. Ellison –

On Thursday morning, the U.S. Senate passed, by a 60-39 vote, H.R. 3590, the Patient Protection and Affordable Care Act.  Last weekend, Sen. Harry Reid (D-NV) unveiled a 383-page Manager’s Amendment to the bill.  The bill retains the discount, rebate, and industry fee provisions we previously reported on, except that the device industry fee (in § 10904) has been eliminated for 2010, and the aggregate annual fee imposed on covered manufacturers or importers of medical devices sold in the U.S. is set at $2 billion for the years 2011 through 2017 and $3 billion for years after 2017.

The Manager’s Amendment also includes changes (at § 10104(j)) to the False Claims Act (“FCA”).  The FCA amendment appears intended to address recent court decisions interpreting the public disclosure and original source provisions of the FCA.  While the stated purpose of these amendments, according to a section-by-section summary of the bill, is “to ensure that whistleblowers who play a significant role in exposing fraud can be included in otherwise meritorious litigation,”  the provisions seem likely to inject further uncertainty into already complicated questions of when a public disclosure has occurred and when a relator is an original source of publicly disclosed information.

The Manager’s Amendment (at § 10606) also changes the intent requirement for health care fraud under 18 U.S.C. § 1347, such that “a person need not have actual knowledge of this section or specific intent to commit a violation of this section.”  In addition, a potentially significant change for FDA-regulated companies, is the insertion of FDC Act § 301 in the definition of “Federal health care offense” at 18 U.S.C. § 24(a).  This means that an FDA offense could be a predicate for a health care fraud case.

The bill (at § 10609) aslo includes the so-called “Generic Loophole Bill” introduced by Sen. Jeanne Shaheen (D-NH) earlier this year.  As we previously reported, the measure would permit FDA to approve a generic drug notwithstanding certain “last minute [labeling] changes” to the reference listed drug labeling that could otherwise delay ANDA approval.  Absent from the Senate bill are proposed amendments (see our previous post here) concerning authorized generics and “pay-for-delay” settlements.

The bill’s provisions on follow-on biologics do not appear to have changed.  Sen. Sherrod Brown’s (D-OH) amendment (SA 2895) that would cut the proposed 12-year exclusivity period for an innovator product short if the innovator’s product is a blockbuster drug is not included in the bill. 

A side-by-side comparison of the drug and device provisions in the House and Senate healthcare reform bills that we prepared is available here.  The Congressional Budget Office’s December 19, 2009 cost estimate of the bill is available here, and the December 20, 2009 corrected cost estimate is available here.  Additional background information on the bill is available here. 

By Nisha P. Shah –

On December 8, 2009, the Food and Drug Administration ("FDA") issued its final, non-binding guidance for industry on “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.”  A draft guidance was published in February 2006.  The final guidance explains how FDA evaluates patient-reported outcomes ("PRO") instruments used in measuring endpoints in clinical trial studies.  The guidance also sets forth standards of how sponsors can generate and use PRO instruments to improve the probability of supporting claims in the product labeling.

The guidance defines PRO as a measurement “coming directly from the patient about the status of a patient’s health condition” without interpretation of the response by a health care professional or anyone else. PRO endpoints can serve as either primary, secondary, or exploratory endpoints. PRO instruments can be useful tools to evaluate the effect of treatment on one or more “concepts,” or how a person functions or feels about a health condition or its treatment. The instruments can capture significant clinical information that traditional evaluations by health care professionals cannot, such as a patient’s perception of improvement in pain and mobility.

In determining whether to use existing PRO instruments or to develop a new one, sponsors should consider “their labeling goals, a PRO instrument conceptual framework, and the relationship of the PRO endpoints to other clinical trial endpoints in preliminary endpoint models for the planned confirmatory trials.” If existing PRO instruments do not adequately support the sponsor’s goals, the guidance describes procedures for sponsors to generate their own PRO instrument.

Regardless of whether an existing or new instrument is used, the guidance cautions against measuring “general concepts”, such as overall physical health, because the instrument may not distinguish adverse events of treatment that may affect the general concept but were unknown at the time the clinical trial study was designed.  The measurement of more specific concepts, such as improvement in pain, may be more useful in supporting labeling claims.

In developing a new instrument, sponsors should conduct patient interviews, focus groups, and additional assessments to ensure comprehension and completeness of the items contained in the PRO instrument, as well as to demonstrate content validity and reliability. Sponsors are advised to maintain appropriate documentation through the evolution of developing and testing the instrument because the agency will examine the final version of the instrument “in light of its development history,” including “the complete list of items generated and the reasons for deleting or modifying items.” The guidance states that FDA will review this documentation along with clinical trial results to determine whether a labeling claim is substantiated.

The guidance also spells out FDA’s specific concerns when using electronic PRO instruments.  FDA expressed concerns particularly over the principal investigator’s ability to maintain control and to have access to the records that serve as the electronic source documentation for the purpose of an FDA inspection. Additional measures the sponsor should address in the protocol when using an electronic PRO instrument include database security and measures to prevent loss of adverse event data. 

Much like capturing the more traditional clinical endpoints, sponsors should consider measures to optimize the quality of the PRO instrument, minimize inconsistencies in conducting the trial, and develop a statistical analysis plan to analyze the PRO endpoints and handle incomplete data. To interpret the clinical trial results, FDA maintains that “it [is] informative to examine the cumulative distribution function ("CDF") of responses between treatment groups to characterize the treatment effect and examine the possibility that the mean improvement reflects different responses in patient subsets,” rather than focusing on the statistical significance of the PRO measures alone.

The guidance encourages sponsors to solicit feedback early in the process of instrument and protocol development and engage the FDA in a discussion about a new PRO instrument before clinical trial protocols are finalized, and includes a checklist of background information to provide when submitting a PRO instrument to FDA for review.

By William T. Koustas & John R. Fleder –

A new lawsuit challenges the government’s ability to exclude individuals from participating in federal health care programs after a person has been convicted of a Food, Drug and Cosmetic Act (“FDCA”) misdemeanor.  Michael Friedman and Howard R. Udell v. Kathleen Sebelius et al, No. 309CV01741RNC (D. Conn. filed Oct. 28, 2009).

In May 2007, Purdue Frederick Co. Inc. (“Purdue”) pleaded guilty to a FDCA felony count of misbranding drug products (OxyContin) with the intent to defraud or mislead.  As part of a global resolution, Howard R. Udell and Michael Friedman, two former senior executives at Purdue, pleaded guilty to FDCA misdemeanor charges of misbranding.  The government believes that persons can convicted under the FDCA misdemeanor provisions without any showing that a person intended to violate the law or even knew about the violation.  This theory is often referred to as the “responsible corporate officer” principle that executives who do not prevent violations of the FDCA may be held strictly liable for those violations.

Though this appeared to be the end of the federal government’s interest in these individuals, in November 2007, the Office of Inspector General of the Department of Health and Human Services (“OIG”) sent Mr. Udell and Mr. Friedman Notices of Intent to Exclude them from participating in Medicare, Medicaid and all federal health care programs, pursuant to 42 U.S.C. § 1320a-7(b)(3), based on their earlier misdemeanor criminal convictions.  That statute permits exclusion if a person has been convicted of a misdemeanor relating to fraud or for the unlawful manufacture, distribution, prescription or dispensing of a controlled substance.  Mr. Udell and Mr. Friedman contend that these provisions are inapplicable to them because their criminal guilty pleas only relate to their status at Purdue, not to their commission of fraud or to controlled substances violations.

According to the Complaint filed in this case, Mr. Udell and Mr. Friedman made written submissions to the OIG challenging their proposed exclusions.  On March 31, 2008, the OIG rejected these submissions by “excluding” the two individuals.  However, they challenged the exclusion decisions in the United States District Court for the District of Connecticut.  That Court refused to rule on the merits of the case until all administrative remedies had been exhausted.  On August 31, 2009, the Department of Health and Human Services (“HHS”) Departmental Appeals Board affirmed the exclusion decisions.  As a result, the two individuals filed another court action challenging what they contend is a final decision by HHS.

Mr. Udell and Mr. Friedman filed this new complaint in October 2009, arguing that: (1) their misdemeanor convictions are not an excludable offense under 42 U.S.C. §§ 1320a-7(b)(1), 7(b)(3); (2) the debarment was an abuse of discretion and arbitrary and capricious as their convictions were merely based on the fact that they were “responsible corporate officers” and never had intent or actual knowledge of the company’s wrongdoing; and (3) their twelve year exclusionary period violates the law because HHS did not consider certain mitigating factors, and the exclusionary period was not supported by substantial evidence.  The plaintiffs are seeking a declaratory judgment that the exclusion was contrary to law as well as seeking an order to enjoin HHS from excluding  the plaintiffs and further publicizing the exclusion actions.

The government has not filed any substantive response to the Complaint.  However, in a filing dated December 23, 2009, the parties agreed to have the case transferred to the United States District Court for the District of Columbia.

This case certainly demonstrates that, as Yogi Berra once said, “It ain’t over until its over.”  People like Mr. Udell and Mr. Friedman think that once they accept responsibility for a company’s action by taking the harsh step of pleading guilty to a crime, solely because of their corporate positions, their problems with the government are in the past.  Surely the government can and should seek to reach a global resolution when someone pleads guilty so that that person is not surprised by a later government action that could make that person unemployable in the health care field.

By Carmelina G. Allis –

Earlier this month, the United States Court of Appeals for the Second Circuit rendered a summary order affirming the District Court’s judgment for dismissal of the case.  We previously reported that FDA had moved to dismiss HiFi DNA Tech, LLC’s (“HiFi’s”) lawsuit alleging that FDA had improperly denied the company’s petition for reclassification of an HPV nested DNA polymerase chain reaction detection device from Class III to Class II.  The U.S. District Court for the District of Connecticut granted FDA’s motion to dismiss the case. 

HiFi appealed the lower court’s ruling and argued that the District Court had erred by not allowing HiFi to introduce evidence outside the administrative record and by concluding that FDA had not acted arbitrarily and capricious when it denied HiFi’s reclassification petition.  The Court of Appeals held that HiFi waived its argument regarding the introduction of evidence outside of the administrative record because the Plaintiff never requested to do so in the District Court.  In addition, the introduction of such evidence is generally appropriate under certain circumstances, such as when the agency acts on bad faith.  In this case, HiFi appears not to have alleged any facts to support such a finding.

The Court of Appeals also determined that HiFi’s arbitrary and capricious argument also failed.  HiFi alleged that FDA acted arbitrarily and capricious when it reviewed its product as a cancer-detection device instead of a virus-detection device.  The court found, however, that based on the intended use for the device as defined by HiFi in its FDA application, the agency reasonably determined that the device’s intended use was to assess a woman’s risk of developing cancer.  Other arbitrary and capricious arguments raised by HiFi were also dismissed for a lack of merit.

The Court of Appeals affirmed the lower court’s judgment.

By Michelle L. Butler –

The Consumer Product Safety Commission (“CPSC” or “Commission”) has now voted to lift the stay of the testing and certification requirements for certain products and extend the stay for others.  The Commission issued a press release last Friday regarding the decision, along with a revised draft Federal Register notice, reflecting changes resulting from the Commission’s vote.  The press release includes a useful chart detailing the categories of products and whether the stay has been lifted or extended as well as links to statements by the Commissioners regarding their votes.  The main changes to the draft Federal Register notice pertain to the extension of the stay for bicycles and lead content – the revised draft shortens the extension for bicycles and lengthens the extension for lead content by six months from August 10, 2010 to February 10, 2011.  See Draft Notice, at 17.

You will remember a discussion in our previous post regarding an ambiguity surrounding the scope of the stay of certification for products regulated under the Poison Prevention Packaging Act (“PPPA”).  (For your convenience, here is a link to our prior, more detailed post.)  In an informal response from an informed CPSC staff member, we were told that this person did not believe that the Commission intended to draw a distinction between PPPA-regulated “consumer products” and other PPPA-regulated products, such as drugs, devices, cosmetics, and food, but rather intended to lift the stay with respect to certification to PPPA requirements generally.  Consistent with this view, we note that in the revised draft Federal Register notice, the heading that had been titled “Consumer Products Where the Commission is Lifting the Stay of Enforcement and for Which General Conformity Certification Will Become Necessary” is now titled “Products Where the Commission is Lifting the Stay of Enforcement and for Which General Conformity Certification Will Become Necessary” – the word “consumer” has been deleted.

By Riëtte van Laack–

Earlier this month, a citizen petition was submitted to FDA requesting that the Agency issue an order confirming that prescription prenatal vitamins containing 1-4 mg folic acid, either alone or in combination with other vitamins and minerals, and used to reduce the risk of neural tube defects in infants, are Generally Recognized as Safe and Effective (“GRAS/E”) prescription drugs and are not new drugs.

The 51-page Petition describes the (at times confusing) history of folic acid regulation in the United States and the numerous occasions that FDA has recognized that prenatal folic acid-containing vitamin products are safe and effective.  Petitioner also references data that have been published in scientific literature as evidence that there can be no question that qualified experts consider folic acid-containing products as safe and effective.  This evidence combined with the long history of safe and effective use confirms that, prescription prenatal vitamins that include folic acid are GRAS/E. 

It is not clear what caused the Petitioner to submit this Petition at this time.  As Petitioner acknowledges, FDA, on various occasions and in different contexts, has affirmed that folic acid-containing products are safe and effective.  Thus far, FDA has not taken action against the marketing of these products as unapproved prescription drug products and Petitioner does not suggest that FDA intends to change its position regarding the marketing of these products. 

Petitioner’s request presumes that prescription vitamin products containing 1 mg or more folic acid are drug products and does not consider the possibility that they may also be legal prescription dietary supplements and/or medical foods, in which case no action by FDA would be required.  Nonetheless, were FDA to grant the petition, that would likley make it easier to obtain reimbursement for these products.

The lack of a stated reason for action by FDA combined with the absence of safety concerns associated with FDA’s current policy regarding prenatal vitamins are likely to result in FDA considering this Petition a low priority.

By Kurt R. Karst –      

A recent decision from the U.S. District Court for the Northern District of Illinois (Eastern Division) presents an interesting solution to a concern about the forfeiture of 180-day exclusivity when a company submits an ANDA containing both a Paragraph IV Certification to one patent and a Paragraph III Certification to another Orange Book-listed patent that does not expire until well into the future.  Such a scenario creates the risk of a court decision trigger under the “failure-to-market” forfeiture provisions that would occur well before the Paragraph III Certification patent expires.  Some companies have been willing to take that risk, however, by submitting their ANDAs early in the race to qualify for 180-day exclusivity. 

Section 505(j) of the Federal Food, Drug, and Cosmetic Act (“FDC Act”), as amended by the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, provides that 180-day exclusivity eligibility is forfeited for a failure-to-market if there is a “later of” date that is calculated based on two events.  Specifically, the failure-to-market forfeiture event (at FDC Act § 505(j)(5)(D)(i)(I)) provides as follows:

(I)  FAILURE TO MARKET. – The first applicant fails to market the drug by the later of –

(aa)  the earlier of the date that is –

(AA)  75 days after the date on which the approval of the application of the first applicant is made effective under subparagraph (B)(iii); or

(BB)  30 months after the date of submission of the application of the first applicant; or

(bb)  with respect to the first applicant or any other applicant (which other applicant has received tentative approval), the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a certification qualifying the first applicant for the 180-day exclusivity period under subparagraph (B)(iv), at least 1 of the following has occurred:

(AA)  In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB)  In an infringement action or a declaratory judgment action described in subitem (AA), a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

(CC)  The patent information submitted under subsection (b) or (c) is withdrawn by the holder of the application approved under subsection (b).

Where there is a later-expiring patent subject to a Paragraph III Certification, a subitem (aa) event will likely occur well before the patent expires.  And because of the early submission of the ANDA containing a Paragraph IV Certification, one of the court decision triggers under subitem (bb) might also occur well before the patent subject to the Paragraph III Certification expires, thereby creating the two dates necessary to calculate a “later of” event under FDC Act § 505(j)(5)(D)(i)(I).  

The Illinois District Court’s decision stems from a Complaint filed by Abbott Laboratories after Abbott received notice of a Paragraph IV Certification from Matrix Laboratories (“Matrix”) involving KALETRA (lopinavir; ritonavir) Tablets.  KALETRA is listed in the Orange Book with 11 patents, that, with pediatric exclusivity, expire between January 2014 and May 2021.  Matrix’s ANDA No. 91-202, which was submitted to FDA on December 23, 2008, contains Paragraph IV Certifications to U.S. Patent Nos. 7,148,359 and 7,364,752, which expire (with pediatric exclusivity) in January 2020 and May 2021, respectively, and Paragraph III Certifications to the remaining 9 patents, the latest of which expires on December 26, 2016 (with pediatric exclusivity).  (As a side note, FDA tentatively approved another Matrix ANDA containing only Paragraph III Certifications for a generic version of KALETRA under the President’s Emergency Plan for AIDS Relief.)  According to FDA’s Paragraph IV Certification List Matrix is a first applicant eligible for 180-day exclusivity. Abbott timely sued Matrix, thereby triggering a 30-month stay of ANDA approval. 

Matrix, perhaps not expecting a patent infringement lawsuit, promptly filed a Motion to Stay requesting the entry of an order: “(i) staying this action until July 1, 2014, (ii) providing that any party may move to lift the stay at an earlier date upon a showing of good cause, and (iii) during the pendency of the Court’s stay, tolling the balance of the thirty-month period [under FDC Act § 505(j)(5)(B)(iii)] with respect to . . .  ANDA No. 91-202.”

Relying on previous decisions in Novartis v. Dr. Reddy’s Labs, Ltd., 2004 WL 2368007 (S.D.N.Y., Oct. 21, 2004) and Amgen, Inc. v. Hoechst Marion Roussel, Inc., 3 F. Supp.2d 104, 109 (D. Mass. 1998), Matrix argued that:

[A]bsent a stay, Defendants are in a Catch-22 situation in view of the forfeiture provision.  If Defendants litigate now and win, their exclusivity will almost inevitably be forfeited because a final court decision would almost certainly occur more than 75 days prior to December 26, 2016.  In that event, Defendants would have undertaken the expense of a successful challenge to the patent obstacle to generic entry, but would then compete with generic competitors who (especially if Defendants prevail on the basis that patent claims are invalid) would not have borne the competitive burden of the litigation expense.  This is contrary to the Congressional purpose for granting the 180-day period of exclusivity, which is to encourage early challenges to patents by preventing free-riding by later generic applicants.  If Defendants lose, then they would presumably be enjoined under 35 U.S.C. §271(e)(4)(A) and unable to compete with later generic applicants until expiration of the patent(s) they would be found to infringe.  In sum, if Defendants win soon, they lose in the marketplace, and if Defendants lose soon they lose in the marketplace.  The only way to avoid the Catch-22 is to stay the action.

The court, after considering Abbott’s Response and Matrix’s Reply, agreed with Matrix and granted the Motion to Stay, but on the grounds of judicial economy:

Defendants . . . raise an argument about the purposes of Hatch-Waxman. Specifically, they argue that the Act’s purpose of spurring generics through a 180-day exclusivity period could be frustrated without a stay.  The Court’s decision to grant a stay rests on traditional factors such as docket control and the efficient use of the Court’s and the parties’ resources.  Legislation serves many purposes, particularly when as here the legislation was part of a carefully crafted, comprehensive scheme. . . .  The Court is not prepared, on the record and briefing before it, to conclude that one among many purposes furnishes the authority to avoid an implication that arises as a result of the language that Congress chose to enact.  Nor is it self-evident that such an outcome would frustrate Congress’s intent.

Although the court’s decision was based on judicial economy, it could lead to greater concerns at FDA over administrative economy.  Indeed, FDA noted the following in the Agency’s Determination of Granisetron Exclusivity:

[A] comment raises a point that has been a source of some concern to the Agency irrespective of the forfeiture provisions, and that is that the “race” to earn 180-day exclusivity by submitting the first ANDA to challenge a patent may result in the submission of ANDAs that may also contain one or more paragraph III certifications to patents that do not expire until well into the future and that will preclude approval of the application for many years.  We have received ANDAs for which, based on the patent expiration dates and corresponding certifications, the sponsor has no intention to obtain approval and market the generic drug for 12 years or more.  [The commenter] is correct when it notes that this practice may result in agency resources being committed to unnecessary reviews.  There is the very real possibility that events will occur in the years between initial review and patent expiration such that the sponsor ultimately will decide not to obtain approval of and market the generic drug product. . . .  Furthermore, should the sponsor seek final approval after the lapse of many years from initial review and tentative approval, the ANDA would almost certainly have to be reviewed a second time before a final approval could issue.

Notwithstanding this concern, it is possible that implementation of FDA’s Document Archiving, Reporting and Regulatory Tracking System (“DARRTS”) in the Office of Generic Drugs (“OGD”) might alleviate the problem.  As we previously reported, DARRTS implementation in OGD is intended to make more efficient use of the Office’s resources so that those applications that can or should be approved sooner than others will be prioritized over applications that might not be approved for several years; for example, because an ANDA contains a Paragraph III Certification to a patent that will not expire for several years. 

Thanks to Shashank Upadhye for alerting us to the decision.

By Michelle L. Butler –

On December 16, 2009, the Consumer Product Safety Commission (“CPSC” or “Commission”) posted on its website a draft Federal Register notice that would announce the Commission’s decision to revise the terms of its stay of enforcement of certain testing and certification requirements under section 14 of the Consumer Product Safety Act (“CPSA”), as amended by section 102(a) of the Consumer Product Safety Improvement Act of 2008 (“CPSIA”).  The Commission must vote on whether to issue the notice before it is published in the Federal Register.

Of particular relevance for manufacturers of products regulated under the Poison Prevention Packaging Act (“PPPA”), such as drugs and dietary supplements containing iron, the Federal Register notice would lift the stay of the certification requirement for products required to be in special packaging under the PPPA and 16 C.F.R. Part 1700.  See Draft Notice, at 14.  Testing based upon a “reasonable testing program” will be required, and “the manufacturers will need to issue a certificate of general conformity to these statutes or regulations (‘general conformity certificate’) beginning on February 10, 2010 for all products manufactured after that date.”  Id. at 15. 

We note, however, that there is some ambiguity regarding this section of the draft Federal Register notice.  CPSIA required general conformity certificates for PPPA-regulated products through the addition of language that a certificate is required for a product that is “subject to a consumer product safety rule under [the CPSA] or similar rule, ban, standard, or regulation under any other Act enforced by the Commission.”  CPSA § 14(a)(1) (emphasis added).  The PPPA is enforced by the Commission, and the CPSC staff have viewed the PPPA special packaging requirements as subject to the general conformity certificate requirements. 

The ambiguity arises with regard to the definition of a “consumer product.”  By statutory definition, a “consumer product” does not include drugs, devices, cosmetics, or foods.  See CPSA, § 3(a)(5)(H), (I).  However, the discussion in the draft Federal Register notice regarding lifting the stay for the testing and certification requirements for PPPA-regulated products comes under a heading titled “Consumer Products Where the Commission is Lifting the Stay of Enforcement and for Which General Conformity Certification Will Become Necessary.”  Draft Notice, at 14 (emphasis added).  The question here is whether the Commission intends to draw a distinction between PPPA-regulated products that are also consumer products (such as turpentine, see 16 C.F.R. § 1700.14(a)(6)) and PPPA-regulated products that are not consumer products (such as drugs, see, e.g., 16 C.F.R. 1700.14(a)(10)) and lift the stay as to the former but not the latter.  [Note also that the that language in the section of the draft notice describing the action the Commission would take also refers to “consumer products” – “Thus, as of February 11, 2010, except as stated above in part II, manufacturers (including importers) and private labelers of consumer products and children’s products must comply with the testing and certification requirements set forth in paragraphs 14(a)(1), (a)(2), (a)(3), and (g) of the CPSA, as amended by section 102(a) of CPSIA.”  Draft Notice, at 20-21 (emphasis added).]  That said, given the facts that the CPSC staff have consistently taken the position that PPPA-regulated products, including drugs, are subject to the general conformity certificate requirements and that the PPPA and its implementing regulations are specifically identified in the draft notice as requirements for which the stay will be lifted, it seems unlikely that the draft Federal Register notice intended to suggest that the stay would be lifted only as to the subset of PPPA-regulated “consumer products,” but the language as currently drafted may leave open that possibility. 

The draft notice also states that “[t]he Commission has concluded that general conformity certificates are not required for labeling requirements under the Federal Hazardous Substances Act because those requirements are not sufficiently similar to consumer products safety standards or bans to warrant certification.”  Draft Notice, at 15.

Other types of standards for non-children’s products for which the Commission would lift the stay include:

• ban on lead in paint in paint and on furniture (16 C.F.R. Part 1303);
• requirements for child-resistance on portable gas containers;
• ban on extremely flammable contact adhesives (16 C.F.R. Part 1302);
• ban of unstable refuse bins (16 C.F.R. Part 1301); and
• standard for refrigerator door latches (16 C.F.R. Part 1750).

See id. at 14.

Over the past year, the Commission has issued many documents pertaining to implementation of CPSIA, including proposed, interim, and final rules, statements of policy, and guidance documents.  The Commission has issued two notices of requirements for accreditation of laboratories for testing of children’s products.  The Federal Register notice would lift the stay of enforcement as to the following:

• children’s products as of February 10, 2010:
• bicycle helmets (16 C.F.R. Part 1203);
• bunk beds (16 C.F.R. Part 1513);
• rattles (16 C.F.R. Part 1510 and §§ 1500.18(a)(15) and 1500.86(a)(7), (8)); and
• dive sticks (16 C.F.R. §§ 1500.18(a)(9), 1500.86(a)(7), (8)).

See id. at 11.

The Federal Register notice would lift the stay for certain other products on a delayed basis.  For example, due to current insufficient testing laboratory capacity, the stay for bicycles (16 C.F.R. Part 1512) would be kept in effect until August 10, 2010.  See id. at 11-12.  With regard to total lead content in children’s products, in order “to allow component testing to form the basis for certifications for lead content and to permit the staff to complete an interpretative rule on the meaning of the term “children’s product,” testing by a third party laboratory and certification based on that testing should begin on products manufactured after August 10, 2010.  See id. at 12. 

The Federal Register notice would continue the stay of enforcement until further notice for a variety of other children’s products:

• carpets and rugs (16 C.F.R. Parts 1630 and 1631, except with regard to guarantees under the Flammable Fabrics Act);
• vinyl plastic film (16 C.F.R. Parts 1611, except with regard to guarantees under the Flammable Fabrics Act);
• wearing apparel (16 C.F.R. Parts 1610, except with regard to guarantees under the Flammable Fabrics Act);
• caps and toy guns (16 C.F.R. § 1500.18(a)(5));
• phthalates (section 108 of CPSIA);
• ASTM F963 (Consumer Safety Specifications for Toy Safety) (section 106 of CPSIA);
• clacker balls (16 C.F.R. §§ 1500.18(a)(7), 1500.86(a)(5));
• baby walkers;
• bath seats;
• children’s sleepwear (16 C.F.R. Parts 1615 and 1616);
• electronic toys (16 C.F.R. § 1500.18(b) and Part 1505); and
• durable infant products (section 104 of CPSIA).

See id. at 15-16.

The Commission stated when it issued the stay last year that all certification requirements in its regulations that existed prior to enactment of CPSIA would remain in effect (e.g., the pre-CPSIA requirements for testing and certification of mattresses), and that remains the case.  The draft Federal Register notice identifies categories of products that were subject to pre-existing testing, labeling, recordkeeping, or certification requirements that may need to modify their certifications to include additional information required by CPSIA.  See id. at 19-20.

The Commission recently conducted a two-day workshop regarding testing and certification requirements, including the contours of “reasonable testing programs” and component testing.  A webcast of the discussion can be found here.  On December 16, 2009, the Commission posted a draft Federal Register notice regarding “Interim Enforcement Policy on Component Testing and Certification of Children’s Products and Other Consumer Products to the August 14, 2009 Lead Limits.”  In the coming days, we can expect to see additional notices and other documents issued by CPSC as they work to provide regulations and guidance on implementation of the certification and testing requirements, and will continue to monitor and report on developments.