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  A draft guidance was published in February 2006.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. 

By Kurt R. Karst –      

Earlier today, FDA Commissioner Dr. Margaret Hamburg announced in an Agency-wide e-mail that Ralph S. Tyler has been appointed to serve as FDA’s Chief Counsel.  Mr. Tyler, who is currently serving as Insurance Commissioner of the State of Maryland, will officially take the reins from Acting FDA Chief Counsel Michael M. Landa on January 19, 2010.  Mr. Landa was appointed as Acting FDA Chief Counsel in April 2009 (see our previous post here) and will return to his position as Deputy Director for Regulatory Affairs at FDA’s Center for Food Safety and Applied Nutrition.  The Maryland Insurance Administration separately announced that Mr. Tyler’s resignation from the Administration will be effective on January 8, 2010.  Below is a copy of Dr. Hamburg’s e-mail announcing the appointment.

Dear Colleagues,

I am pleased today to announce the appointment of Ralph Tyler as our new Chief Counsel. Ralph is currently serving as the Insurance Commissioner of the State of Maryland and will be joining our team on January 19.

Ralph brings decades of experience to the post, having served as Chief Legal Counsel to Maryland Governor Martin O’Malley and as Baltimore City Solicitor. He was a partner in the international law firm Hogan & Hartson, L.L.P. Prior to that, he served in the Maryland Attorney General’s office from 1982 through 1996, holding the titles of Deputy Attorney General, Chief of Litigation and Assistant Attorney General.
 
He holds a B.A. from the University of Illinois, a J.D. from Case Western Reserve University, and a LL.M. from Harvard University.

As we welcome Ralph to the FDA, I want to express my sincerest gratitude to Mike Landa for serving these many months as our acting Chief Counsel. Except for a hiatus in the private sector midway through his career, Mike has been with FDA since receiving his LL.M. from New York University in 1978, and over the years became one of the agency’s most respected and admired leaders. Mike led OCC in advising both our medical device and veterinary medicine programs, served as deputy chief counsel, and as deputy director for regulatory affairs of the Center for Food Safety and Applied Nutrition as well.

During the seven months that I have worked with Mike as acting Chief Counsel, I have come to rely on his poise, good judgment, and good humor as we have wrestled with all manner of policy and legal issues. When Ralph comes on board in mid-January, Mike will return to his position as Deputy Director for Regulatory Affairs at CFSAN. I know we all will continue to rely on Mike’s skill and expertise as we move into the new year.

Please join me in thanking Mike for his extraordinary contributions and in welcoming Ralph to his new post.

Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs

By Cassandra A. Soltis –

At the Federal Trade Commission’s ("FTC’s") conference yesterday on food marketing and childhood obesity, officials from the FTC, the Centers for Disease Control and Prevention, the Food and Drug Administration, and the United States Department of Agriculture unveiled tentative proposed standards for companies marketing foods to children aged 2-17.  The draft standards are the result of Congress’ 2009 Omnibus Appropriations Act (H.R. 1105), which directed these federal agencies to create an interagency working group to study and develop recommendations for such standards and to determine the scope of media to which the standards should apply. 

There are currently three tentative standards that companies can use in deciding whether a food can be marketed to children.  A food falling within Standard One is deemed to be a part of a healthful diet and may be marketed to children without regard to the requirements of Standards Two and Three.  Standard One foods include 100% fruit and fruit juices in all forms, 100% whole grains, and 100% non-fat and low-fat milk and yogurt.  “100%” is defined “as no added nutritive or non-nutritive sweeteners and no other functional ingredients added to the product, except for flavoring for water, milk, and yogurt.” 

Standards Two and Three are intended to be read together.  Standard Two lists foods that provide a meaningful contribution to a healthful diet, and Standard Three lists limits on the amounts of certain nutrients that can be present in Standard Two foods.  Standard Two foods include fruits, fruit juices, beans, vegetables, fish, nuts, and eggs, among other items.  Standard Two foods must be present in the product in a specific amount.  Standard Three limits the amount of trans fat, saturated fat, sugar, and sodium in the Standard Two foods.  Accordingly, if a vegetable product contains enough vegetables to qualify as a Standard Two food but contains, for example, 0.5 g or more of trans fat per reference amount customarily consumed, the food should not be marketed to children.   

The interagency working group stressed that the standards are not a regulatory proposal, but the final report on the standards will be given to Congress no later than July 15, 2010.  The group will publish a notice in the Federal Register that will request comments on the draft standards and ask for feedback on several questions, such as whether there should be standards for two age groups instead of one large age group, whether certain foods should be added or eliminated from the standards, and how “marketing to children” should be defined.

By Carrie S. Martin –

New Jersey’s Attorney General recently endorsed a report prepared by the Division of Consumer Affairs (the “Division”), recommending certain restrictions and obligations on physicians and industry to limit potential conflicts of interest.  Many of the recommendations are similar to those in the codes adopted by the Pharmaceutical Research and Manufacturers of America (“PhRMA”) and the Advanced Medical Technology Association (“AdvaMed”), which prohibit manufacturers from providing entertainment, non-educational gifts, and lavish meals to physicians, among other things. 

They also include proposed manufacturer reporting requirements, which are already on the books in states like Minnesota, Vermont, and Massachusetts.  However, the New Jersey Division’s proposals go even farther:  not only do they propose to impose reporting obligations on pharmaceutical and device manufacturers, they recommend imposing obligations on physicians as well. 

Here, in brief, are some of the most salient proposals: 

• The Division proposes to require physicians to disclose – as a condition of the biennial medical license renewal process – whether they have accepted more than $200 during the preceding two years from manufacturers, including money from consulting or research arrangements, honoraria, food, or any other economic benefit.  The Division further proposes that this information be made publicly available.

• The Division proposes to ban physicians from accepting food from manufacturers in all venues, including in-office meals, except for modest meals provided at accredited continuing medical education (“CME”) events.  The CME meals, however, must be paid for by the CME provider, not paid directly by manufacturers.

• The Division recommends that all physicians be notified of their ability to opt-out of data mining (i.e., to prevent companies from selling information about the physician’s prescribing habits).  In addition, the Division recommends that the State enact legislation to prohibit the use of information collected via data mining for commercial purposes.

The report also proposes to amend New Jersey regulations regarding gifts to physicians, CME requirements, physicians-in-training, physician accountability, health care facilities and academic detailing.

The relevant New Jersey agencies are now working on draft regulations in response to the Division’s recommendations.  If the Division and Attorney General get their way, New Jersey will have the most restrictive disclosure laws to date.

By Kurt R. Karst –      

Tick tock!  Tick tock!  Like sand through the hourglass so too are the days that The Medicines Company (“TMC”) has to convince Congress or the U.S. Patent and Trademark Office (“PTO”) to allow a Patent Term Extension for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering ANGIOMAX (bivalirudin), an anticoagulant drug product FDA first approved late on Friday, December 15, 2000 (9 years ago today) under New Drug Application (“NDA”) 20-873.  The ‘404 patent expires on March 23, 2010, but is subject to a 6-month period of pediatric exclusivity.

We recently reported that TMC has been lobbying Congress to pass legislation that would amend the PTE statute at 35 U.S.C. § 156 to permit the PTO to accept the late filing of a PTE application, and in particular, TMC’s PTE application for the ‘404 patent – but for a $65 million fee.  Thus far, TMC’s lobbying efforts have not been fruitful. 

As background, TMC submitted a PTE application to the PTO 62 days after FDA approved the company’s ANGIOMAX NDA.  Under 35 U.S.C. § 156(d)(1), the submission of a PTE application must occur “within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use” (i.e., within 60-days of the date of NDA approval).  In April 2007, the PTO denied the PTE request.  Among other things, the PTO cited Unimed, Inc. v. Quigg, 888 F2d 826; 12 USPQ2d 1644 (Fed. Cir. 1989), in which the U.S. Court of Appeals for the Federal Circuit addressed the timeliness of a PTE application submission and observed that “section 156(d)(1) admits of no other meaning than that the sixty-day period begins on the FDA approval date.”  (For additional information, see our previous blog posts here and here.)

Apparently not having any success on the Hill, TMC has once again turned to the PTO.  Earlier this month, TMC submitted a Petition and a Request for Reconsideration of its PTE application to the PTO. 

The Petition requests that the PTO suspend its regulations at 37 C.F.R. § 1.750 “to the extent they limit requests for reconsideration of patent term extension applications to a single submission within the times specified in the rule.”  TMC had already requested reconsideration of the PTO’s denial of a PTE for the ‘404 patent on the basis that the date of approval of the ANGIOMAX NDA was in fact first effective as of Monday, December 18, 2000, the next business day after the December 15, 2000 NDA approval.

The Request for Reconsideration asks the PTO to employ a “rule of construction” under which the Office would consider the 60-day PTE application submission period at 35 U.S.C. § 156(d)(1) to commence on the first business day after the day the FDA transmits notice of NDA approval of the drug product if that transmittal occurs after normal business hours.  In the case of the PTE application for the ‘404 patent covering ANGIOMAX, that would mean the 60-day period would have begun on December 18, 2000 and the PTE application would have been timely filed within 35 U.S.C. § 156(d)(1).  TMC explains in its Petition for Reconsideration that:

PTO can and should interpret the language of § 156(d)(1) to conclude that the present application was timely filed.  The PTO can do this by concluding that this application was filed within 60 days of the first business day on which the product had “received permission . . . for commercial marketing.”  Recognizing that the notice of approval of Angiomax was sent after the close of the FDA’s normal business hours, it is reasonable for the PTO to conclude that the first day of the period specified in § 156(d)(1) was the first business day after Friday, December 15, 2000 – namely, Monday, December 18, 2000.

As justification for its proposed “rule of construction,” TMC argues that the determination the PTO makes under 35 U.S.C. § 156(d)(1) is distinct from the question of when an NDA  is “approved” under the Food, Drug, and Cosmetic Act (“FDCA”), as well as from FDA’s determination of the end of the “regulatory review period” under 35 U.S.C. § 156(g)(1)(B)(ii) for PTE calculation purposes.  “Those distinct dates are phrased in different statutory language, have distinct purposes, and are properly determined by the FDA,” states TMC in its Request for Reconsideration.  “Specifically, provisions in the FDCA refer to the ‘effective’ date of ’approval’ of [an NDA] and generally concern the legal effect of approval of [an NDA] and FDA obligations regarding review of those applications.  Section 156(g)(1)(B)(ii) similarly refers to the date [an NDA] was ‘approved’ and serves to define the end of the regulatory review period of that application.”

Moreover, TMC argues that its Request for Reconsideration is “particularly appropriate in this case” given the PTO’s “newly announced approach to counting days under § 156(d)(1).”  As we previously reported (here and here), the PTO, after being challenged as to the date on which the 60-day period at 35 U.S.C. § 156(d)(1) begins, ruled in the context of another PTE application (for PRILOSEC OTC) that although the PTO had in some instances started counting the 60-day period on the date after NDA approval, “[b]y not counting the date of FDA approval as one of the sixty days included in the time period for filing a PTE application, the USPTO was failing to comply with section 156 and case law.”  TMC comments in its Request for Reconsideration that “[a]bsent adoption of the proposed next business day rule, application of this new interpretation in cases where the FDA transmits notice of approval of the drug product after normal business hours would impermissibly shorten the period for filing a § 156 application to less than the 60 days the statute requires.”

Presumably, TMC’s Petition and Request for Reconsideration are being fast-tracked at the PTO given the March 23, 2010 expiration date of the ‘404 patent.  We will continue to update our loyal readers on any developments – both at the PTO and on the Hill – that we become aware of.

By Nisha P. Shah & Michelle L. Butler –

We recently blogged about an action commenced by Winston Laboratories, Inc. (“Winston”) against FDA, which denied a small business waiver for a new drug application (“NDA”) user fee under the Prescription Drug User Fee Act.  See Winston Labs, Inc. v. Sebelius, No. 1-09-cv-04572 (N.D. Ill. 2009).  On October 1, 2009, FDA filed a motion to dismiss Winston’s law suit on the basis that FDA’s decision is consistent with the plain language of the statute (Chevron step one) and, even if the language of the statute is ambiguous, FDA’s decision should be afforded deference since it is based on a permissible interpretation of the statute (Chevron step two).  On December 11, 2009, the U.S. District Court for the Northern District of Illinois denied FDA’s motion to dismiss under step one of the Chevron standard for agency interpretation.

Pursuant to the FDC Act, FDA will grant a waiver or reduction of user fees where “the applicant involved is a small business submitting its first human drug application to [FDA] for review.”  FDC Act § 736(d)(1)(D).  The FDC Act specifies that FDA will waive “the application fee for the first human drug application that a small business or its affiliate submits to [FDA] for review.”  FDC Act § 736(d)(4)(B) (emphasis added).  A “small business” means “an entity that has fewer than 500 employees, including employees of affiliates, and that does not have a drug product that has been approved under a human drug application and introduced or delivered for introduction into interstate commerce.”  FDC Act § 736(d)(4)(A).  The term “affiliate” means “a business entity that has a relationship with a second business entity if, directly or indirectly – (A) one business entity controls, or has the power to control, the other business entity; or (B) a third party controls, or has power to control, both of the business entities.”  FDC Act § 735(11) (emphasis added).

A brief description of the relevant facts: The case hinges on Winston’s historical relationship with a defunct pharmaceutical company .  Specifically, Dr. Joel Bernstein and his immediate family members own approximately 60 percent of Winston.  Dr. Bernstein was President and owned a majority of shares of Northbrook Testing Co., Inc. (“Northbrook”), which had submitted an NDA prior to its dissolution in 1984.  According to Winston, since Winston and Northbrook were not in existence at the same time, at no time did Winston control or have the power to control Northbrook or did a third party control or have the power to control both Winston and Northbrook.  However, FDA concluded that because Dr. Bernstein had controlled Northbrook prior to its dissolution in 1984, which was 14 years prior to the incorporation of Winston in 1998, Northbrook was considered an “affiliate” of Winston.  Since Northbrook had submitted an NDA prior to Winston’s NDA submission and application fee waiver request for Civanex® cream, FDA denied Winston’s request for a waiver.  (Dr. Bernstein was also a minority shareholder and Chairman and CEO of GenDerm Corporation, which merged into Medicis Pharmaceutical Corporation; however, on appeal within the Agency, FDA concluded that there was insufficient evidence to determine whether GenDerm and Winston were affiliates.  Accordingly, the instant litigation turns on Winston’s purported affiliation with Northbrook.)

The district court analyzed FDA’s motion to dismiss under the Chevron standard of agency interpretation.  Under step one of Chevron, a court must evaluate the plain language of the statute.  If the language is clear, then the court and the agency must adhere to the plain language of the statute.  If the language is ambiguous, then courts must apply step two of Chevron, under which a court must determine if the agency’s interpretation is a permissible construction of the statutory language.  Generally, an agency’s interpretation of a statute under Chevron step two is afforded great deference by the courts.

In this case, the district court determined that, under Chevron step one, FDA has not established that Winston cannot succeed on its claims.  In doing so, the court rejected FDA’s argument that because Dr. Bernstein had controlled Northbrook at some point in the past, Northbrook was considered an “affiliate” of Winston.  Persuaded by the “clear” language of the definition of “affiliate,” the district court agreed with Winston that the relevant terms – “has” and “controls” – contained in the definition of “affiliate” indicated a requirement for “present control or present power to control.”  Dr. Bernstein’s historical relationship with Northbrook, according to the court, should not affect Winston’s waiver request.  Additionally, FDA presented no evidence to convince the court that it should support the Agency’s claim that applying the present-tense definition of the term “affiliate” is contrary to congressional intent.  Because the court ruled against FDA on Chevron step one, the court did not need to analyze Chevron step two and whether FDA’s decision was based on a permissible interpretation of the statute.

While this decision is certainly good news for Winston, the case is not over yet.  We expect Winston may try to position the case for an early summary judgment motion.  Winston may also seek some targeted discovery to solidify the summary judgment record.  It seems less likely – but nevertheless possible – that FDA may seek discovery from Winston or third parties to elicit evidence that would fit within the court’s interpretation of “affiliate.”

By Ricardo Carvajal –

FDA has prevailed on summary judgment in a lawsuit brought by BBK Tobacco & Foods, LLP ("BBK") which sought a declaration that separately sold flavored rolling papers are not tobacco products subject to regulation under the FDCA.  Previously, FDA issued a draft guidance document and sent a letter to industry stating the agency’s belief that flavored rolling papers are banned by the FDCA as amended by the Family Smoking Prevention and Tobacco Control Act ("Tobacco Act").  BBK challenged FDA’s interpretation of the statute, and alleged that FDA’s actions had caused customers to stop buying BBK’s products. 

The court ruled that the issues presented by BBK were not ripe for judicial review because FDA’s actions were not final agency action.  The court noted that no legal consequences flow from FDA’s publication of guidance.  Further, the court found that the hardship suffered by BBK had been largely the result of its own voluntary decision to stop distributing its products on the effective date of the Tobacco Act, and of BBK customers’ voluntary decisions to return BBK products.  FDA had taken no action that specifically targeted BBK or its products.  The court further ruled that BBK had failed to exhaust its administrative remedies because it had not filed a citizen petition with FDA seeking a “formal determination of whether the Tobacco Act applies to BBK’s products.”

The moral of the story?  If an FDA draft guidance suggests that your product is unlawful, you'll need to file a citizen petition and/or face a warning letter or injunction before you can get judicial relief.

By Susan J. Matthees & A. Wes Siegner –

Last week FDA published a new guidance document titled “Guidance for Industry:  Factors that Distinguish Liquid Dietary Supplements from Beverages, Considerations Regarding Novel Ingredients, and Labeling for Beverages and other Conventional Foods.”  The guidance document includes a discussion of the factors that FDA uses to determine whether a liquid is a beverage (i.e., a conventional food) or a dietary supplement and a reminder to manufactures and distributors about the ingredient and labeling requirements of the Federal Food, Drug, and Cosmetic Act (FDC Act). 

Of particular note in the guidance document is FDA’s statement that it will consider the “packaging” of a product in its consideration of whether the product is a dietary supplement or a conventional food.  Just before publishing the guidance, FDA also issued three Warning Letters to companies marketing liquid dietary supplements in large bottles that were intended to be consumed in quantities equivalent or almost equivalent to the average total daily drinking fluid intake.  The extent that FDA will now consider packaging in the determination of whether a product is a dietary supplement is unclear, but it does appear that FDA is looking to packaging as a factor in determining how to classify a product.

By Kurt R. Karst –      

Although much discussion has been devoted over the past few days to Sen. Byron Dorgan’s (D-ND) proposed amendment (SA 2793) to the Senate Health Care Reform Bill that would let U.S. pharmacies and drug wholesalers import FDA-approved drugs from certain countries, and FDA’s letter expressing concern about the amendment, several amendments affecting generic drug manufacturers have also been proposed.

Sen. Herb Kohl (D-WI) filed an amendment (SA 2862) concerning so-called “pay-for-delay” settlements.  The amendment is almost identical to the substitute amendment to S. 369, the Preserve Access to Affordable Generics Act, that was passed out of the Senate Judiciary Committee earlier this year.  As we previously reported, the Kohl amendment would amend the Federal Trade Commission Act to permit the Federal Trace Commission (“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.” 

And while we are on the topic of pay-for-delay settlements, FTC Commissioner J. Thomas Rosch recently gave a speech at the World Generic Medicine Congress providing his thoughts on how competition law can best protect consumer welfare in the pharmaceutical context.  In addition to settlement agreements, Commissioner Rosch also discussed follow-on biologics and authorized generics, which, as discussed below, have also been the subject of recent amendments to the Senate Health Care Reform Bill.

Sen. Jay Rockefeller (D-WV) filed an amendment (SA 2952) that would  prohibit the marketing of authorized generics during a generic applicant’s 180-day exclusivity period.  The amendment is almost identical to legislation Sen. Rockefeller introduced earlier this year.  A similar version of the bill was introduced in the House of Representatives by Rep. Jo Ann Emerson (R-MO) (see our previous post here). 

Sen. Sherrod Brown (D-OH) filed an amendment (SA 2895) concerning biosimilars that would cut the proposed 12-year exclusivity period for an innovator product short if the innovator’s product is a blockbuster drug; that is, a biologic for which “the Secretary determines that the gross sales in the United States of the reference product equals or exceeds $3,500,000,000.”  A similar blockbuster proposal with respect to the availability of pediatric exclusivity was considered and rejected during consideration of the 2007 FDA Amendments Act, which, among other things, amended and reauthorized the Best Pharmaceuticals for Children Act.  FDA Week (subscription required) has reported that another amendment concerning biosimilars from Sen. Bernie Sanders (I-VT) is in the works that could also affect the availability of the proposed 12-year exclusivity period for innovator products. 

Finally, Sen. Jeanne Shaheen (D-NH) filed an amendment (SA 2961) that would add her so-called “Generic Loophole Bill” to the Senate bill.  As we previously reported, S. 1778, the Access to Affordable Medicines Act, would amend the FDC Act’s ANDA provisions at § 505(j) to permit FDA to approve a generic drug notwithstanding “last minute [labeling] changes” to the reference listed drug labeling hat could otherwise delay ANDA approval. 

The Drug Price Competition Act of 2009, which was introduced earlier this year by Sen. Bill Nelson (D-FL), and in the house by Rep. Alcee Hastings (D-FL), does not yet appear to be the subject of an amendment to the Senate Health Care Reform Bill.  As we previously reported (here and here), the bill 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 be eligible for exclusivity.  Rep. Hastings initially proposed his bill as an amendment to the House Health Care Reform Bill, but then withdrew it from consideration.