On October 27, 2009, the European Food Law Association (“EFLA”) will hold its first international EU-US Food Law Conference at the Brussels Sofitel, Place Jourdan 1 – 1000, Brussels.  EFLA is an international scientific association whose primary goal is to study and to promote Food Law.  The title of the conference is “Placing Products on the Market.”  A copy of the conference brochure is available here.  According to EFLA:

This first EFLA Conference, specifically devoted to International Relations in the Food Law Sector, will foster the exchange of ideas and experiences between European and American practitioners. This exchange will focus on the respective substantive laws and their practical effects as seen by practitioners over the years and at present.  The speakers will present general outlines of the topics, and the audience will be invited to actively participate in the debates and contribute their own views and insights.

Hyman, Phelps & McNamara, P.C.’s Diane B. McColl will chair a session at the conference comparing the main aspects of the substantive EU and US food laws, which will include a presentation from Wim Debeuckelaera of the European Commission Directorate General for Health and Consumer Affairs. 

By Ricardo Carvajal –

FDA has issued a draft guidance document that addresses FDCA section 201(rr)(4), which prohibits a tobacco product from being “marketed” in combination with any other FDA-regulated product.  The guidance provides the following as an example of prohibited conduct: "Nicotine that is derived from tobacco is added to water, juice, or soda (which are foods under the FDCA) and the water, juice, or soda is identified as containing a tobacco product."

This example suggests that, if a food is not “identified” as containing a tobacco product, then the prohibition in section 201(rr)(4) does not apply because the tobacco product has not been “marketed.”  This result is consistent with FDA’s interpretation of the term “marketed” as used in FDCA section 201(ff)(3)(B), otherwise known as the dietary supplement exclusionary clause.  In part, the exclusionary clause excludes from the definition of a dietary supplement an article that is approved as a new drug unless it is first “marketed” as a dietary supplement (or as another type of food).  In applying the exclusionary clause, FDA has taken the position that an article is not “marketed” as a supplement when it is merely present in a supplement that is offered for sale; rather, the article must have been sold or offered for sale as a supplement, or as a component of a supplement where the labeling or advertising for the supplement identified the presence of the article.

What FDA’s draft guidance leaves unsaid is that one can circumvent the prohibition in section 201(rr)(4) by not “identifying” a food as containing a tobacco product, but still run afoul of several adulteration and misbranding provisions of the FDCA.

By Kurt R. Karst –      

In what could shape up to be a very interesting (and important) precedent, the U.S. District Court for the Eastern District of Michigan (Southern Division) recently ruled and issued an Order and Injunction requiring Novo Nordisk, Inc. (“Novo”) to change an Orange Book-listed patent use code for a patent (U.S. Patent No. 6,677,358 (“the ’358 patent”)) on its drug product, PRANDIN (repaglinide) Tablets.  Novo has appealed the decision to the U.S. Court of Appeals for the Federal Circuit.  The district court’s decision follows an earlier decision in which the district court ruled that the counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I), as added by the Medicare Modernization Act (“MMA”), could be used to correct or delete a patent use code, and not only the patent number and expiration date.

For the uninitiated, patent use codes are listed in an Orange Book Addendum with a number and a descriptor.  Those patent use codes correspond with various patents with method-of-use claims listed in the Orange Book for a particular approved drug product.  Although FDA created patent use code descriptors prior to the Agency’s June 2003 finalization of its revised patent submission and listing requirements, with the new regulations, NDA sponsors are now required under 21 C.F.R. § 314.53(c)(2)(ii)(P)(3) to supply the descriptor language on Form FDA 3542. 

This case has quite a bit of back-story.  It stems from a patent infringement action Novo brought against Caraco Pharmaceutical Laboratories, Ltd. (“Caraco”) and Sun Pharmaceutical Laboratories, Ltd (“Sun”) with respect to the ’358 patent.  It is also related to two citizen petitions Novo and Caraco initially submitted to FDA in 2008 (FDA-2008-P-0343  FDA-2008-P-0441 – see our 505(q) Citizen Petition Tracker) concerning generic drug labeling carve-out and split patent certification (i.e., a Paragraph IV Certification and a “section viii” statement to the same patent) issues.  Novo submitted its petition to FDA after the Agency required the company to amend PRANDIN’s labeling to reflect a new Indications and Usage statement.  Previously, the PRANDIN Indications and Usage labeling statement discussed both monotherapy and combination therapy.  FDA required a unitary indication statement stating: “PRANDIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.” 

In FDA’s December 2008 citizen petition decision, the Agency ruled that an ANDA for repaglinide that omits patent-protected information on metformin combination therapy would not be less safe or effective for the remaining, non-protected conditions of use, and that a split certification is appropriate as to the ’358 patent.  Novo subsequently filed a Petition for Reconsideration (“PRC”) and a Petition for Stay of Action (“PSA”) requesting FDA to reconsider its December 2008 petition decision and to stay the response and to refrain from taking any regulatory action consistent with the petition response (including granting any tentative or final approval for an ANDA for a generic version of PRANDIN that omits metformin combination information from the labeling).   

During FDA’s consideration of Novo’s PRC and PSA, Novo amended its Orange Book patent listing for the ’358 patent.  Previously, the ’358 patent was listed in the Orange Book with a “U-546” code, which is defined as “USE OF REPAGLINIDE IN COMBINATION WITH METFORMIN TO LOWER BLOOD GLUCOSE.”  The new use code, “U-968,” is defined as “A METHOD FOR IMPROVING GLYCEMIC CONTROL IN ADULTS WITH TYPE 2 DIABETES MELLITUS.” 

FDA, as a result of this use code change, denied Novo’s PRC and PSA as moot, stating that:

Because the use code for the ‘358 patent has changed since our issuance of the Citizen Petition Response and because our analysis and conclusions regarding labeling carveouts in that Citizen Petition Response were based on the previous use code, the factual predicate on which our previous response was based no longer applies.  As a result, your PRC and Petition for Stay are denied as moot. 

Although FDA denied the Novo PRC/PSA as moot, the district court deciding the patent infringement action has stated that “[a]s a result of the revised use code, the FDA will no longer permit Caraco to file a ‘section viii statement’ carving out the patented repaglinide-metformin combination therapy as a predicate for securing approval of Caraco’s ANDA to market its generic repaglinide for non-infringing uses.”  In other words, FDA has apparently required a “full” Paragraph IV Certification from Caraco as to the ‘358 patent as a result of the use code change.

Caraco challenged Novo’s use code change in a counterclaim submitted pursuant to FDC Act §505(j)(5)(C)(ii)(I) seeking an order from the court requiring Novo to amend the ‘358 Orange Book patent listing to revert back to the U-546 use code.  In granting Caraco’s Motion for Summary Judgment, the court found that Novo “improperly filed with the FDA for listing in the Orange Book the use code narrative for the method of use of claim 4 of the ’358 patent relating to Prandin,” and that Caraco and Sun “are entitled to a mandatory injunction requiring Novo to request the FDA to delist the U-968 listing for Prandin, and reinstate its former U-546 listing for Prandin.”  The court issued an Order and Injunction requiring Novo to submit to FDA a revised Form FDA 3542 reinstating the former U-546 listing for PRANDIN within twenty days from the date of the Order and Injunction.  Novo promptly appealed the decision to the Federal Circuit, where the company is seeking a stay of the district court’s Order and Injunction.

The district court’s decision is, to our knowledge, the first instance in which a court has interpreted the counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I) added by the MMA to order a company to correct or delete patent use code information.  That provision states:

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

Under FDC Act §§ 505(b) and (c), an NDA holder must submit with its application and after NDA approval “the patent number and the expiration date of any patent which claims the drug for which the applicant submitted the application or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture use, or sale of the drug” (emphasis added).

As it did in the district court, Novo argues in its Emergency Motion to Stay the district court’s injunction that the statute authorizes only two specific counterclaims by an ANDA filer for correction of the patent information submitted by an NDA holder; namely, the correction of the patent number and the patent expiration date.  

By Ricardo Carvajal &  Susan J. Matthees –

When the Federal Trade Commission (FTC) sought comments in 2008 on proposed revisions to its Guides Concerning the Use of Endorsements and Testimonials in Advertising, we noted that endorsers (including expert endorsers and celebrities) and bloggers should beware.  FTC has now announced its adoption of the revised Guides.  That same day, senior FTC officials spoke about these changes at a National Advertising Division (NAD) of the Better Business Bureaus conference.  David Vladeck, Director of the FTC's Bureau of Consumer Protection and Mary Engle, Associate Director for Advertising Practices at the FTC, commented on the new guidelines.

The FTC last updated these Guidelines in 1980.  According to the FTC, under the revised Guidelines, advertisements that feature a consumer and convey his or her experience with a product or service as being "typical" when that is not the case, will be required to clearly disclose the results that consumers can generally expect.  In addition, the FTC has now made it clear that advertisers must clearly disclose "material connections" between the advertiser and the person endorsing a product or service.  This disclosure would apply to typical marketers of products, but also to "bloggers" who receive an inducement to review a product or service.  The Guidelines also address "celebrity endorsers" by stating that such endorsers can themselves be liable for false or unsubstantiated claims in advertisements.  In fact, the Guidelines state that when a celebrity makes statements about a product or service on talk shows or in social media, the celebrity is required to identify his or her connection to an advertiser.

Anyone with even a casual interest in the use of endorsements and of advertising through “new media” (e.g., blogs and other forms of consumer-generated content) should give the revised Guides a close read.  Below we paraphrase parts of some of the examples that FTC modified since FTC published the proposed Guides last November, and provide citations to those examples and the views of the FTC as to the legality of those practices:

• A consumer joins a network marketing program through which she receives free products for which she can choose to write reviews.  If she receives a free product and writes a positive review, that review is an endorsement.  Section 255.0, Example 8.
• A blogger who participates in a blog advertising service and agrees to promote an advertiser’s product is liable for any misleading or unsubstantiated representations the blogger makes (as is the advertiser), and is liable if the blogger fails to disclose that she has been paid for her services.  Section 255.1, Example 5.  
• A celebrity endorser touts a medical service provider to fans in real time via her social networking site (think Twitter).  She should disclose her relationship with that medical service provider because the nature of that medium is such that consumers may not realize that she is a paid endorser.  Section 255.5, Example 3.
• An influential blogger writes a positive review of a valuable product given to him by a manufacturer that has given him similar products in the past.  The blogger should disclose that he received the product for free; moreover, the manufacturer should advise him of the need for disclosure and should monitor his postings to ensure he complies.  Section 255.5, Example 7.

Also of interest:

• If an advertisement is likely to convey that a consumer’s experience with a product is representative of what consumers generally achieve, but consumers cannot generally expect to achieve that result, the advertisement should disclose the result that consumers can expect to achieve in whatever circumstances are depicted.  Section 255.2, Example 4.

A drug company provides substantial payments to an outside entity to design and conduct research on one of its products.  In its advertising, the company represents the research results as the findings of the outside entity. The company should disclose the fact that it funded the research.  Section 255.5, Example 1. 

The FTC received a number of comments urging it to steer away from new media in its revisions to the Guides.  However, as noted by FTC, whether or not the Guides address new media “does not affect the potential liability of those who use these media to market their products and services.”  That liability purportedly arises not under the Guides, but under section 5 of the Federal Trade Commission Act (FTC Act), which prohibits unfair or deceptive practices.

At the NAD conference, someone asked what an advertiser should do if one of its paid bloggers doesn't disclose the relationship.  Ms. Engle responded that the company should have a policy in place that all bloggers must disclose their relationship and if a blogger doesn't follow this policy, the company should "fire" the blogger.  Ms. Engle said that the FTC wouldn't sue "right away" for a violation of the failure of a blogger to disclose a connection (the audience laughed quite a bit at this comment).  Nevertheless, the revised Guides are already raising a ruckus in the blogosphere.  Finally, Ms. Engle commented that if employees of a company contribute to a work board that is public or post comments about the company on Facebook or Twitter, they need to disclose their relationship to the company.  

There are two enforcement points that people, including but not limited to bloggers and other users of new media, may want to keep in mind.  First, the Guides are guidance, not law.  In any given case, FTC must still show a violation of section 5 of the FTC Act.  Indeed, Ms. Engle reminded the NAD audience that the FTC guidance is merely that- a guidance, not rules, and the FTC still needs to show a violation of the law even if conduct appears to violate the Guides.

Second, the FTC can be expected to direct its limited enforcement resources toward big fish.  In fact, Ms. Engle also reminded the NAD audience that the FTC has limited resources and is only going to go after the "big fish" bloggers- a mom who gets free Pampers a few times and then writes a report on them is not going to surface on the FTC's radar.  That’s little comfort to big fish, but given that the evolution of new media has been propelled mostly by small fry, we expect that they may not be immune from FTC scrutiny.

At the NAD conference, Director David Vladeck spoke more generally about the FTC's priorities, and stated that the FTC is particularly concerned about food advertisements directed to children, internet advertising, testimonials, and green claims.  He indicated that the FTC is also trying to work more closely with FDA, EPA, and other relevant agencies in order to focus on these areas. There was also discussion about disclaimers.  Ms. Engle made it clear that a footnote comment on the results is not sufficient to act as an adequate disclaimer.  Instead, the FTC will consider the net impression of the entire ad.

By Susan J. Matthees –

FDA recently announced two new developments related to its review of proprietary name submissions.  First, FDA announced the availability of a new manual of policies and procedures (“MAPP”), MAPP 6720.2: Procedures for Handling Requests for Proprietary Name Review, that details the Center for Drug Evaluation and Research’s (“CDER’s”) procedures for handling request for proprietary name reviews.  Second, after the release of the new MAPP, FDA announced a pilot program to evaluate proposed proprietary name submissions.  

The new MAPP fulfills CDER’s PDUFA IV goal to develop a MAPP by the end of fiscal year 2009, and comes almost a year after FDA announced the availability of a guidance document on contents of a complete submission for evaluation of proprietary names and the Center for Biologics Evaluation and Research (“CBER’s”) MAPP on proprietary name review.    

The CDER MAPP applies to requests for proprietary name review that are submitted to INDs, NDAs, efficacy supplements, labeling supplements, and therapeutic biological products (“BLAs”) regulated by CDER.  The MAPP will also apply to requests for review for ANDAs, although ANDAs are not subject to PDUFA.  Accordingly, the MAPP provides the review procedures to be used by CDER’s, the Office of Surveillance and Epidemiology (“OSE”), including the Division of Medication Error Prevention and Analysis (DMEPA), the Office of New Drugs (“OND”), and the Division of Drug Marketing, Advertising, and Communication (“DDMAC”).  The MAPP will also be followed by the Office of Generic Drugs (“OGD”) for the review of ANDA proprietary name submissions. 

Pursuant to the MAPP, FDA must review a request for a proposed proprietary name during the IND phase within 180 days of receiving the request.  If the name is submitted with an NDA or as part of a supplemental application, FDA must complete a review within 90 days of receiving the request. 

Interestingly, the MAPP states that FDA has the authority to require a prior approval supplement for a name and that any addition or change to the proprietary name must be submitted as a prior approval supplement because of the potential for safety concerns.  This seems to be a higher standard for a prior approval supplement than what is set forth in existing regulations and we are interested in seeing whether the statement will be challenged.   

The pilot program to evaluate proposed proprietary name submissions is a voluntary 2-year program that FDA states “will enable participating pharmaceutical firms to evaluate proposed proprietary names and submit the data generated for those evaluations to FDA for review.”  FDA began accepting requests to register for the program, which is available for submissions to CDER and CBER, on October 1.

The pilot program fulfills FDA’s obligations under PDUFA IV to implement a pilot program that allows pharmaceutical firms to evaluate their own proposed proprietary names and submit data from those evaluations to FDA for review.   FDA published a concept paper on the pilot program last October. 

In order to participate in the program, interested parties must contact the appropriate FDA center (CDER or CBER) to register and provide the approximate month for the intended submission.  FDA states that it “will strive to include a cross-section of applicants that represent large, medium, and small companies.”   Accordingly, FDA will make a determination whether it has space for an applicant during the requested time period.  If there is space for the application, FDA will confirm the applicant’s registration via email.

At the end of the 2-year program, FDA will evaluate the program to determine whether applicants should perform their own proprietary name analysis.  FDA promises to hold a meeting to discuss the results of the program and publish a draft guidance describing the best test methods for proprietary name evaluation.

 By Alan M. Kirschenbaum –

Last Friday the Senate Finance Committee completed its mark-up of the “America’s Healthy Future Act of 2009.”  The Committee is awaiting scoring by the Congressional Budget Office before it votes on the bill this week.  Earlier we reported on the original Chairman’s Mark and prepared a summary of the provisions of direct interest to drug and device manufacturers.  Although the bill emerged from mark-up with no major amendments to the fees and rebates imposed on the drug and device industries, there were nevertheless a number of amendments of interest to drug and device companies.  We’ve now updated our summary to incorporate the more notable amendments added during the mark-up.  The revised summary can be found here. 

After the bill is voted out of the Finance Committee, it will be merged with the Senate Health, Education, Labor, and Pensions Committee bill before moving to the full Senate for a vote later this month.  We will continue to track these drug and device provisions as healthcare reform progresses. 

By Kurt R. Karst –      

Last week, the U.S. District Court for the District of New Hampshire ruled in a 67-page opinion that various state law tort claims brought against generic drug manufacturer Mutual Pharmaceutical Company, Inc. (“Mutual”) are not preempted by Title I of the Hatch-Waxman Amendments to the FDC Act.  The decision is the latest in a string of cases in which court have ruled that state law tort claims alleging the defective labeling of generic drugs are not preempted by the FDC Act (see e.g., Stacel v. Teva Pharms., USA, 620 F. Supp. 2d 899 (N.D. Ill. 2009), Kellogg v. Wyeth, 612 F. Supp. 2d 421 (D. Vt. 2008), Schrock v. Wyeth, Inc., 601 F. Supp. 2d 1262 (W.D. Okla. 2009), and Demahy v. Wyeth, Inc., 586 F. Supp. 2d 642 (E.D. La. 2008)).  The generic drug preemption question is also the subject of appeals in the 5th (Demahy v. Wyeth, Inc., No. 08-31204 (5th Cir. Dec. 16, 2008)), 6th (Morris v. Wyeth, Inc., No. 09-5509 (6th Cir. Apr. 27, 2009)), and 8th (Mensing v. Wyeth, Inc., No. 08-3850 (8th Cir. Dec. 10, 2008)) Circuit Courts, and is a topic of intense debate on Capitol Hill. 

In Bartlett v. Mutual Pharma. Co., plaintiffs Karen L. and Gregory S. Bartlett claim that Mrs. Bartlett suffered serious injuries after taking the non-steroidal anti-inflammatory drug Sulindac Tablets, which is marketed by Mutual under an Abbreviated New Drug Application ("ANDA") FDA approved in 1991 (ANDA No. 72-051).  (Mutual’s product is an AB-rated version of Merck’s CLINORIL (sulindac) Tablets, which FDA approved in September 1978 under NDA No. 17-911.)  Specifically, the Bartletts claim that after taking Mutual’s Sulindac Tablets in December 2004, Mrs. Bartlett was diagnosed with Stevens-Johnson syndrome progressing to toxic epidermal necrolysis (a serious and potentially fatal condition), and allege that Mutual “had an ongoing duty to conduct postmarketing safety surveillance for any reports of serious adverse events associated with Sulindac including any such report in the medical literature,” and that had Mutual done so, the company would have discovered information compelling the company “to warn physicians about the dangers” of its drug product with respect to Stevens-Johnson syndrome and toxic epidermal necrolysis.  The Bartletts assert several state law tort claims, including strict product liability (failure to warn and design defect), breach of implied warranty, breach of express warranty, fraud, negligence, and gross negligence.

Mutual filed a Motion for Judgment on the Pleadings arguing that Title I of the Hatch-Waxman Amendments, which, among other things, amended the FDC Act to create the generic drug approval procedures at § 505(j), and various FDA regulations implicitly preempt the Bartletts’ state law claims.  Specifically, the Bartletts argue that:

having obtained FDA approval for their generic version of Sulindac under the ANDA procedure envisioned by Hatch-Waxman, they could not change Sulindac’s design, or the warnings included in the drug’s labeling, without running afoul of federal law (impossibility pre-emption).  They further argue that, even if the FDA could approve such a change, it could come only after “substantial expense to obtain the scientific substantiation necessary to support [it],” frustrating Hatch-Waxman’s goal to “increase the availability of low-cost generic drugs” by opening the ANDA process to them (frustration-of-purpose pre-emption).

To support its position, Mutual points to the “same labeling” requirement in the FDC Act and in FDA’s regulations applicable to generic drug applicants seeking approval of a duplicate of a brand-name drug (arguing that the company could not have changed its  labeling to add or strengthen a warning absent a change by Merck), and FDA’s Changes Being Effected (“CBE”) regulations (which the company argues apply only to NDA-approved drug products).  In particular, Mutual points to a statement FDA included in a footnote in the preamble to the Agency’s proposed CBE regulations (and elsewhere) that “CBE changes are not available for generic drugs approved under an [ANDA].  To the contrary, a generic drug manufacturer is required to conform to the approved labeling for the listed drug.” 

In denying Mutual’s motion, the court, relying on the Supreme Court’s preemption decisions in Wyeth v. Levine and Medtronic, Inc. v. Lohr (and the often quoted statement from the Court that in preemption cases “in which Congress has legislated . . . in a field which the States have traditionally occupied,’ we start with the assumption that the historic police powers of the States were not to be superseded by the Federal Act unless that was the clear and manifest purpose of Congress.)” ruled that neither the Hatch-Waxman Amendments nor FDA’s regulations explicitly or implicitly preempt the Bartletts’ state law claims.  According to the court:

To fit their claimed predicament into this framework, the defendants would need to show a federal law saying “You may not change your label” to conflict with the state law underlying the Bartletts’ failure-to-warn claims, i.e., “You must change your label.” So the defendants’ assertion that the FDCA does not say one way or the other whether they can change their label is insufficient. [(underline in original)]

It is also incorrect, because . . . the [FDA Modernization Act] allows, “[w]ith respect to a drug for which there is in effect an approved application under section 355 . . . , a change from the manufacturing process approved pursuant to such application.” 21 U.S.C. § 356a(a)(1).  Both NDAs and ANDAs, of course, are approved under section 355. . . . 

Because 21 U.S.C. § 356a expressly authorizes a manufacturer’s changes to an application approved under § 355 of the Act – whether under subsection (b), as in the case of an NDA, or under subsection (j), as in the case of an ANDA – the defendants are incorrect that nothing in the Act permits a manufacturer to change its label post-approval.

And with respect to FDA’s ANDA and CBE regulations, the court stated that:

The FDA’s footnote-bound position that “CBE changes are not available for generic drugs approved under an [ANDA] under 21 U.S.C. § 355(j)” is not persuasive . . . .  First, the footnote did not so much as acknowledge 21 C.F.R. § 314.97 [concerning supplements to approved ANDAs].  Second, while the footnote did cite § 314.150(b)(10), that rule, as already discussed at length, provides only that the FDA may attempt to withdraw its approval of an ANDA if “the labeling for the drug product that is the subject of the [ANDA] is no longer consistent with that for the listed drug”; it says nothing at all about CBE changes, and cannot be read to prevent them in light of the other provisions of the ANDA rules.  Third, while the footnote also cited certain of the agency’s comments in promulgating the ANDA regulations, those comments, as also already discussed at length, do not support excluding generic manufacturers from the CBE process.  Based on these deficiencies, this court joins with those others that have refused to adopt the view set forth in the FDA’s footnote.

As if to provide a perfect transition for us to report on what is happening on Capitol Hill, the district court concluded its opinion noting that it cannot grant Mutual’s motion finding preemption absent “a clear expression of intent” from Congress.  And in fact, Congress is working on providing that “clear expression of intent.” 

Sen. John Cornyn (R-TX) recently filed an amendment to both the Senate Finance Committee’s health reform bill and in the Judiciary Committee to Sen. Herb Kohl's (D-WI) “reverse payment” (S. 369) bill that would preempt tort suits against generic drug makers.  Specifically, Sen. Cornyn’s amendment would amend the law to state:

Notwithstanding any other provision of State or Federal law, a person who manufacturers a generic drug approved under an abbreviated new drug application shall not be liable because the label did not warn against an adverse reaction, unless the Food and Drug Administration required a change to the label to provide such warnings and the manufacturer failed to comply with such requirement, or the manufacturer failed to provide to the Food and Drug Administration health and safety information otherwise required to be provided under regulations issued by the Secretary for Health and Human Services regarding such drug.

By William T. Koustas –

FDA recently issued its most extensive guidance for industry regarding Risk Evaluation and Mitigation Strategies (“REMS”) since their enactment of the Food and Drug Administration Amendments Act of 2007 (“FDAAA”).  The “Draft Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications” (“REMS Guidance” or “Guidance”) addresses issues that drug companies may struggle with as they develop REMS.  While some of the information found in the REMS Guidance is not new, it is one of the few times FDA has revealed its thinking on these issues to this extent to the public.  The REMS Guidance mainly addresses three issues: (1) the content of a proposed REMS submission; (2) REMS assessment and modification of proposed REMS; and (3) communicating with FDA about REMS.  The introduction and background sections of the guidance also contain useful information about REMS and their relationship to RiskMAPs.  Interestingly, the REMS Guidance also contains an example of a REMS for a fictitious drug product.  Though much of this information can be gleaned from already approved REMS, it is likely a useful tool for sponsors to examine as they struggle to develop a REMS of their own.

I.  Content of a Proposed REMS Submission to FDA

This section of the REMS Guidance essentially describes what FDA expects a REMS to contain in the “proposed REMS” and “REMS supporting document” sections of the REMS submission.  As described in this guidance, the “proposed REMS” section of this submission should contain information regarding the goals of the REMS as well as the elements the sponsor proposes to implement in order to achieve those goals.  FDA notes that goals should “target the achievement of particular health outcomes or knowledge related to known safety risks and should be stated in a way that aims to achieve maximum risk reduction.”  FDA, Draft Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications (Sept. 2009) at 9.  This part of the Guidance also gives generic examples of how a sponsor may phrase a goal as well as objectives.  The “proposed REMS” should also contain one or more of the REMS elements many are familiar with – medication guides or patient package inserts, communication plans, elements to assure safe use, an implementation system and a timetable for submission of assessment – as required by FDA or FDAAA.  Id. at 10-15. 

The “REMS supporting document” section of this Guidance describes the information and format of such a document.  According to the REMS Guidance, the supporting document should include a background section explaining why the sponsor believes a REMS is necessary; a goals section describing the rationale for each goal stated in the “proposed REMS;” supporting information about the proposed elements so that it is clear to FDA how each element will contribute to the goals; and a REMS assessment plan which should permit the sponsor to evaluate how the REMS elements are, or are not, achieving the stated goals and whether these elements or goals should be modified.  Id. at 16-21.

II.  REMS Assessment and Proposed REMS Modification Submission to FDA

The REMS Guidance devotes an entire section to REMS assessments and modifications, which describes what FDA expects sponsors to include in the REMS assessments that must be submitted according to the timetable for submission of assessments included in the “proposed REMS.”  The assessment may propose modifications to approved REMS elements either at the sponsor’s initiative or when FDA determines that new safety information requires the modification of the REMS.  Id. at 22.  Any modifications to approved REMS must be submitted as a new prior-approval supplemental application and each modification should include a new “proposed REMS” as well as an updated “REMS supporting document” that describes the rational for the modifications.  Id.

III. Communicating with FDA Regarding REMS

The REMS Guidance also describes how a sponsor should communicate with FDA regarding REMS submissions.  A proposed REMS may be submitted in the original drug application, as a supplement to an existing application or as an amendment to an original or supplemental application.  Id. at 23.  While submission of a REMS assessment alone is not considered a supplemental application, a REMS assessment with a proposed modification to an approved REMS would be.  Id.  Additionally, a supplemental application for a new indication for a drug with an approved REMS should include a REMS assessment and proposed modifications if necessary.  FDA also identifies how the initial pages of a REMS submission should be formatted such that it is able to quickly identify it.  Id. at 24-26.  FDA notes that sponsors should contact  their regulatory project manager in the division assigned to the drug, while the a sponsor of an ANDA should contact the Director of the Division of Labeling and Program Support in the Office of Generic Drugs with questions.  Id. at 26. 

By Kurt R. Karst –      

We previously reported on a Senate floor amendment to the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (H.R. 2997) co-sponsored by Senators Sam Brownback (R-KS) and Sherrod Brown (D-OH) that would establish within FDA two new review groups to recommend solutions for the prevention, diagnosis, and treatment of rare diseases and neglected diseases of the developing world.  Earlier this week, after Senate and House conferees hammered out a compromise bill, a Conference Report was released that retains the Brown/Brownback amendment, albeit with some changes.

The amendment, which is reprinted below, and is now included as Section 740 of the bill, 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 rare diseases,” and another group that is required to do the same with respect to neglected diseases of the developing world.  The previous version of the amendment stated that FDA may establish the groups.  Also, whereas the previous version of the amendment stated that each review group would be composed of 8 FDA employees, the conference version omits any reference to the number of FDA employees in each review group.  It is unclear whether any additional guidance will be given as to the composition of each review group.

SEC. 740. (a) The Commissioner of Food and Drugs shall establish within the Food and Drug Administration 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 rare diseases: Provided, That the Commissioner of Food and Drugs shall appoint individuals employed by the Food and Drug Administration to serve on the review group: Provided further, That members of the review group shall have specific expertise relating to the development of articles for use in the prevention, diagnosis, or treatment of rare diseases, including specific expertise in developing or carrying out clinical trials.

(b) The Commissioner of Food and Drugs shall establish within the Food and Drug Administration 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: Provided, That the Commissioner of Food and Drugs shall appoint individuals employed by the Food and Drug Administration to serve on the review group: Provided further, That members of the review group shall have specific expertise relating to the development of articles for use in the prevention, diagnosis, or treatment of neglected diseases of the developing world, including specific expertise in developing or carrying out clinical trials: Provided further, That for the purposes of this section the term ‘‘neglected disease of the developing world’’ means a tropical disease, as defined in section 524(a)(3) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360n(a)(3)).

(c) The Commissioner of Food and Drugs shall –

(1) submit, not later than 1 year after the date of the establishment of review groups under subsections (a) and (b), a report to Congress that describes both the findings and recommendations made by the review groups under subsections (a) and (b);

(2) issue, not later than 180 days after submission of the report to Congress under paragraph (1), guidance based on such recommendations for articles for use in the prevention, diagnosis, and treatment of rare diseases and for such uses in neglected
diseases of the developing world; and

(3) develop, not later than 180 days after submission of the report to Congress under paragraph (1), internal review standards based on such recommendations for articles for use in the prevention, diagnosis, and treatment of rare diseases and for such uses in neglected diseases of the developing world.

By William T. Koustas –

The United States Court of Appeals for the District of Columbia Circuit (“Court”) recently issued an opinion affirming the FDA’s (or “Agency”) approval of the anthrax vaccine for all known routes of infection and rejected the Plaintiffs’ efforts to enjoin the Defense Department from administering it.  Eight servicememebers (“Plaintiffs”) brought suit against FDA claiming that the Agency’s approval of the anthrax vaccine as effective was arbitrary and capricious as it relied on a study that could not “support a finding of effectiveness against anthrax contracted by inhalation” nor could the study support FDA’s findings that the current version of the anthrax vaccine is effective.  Rempfer v. Scharfstein, No. 08-5117 at 8 (D.C. Cir. Sept. 29, 2009).  The Court noted that the Plaintiffs did not contest the vaccine’s safety, only its effectiveness.  See id. at 8.

Plaintiffs’ first argument is that the main study relied on by FDA for approval of the current vaccine, the Brachman Study, included very few cases of inhalation anthrax and thus cannot support the Agency’s conclusion that the vaccine is effective against all routes of exposure.  See id. at 10.  However, the Court found that FDA used its scientific judgment to determine that the route of exposure is irrelevant to determining the efficacy of the anthrax vaccine.  See id. at 12.  Therefore, it was reasonable for FDA to determine the vaccine’s effectiveness based on all cases of anthrax exposure in the Brachman Study and FDA did not need to determine the vaccine is effective for inhalation routes of exposure separately.  As the Court stated:

…the plaintiff’s claim that the Brachman Study establishes nothing in regard to “inhalation anthrax” relies on the proposition that route of exposure is scientifically relevant.  But FDA’s contrary determination is a scientific judgment within its “area of expertise,” the kind of judgment to which this court gives a “high level of deference.”

Plaintiffs’ second contention is that the Brachman Study used an earlier version of the anthrax vaccine, so the results of that study cannot be applied to the current generation of vaccine. See id. at 13.  Again, the Court rejected this claim, noting that FDA has an established protocol for analyzing changes in the manufacturing process and that the new version of the vaccine has been tested in animals and in clinical studies demonstrating that the antibody response between all versions of the vaccine is similar.  2005 Final Order, 70 Fed. Reg. 75,180 (Dec. 19, 2005).  Therefore, the determination by FDA that the new version of the vaccine is just as effective as the version used in the Bachman Study is a scientific judgment which, as the Court previously explained, is entitled to “considerable deference.”  Rempfer at 14. 

With regard to Plaintiffs’ effort to enjoin the Defense Department from administering the vaccine, the Court affirmed the district court’s determination that Plaintiffs do not have standing to ask for such a remedy as they did not suffer an injury in fact.  See id. at 15.  Plaintiffs’ only alleged that military personnel whose vaccination series (the anthrax vaccine is a six-shot series) was interrupted due to a shortage in 2000-2002 were harmed because the Defense Department resumed the vaccinations after 2002 without taking the interim period into account.  See id.  However, the Court reasoned that since none of the plaintiffs are among those personnel whose vaccine series was interrupted, they did not have standing to ask for an injunction.  See id.

By David B. Clissold & Ricardo Carvajal –

An importer and distributor of cigars has sued FDA to enjoin the agency from taking any adverse action with respect to Djarum brand cigars under Chapter IX of the FDCA until such time as the agency lawfully asserts jurisdiction over cigars (Chapter IX was added to the FDCA by the Family Smoking Prevention and Tobacco Control Act).  Chapter IX currently applies only to cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco.  It does not apply to cigars or any other type of tobacco product until FDA issues a regulation under FDCA section 901(b) asserting authority over those products.  According to the complaint, Djarum brand cigars meet statutory and regulatory definitions of a “cigar” for purposes of taxation (e.g., 26 U.S.C. § 5702) and have been classified as cigars by the Alcohol and Tobacco Tax and Trade Bureau (“TTB”).  As such, Djarum brand cigars cannot be subject to regulatory action under the authority of Chapter IX unless and until FDA issues a regulation under section 901(b).

The suit was prompted by recent FDA statements relating to flavored cigarettes.  FDCA section 907(a)(1) bans cigarettes that contain a “characterizing flavor” as of September 22, 2009.  FDA issued a Letter to Industry on the eve of the ban stating that the ban “applies to all tobacco products that meet the definition of ‘cigarette’ in section 900(3) of the Act even if they are not labeled as ‘cigarettes’ or are labeled as cigars or as some other product” (see our prior post here).  The wording of FDA’s letter aroused concern that the agency might interpret the ban to apply to cigars that contain a “characterizing flavor.”  In addition, FDA had been petitioned by retailers either to clarify the products of concern or exercise enforcement discretion until it had done so, but FDA denied that request (see our prior post here).  According to the complaint, because of the resulting uncertainty in the cigar industry and the potential for seizure and civil penalties, plaintiff sued FDA asking the court to determine that the agency was precluded from taking enforcement action against the Djarum products.

This case may help to clarify where FDA intends to draw the definitional line between cigarettes and cigars.  What the case is unlikely to resolve is whether, and to what extent, FDA might in the future seek to curtail the marketing of flavored cigars.

By Jeff Wasserstein –

We previously blogged on the effort by W. Scott Harkonen, the former CEO of InterMune, to dismiss an indictment for misbranding and fraud.  That effort was unsuccessful, and Mr. Harkonen was convicted after trial of one count of wire fraud.  He was acquitted of the FDC Act charge.

By Jeffrey K. Shapiro –
 
FDA’s Office of Combination Products (“OCP”) recently issued a proposed rule (74 Fed. Reg. 48,423) setting forth current good manufacturing practice (“cGMP”) requirements for combination products.    

The proposed rule does not independently establish new requirements; rather, it clarifies which set of existing cGMP regulatory requirements apply when drugs, devices, and biological products are combined to create a combination product.  Because FDA has separate cGMP regulations for each type of product, there has been confusion as to which regulations apply when the various products are combined.  The confusion has been particularly acute for combination products where the constituents are physically combined into a single entity or in co packaging.  In the proposed rule, FDA offers a streamlined option to avoid having to establish duplicative drug and device quality systems.

FDA describes the rationale for the proposed rule as follows (74 Fed. Reg. at 48,429):

The proposed rule has two related purposes. The first is to clarify the cGMP requirements that apply to combination products, and the second is to help ensure the consistent and appropriate application and enforcement of these requirements. Constituent parts and manufacturing practices vary among combination products; different cGMP requirements apply depending upon the constituent parts in the combination product and what manufacturing practices are used. Second, the proposed rule attempts to streamline the practical implementation of cGMP requirements for co packaged and single-entity combination products. 

FDA estimates that approximately 300 manufacturers of combination products will be affected by the proposed rule.  Id.

FDA’s Definition of Combination Products

A “combination product” is defined as a product comprised of two or more FDA regulated components. 

The regulated components could include drugs, biologics (including blood and blood components), medical devices or human cell and tissue products (called “361 HCT/Ps” or just “HCT/Ps”).  FDA regulates drugs and devices under the Federal Food, Drug, and Cosmetic Act (“FDCA”), biological products under section 351 of the Public Health Service Act (“PHS Act”), and HCT/Ps under section 361 of the PHS Act.

A combination product can be created either:

• by physically combining during manufacture to create a single entity product or by placing two separate components in the same package (known as “co packaging”), or

• by cross labeling, where the components are separately manufactured and packaged, but are expressly labeled for use with one another. 

The full regulatory definition of a combination product is set forth in 21 C.F.R. § 3.2(e)(1)-(4).

Which Current Good Manufacturing (CGMP) Regulations Apply?

FDA has cGMP regulations for drugs, biologics, medical devices and HCT/Ps:

• cGMP for drugs (21 C.F.R. Parts 210 and 211),
• cGMP for biological products, including blood and blood components (21 C.F.R. Parts 600 through 680),
• Quality System Regulation (“QSR”) for medical devices (21 C.F.R. Part 820), and
• Donor eligibility screening and Good Tissue Practice (“GTP”) for HCT/Ps (21 C.F.R. Part 1271).

A long standing question has been how these various regulations apply to combination products.  In 2004, the OCP issued a draft guidance on this question, but did not finalize it.  Now, the OCP has decided not to finalize the guidance, but rather, to create a new regulation that is similar in form to the approach proposed in the draft guidance.  Thus, the agency has issued a proposed rule, with a preamble that describes some of the commentary on the draft guidance.  Comments are due by December 22, 2009.

If the usual administrative process is followed, FDA will review the comments and issue a final rule, which may be somewhat revised as compared to the proposed rule, to address the various comments.  The agency proposes to make the final rule effective 180 days from the date of publication.  From an administrative law standpoint, the issuance of a regulation is a much more solid foundation for agency action than issuing non binding guidance.

The Proposed Rule

The proposed rule would create new 21 C.F.R. Part 4 in FDA’s regulations that would specify how to determine which cGMP requirements apply to a combination product.

Here is a brief section by section analysis of the proposed rule:

Sec.  4.1.  This section simply explains that the regulation establishes which cGMP requirements apply to combination products. 

Sec.  4.2.  This section defines the terms used in the regulation.

Sec.  4.3.  This section identifies the cGMP regulations that apply to the constituent parts of any combination product.  For example, FDA identifies the drug cGMP regulations (21 C.F.R. Parts 210 and 211) as applicable to drug constituents of a combination product.  As another example, FDA identifies the QSR for devices (21 C.F.R. Part 820) as applicable to device constituents of a combination product.

FDA takes the position that this section is all that is needed to determine cGMP requirements for combination products created by cross labeling.  The reason is that the constituent parts of such combination products are manufactured and packaged separately.  Therefore, it is fairly straightforward to apply the relevant cGMP regulation to each constituent part.

Sec.  4.4.  In general, FDA takes the position that the constituent parts of a combination product retain their regulatory status (as a drug or device, for example) even after they are combined.  Accordingly, the cGMP requirements that apply to each of the constituent parts continue to apply when they are physically combined in a single entity or co packaged product.

Thus, if a drug and device are combined in a single entity or via co packaging, then theoretically the manufacturer must comply with both the drug cGMPs for the drug constituent and the QSR for the device constituent.  Section 4.4(a) requires such duplicative compliance for each applicable cGMP regulation, unless the manufacturer elects to follow the streamlined compliance in section 4.4(b).  Such compliance might require the manufacturer to establish complete cGMP and QSR operating systems at a single facility.  Obviously, this requirement is onerous.

In section 4.4(b), FDA offers an option to help manufacturers avoid such duplicative cGMP operating systems.   A manufacturer may demonstrate an operating system in primary compliance with either the drug cGMPs or QSR for devices, and then need only demonstrate compliance with selected provisions from the other regulation.  FDA specifies these provisions in section 4.4(b) based upon its analysis as to areas in which there is not an overlap. 

For example, a manufacturer who demonstrates primary compliance with the drug cGMPs must still show compliance with the design controls provision in the QSR (21 C.F.R. § 820.30) to the extent it is applicable, based upon FDA’s view that there is not a comparable provision in the drug cGMPS.  But the manufacturer avoids having to operate under both cGMPs and QSRs for the same product.

If there is a biological component, the manufacturer would still have to show compliance with the cGMPs for biologics (21 C.F.R. Parts 600 through 680).  If there is an HCT/P component, the manufacturer would still have to show compliance with donor screening and GTPs (21 C.F.R. Part 1271).

Section 4.4(c) prescribes that when manufacture of a constituent part occurs at a separate facility, the cGMP requirements for that constituent part apply, and the streamlined approach is not available. 

Under section 4.4(d), however, the streamlined approach is available whenever the constituent parts arrive at the same facility or are being processed there.

Section 4.4(e) indicates that the regulations in the proposed rule do not supersede the specific cGMP regulations whenever there is a conflict.

The latest FDLI Update article by Hyman, Phelps & McNamara, P.C.’s Jamie K. Wolszon and John R. Fleder explores the so-called “strict liability” criminal prosecution doctrine in FDA cases that largely derives from the 1975 U.S. Supreme Court case of United States v. Park. 

FDA believes that the Park doctrine allows the government to obtain a misdemeanor criminal conviction against a company official for violations of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) – even if the corporate official was unaware of the existence of the violation – if the official was in a position of authority to prevent or correct the violation and did not do so.  Despite the doctrine’s extensive use in the 1960’s and 1970’s, prosecutors thereafter instead favored “intent to defraud or mislead” felonies under the FDC Act, and other criminal offenses under Title 18 of the U.S. Code, prompting some within FDA-regulated industries to speculate that the Park doctrine is dead.  Recent events, however, may suggest a reemergence of the doctrine.  The article explains the genesis of the Park doctrine, its early use, the shift towards prosecution of FDC Act intent to defraud or mislead felony or Title 18 offenses, and the recent events that may indicate a possible reawakening of the doctrine.

By Douglas B. Farquhar –     

In a 98-page decision filed on September 23rd, the United States Court of Appeals for the First Circuit affirmed the judgment of Boston federal court Judge Patti Saris awarding certain “Medigap” insurance companies, patients and third-party payors $13 million from pharmaceutical manufacturer AstraZeneca for allegedly committing unfair and deceptive trade practices relating to published AWPs (Average Wholesale Prices). 

By way of background, Judge Saris’s decision that was the subject of the appeal was issued in a class action after she certified (in relevant part) two classes of plaintiffs who paid for Zoladex, an AstraZeneca brand drug used to treat prostate cancer, in Massachusetts.  One of the classes was insurance companies that paid Massachusetts patients' copayments under the Medicare program (so-called “Medigap” insurers).  During the relevant period, Medicare reimbursements for brand drugs were based on AWPs, which drug manufacturers have contended were list or suggested price benchmarks not intended to represent an actual average of net prices from wholesalers to retailers or health care providers (like hospitals or physicians).  The second class certified included patients and third-party payors who paid for Zoladex, or reimbursed the cost of Zoladex prescriptions, outside of the Medicare program, when payments were computed using a formula based on AWP.

Our discussion of this case is limited because of our law firm’s past and continuing representation of some of the defendants in the district court proceedings (and some state court proceedings) relating to AWP cases.  However, in broad strokes, the First Circuit decision finds that Judge Saris did not err in applying a “plain meaning” definition to the term “average wholesale price” as used in various Medicare statutes and regulations, holding that, although the “precise meaning of ‘average wholesale price’ was unsettled,” it was not a “term of art,” as AstraZeneca contended.  The appellate court also noted, though, that its ruling was not dependent on whether the district court's “plain meaning” analysis was correct.  Rather, the First Circuit affirmed the lower court decision because damages were awarded in the Class Action only to the extent that the actual discount for providers on Zoladex exceeded “industry expectations.”  The appellate court then held that Judge Saris had not committed “clear error” in finding that industry expectations were that AWP on brand drugs would be no more than 30 percent higher than the actual average sales price to providers (the so-called 30 percent “speed limit”), thus immunizing sales at such prices from liability under the “speed limit” analysis.  The appellate court countenanced Judge Saris’s use of three factors to measure liability under the Massachusetts statute prohibiting unfair and deceptive trade practices: whether the spread (the difference between the AWP and the net cost after discounts and rebates) on Zoladex exceeded the 30 percent “speed limit,” whether AstraZeneca raised the AWP for its drug when actual wholesale prices were dropping, and whether the company “marketed the spread” (defined by the First Circuit as meaning that the company “advertised . . . to providers” the amount of profit they would make because their AWP-based reimbursement would be higher than their actual cost for the drug).

Likewise, the appellate court held that the Massachusetts state law on deceptive or unfair trade practices was not pre-empted by federal law, and that the class-wide award of damages was appropriate.