By Ricardo Carvajal –
 
FDA updated its guidance on administrative detention of food to reflect the expansion of the agency’s authority under the Food Safety Modernization Act ("FSMA").   As we noted in a prior blog posting, the FSMA made it easier for FDA to administratively detain food; FDA now needs only a reason to believe that a food is adulterated or misbranded.  The agency recently announced its first seizure of a food that was administratively detained under the new standard.

The guidance makes clear that the administrative detention authority extends to dietary supplements.  The guidance further states that the authority extends to food solely in intrastate commerce.  The guidance is effective immediately.

By Kurt R. Karst –      

Like the character Michael Keaton plays in the 1988 film “Beetlejuice,” in which spirit (a “bio-exorcist”) comes back from the afterlife (after having his name said three times) to wreak havoc and to try and scare away the new inhabitants of a home, the so-called Reference Listed Drug (“RLD”) theory of liability is being used by plaintiffs’ attorneys in an attempt to exorcize the U.S. Supreme Court’s June 23, 2011, 5-4 landmark decision in PLIVA Inc. v. Mensing from generic drug product liability litigation.  In Mensing, the Supreme Court ruled that generic drug manufacturers are not permitted to change their labeling except to mirror the label of the brand, RLD manufacturer whose drug product is approved under an NDA.  The RLD theory posits that FDA’s regulations impose new or additional responsibilities on an ANDA sponsor whose drug product is unilaterally designated by FDA as an RLD once the brand-name RLD NDA drug product is discontinued and withdrawn from the market, and that the Court’s Mensing decision is inapplicable under such circumstances. 

By way of background, FDA’s practice has been to designate a single RLD – the market leader at a given point in time as determined by the Agency on the basis of unconfirmed commercial data and other information – when the brand-name drug product and former RLD is no longer marketed and is moved to the Discontinued Drug Product List section of the Orange Book.  Specifically, FDA has stated that the Agency “will designate [RLDs].  Generally, the [RLD] will be the NDA drug product for a single source drug product.  For . . . multiple source drug products without an NDA, the [RLD] generally will be the market leader as determined by FDA on the basis of commercial data.”  FDA, Final Rule, ANDA Regulations, 57 Fed. Reg. 17,950, 17,958 (Apr. 28, 1992).  That RLD designation does not change, “even if the drug is later replaced as the market leader.”  Id.  FDA has stated time and time again that when an NDA designated as the RLD is discontinued for reasons other than safety or effectiveness, approved ANDAs that refer to the NDAs “are unaffected by the discontinued marketing of the products subject to those NDAs,” and that “[i]f FDA determines that labeling for these drug products should be revised to meet current standards, the agency will advise ANDA applicants to submit such labeling.” 

We’ve seen the RLD theory raised before.  First, Nevada State Court Judge Jerry Wiese II alluded to it in his recent decision in three propofol hepatitis infection cases (see our previous post here).  Second, Public Citizen alluded to it in its recent Citizen petition (Docket No. FDA-2011-P-0675), in which the organization states its understanding “that under current regulations, a generic manufacturer is designated by the FDA to maintain the label of a drug when the name-brand manufacturer of that drug withdraws from the market,” and says that “[t]his procedure manifests the FDA’s confidence in the ability of generic manufacturers to perform ongoing pharmacovigilance duties – which makes sense, given their substantial scientific and financial resources, as well as the effort they must already invest to comply with post-approval safety regulations” (see our previous post here).  Now, the RLD theory has taken center stage in the Court of Common Pleas of Philadelphia County in In re: Reglan/Metoclopramide Litigation. 

Morton Grove Pharmaceuticals, Inc. (“MGP”), a U.S. affiliate of Wockhardt USA LLC (“Wockhardt”), recently filed a brief with the Court of Common Pleas of Philadelphia County in the metoclopramide litigation refuting Plaintiff’s RLD theory of liability.  MGP also recently submitted comments to FDA requesting that the Agency deny the Public Citizen petition and “affirmatively state that the holder of an approved ANDA does not bear any additional responsibility for the content of product labeling if and when FDA unilaterally designates that ANDA drug product as the RLD.”  MGP/Wockhardt clearly has a significant interest in the issue, given that FDA unilaterally designated Wockhardt’s ANDA No. 074703 for Metoclopramide HCl Oral Solution as the RLD in 2006.  The “+” sign in the Orange Book indicating RLD status has transformed into crosshairs, making MGP/Wockhardt (or any other ANDA RLD) a target for Plaintiffs’ attorneys.  

MGP states in its comment to FDA on the Public Citizen petition that “[a]ny argument that FDA’s unilateral RLD designation imports responsibility to an ANDA sponsor for the content of the label has no legal, or regulatory, mooring.  This premise directly and irresponsibly contradicts the current regulatory framework, well-established responsibilities of generic drug manufacturers, and the Supreme Court’s decision in Mensing.”  MGP goes on to state that “FDA’s unilateral designation of an ANDA drug product as the RLD does not in any way alter the well-established regulatory framework established for brand and generic drug manufacturers with regard to labeling.  It does not transform an ANDA into an NDA or somehow create new responsibilities for the ANDA holder.”  Among other things, MGP cites various FDA guidance documents and Federal Register notices to support its position, including FDA’s April 2011 “Draft Guidance for Industry – Safety Labeling Changes – Implementation of Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act,” in which FDA outlines its notification procedures for required safety labeling changes once FDA has determined that new safety information is available and should be included in labeling.  “In identifying the categories of manufacturers to whom notice will be given,” says MGP, “FDA clearly delineates between the holder of an NDA, on the one hand, and an ANDA without a marketed NDA RLD, on the other hand.”  The bottom line for MGP is that:

to avoid future instances in which an ANDA sponsor is unfairly targeted – e.g., in product liability litigation – merely because FDA has identified its drug product as the RLD, FDA should include in its response to Public Citizen’s petition (and in the preface to the Orange Book) further confirmation that a RLD designation of an ANDA when the brand-name reference drug is withdrawn does not confer any additional or special responsibilities or obligations on an ANDA RLD sponsor.

Several of the points MGP makes in its comments to FDA are reiterated in the MGP/Wockhardt brief recently filed with the Court of Common Pleas of Philadelphia County in In re: Reglan/Metoclopramide Litigation.  According to MGP/Wockhardt:

Plaintiffs here are improperly, and without the support of any legal authority, attempting to impose “brand” or “NDA” status, and the responsibilities that come with such status, on ANDA holder Morton Grove where no such responsibilities exist.  An ANDA holder cannot step into the shoes of an NDA holder.  Plaintiffs have not cited to a single statutory or regulatory authority that imposes any additional responsibilities upon a generic manufacturer who is subsequently and unilaterally designated an RLD by FDA. . . .

FDA unilaterally designated Morton Grove as the RLD so that subsequent ANDA applicants have a drug to reference for purposes of application submission and approval. See 314.94(a)(7).  However, this unilateral designation does not alter the well-established regulatory framework for brand and generic drug manufacturers with regard to labeling by transforming Morton Grove, and ANDA holder, to an NDA holder.  Such a position directly contradicts the current regulatory framework, well-established responsibilities of generic drug manufacturers and the [Supreme Court's] decision in Mensing.

The Plaintiffs in the case recently fired back with their response to the MGP/Wockhardt brief, stating that “[t]he Mensing Court did not address and, therefore, did not preempt any claims arising against a generic manufacturer that has become the RDL holder, the issue central to the RLD holder preliminary objection here” (emphasis in original).  According to them, “[t]his distinction is critical because neither the Court nor FDA even considers an RLD a generic drug for regulatory purposes.”  This is quite a shocking statement, as it seems to indicate the Plaintiffs’ position that a drug product approved under an ANDA is somehow magically transformed into an NDA when the brand-name RLD NDA drug product is discontinued.  But it fits hand-in-glove with the Plaintiffs’ endgame: that “a court should apply the impossibility preemption analysis utilized in [Wyeth v. Levine] for name-brand drugs and require that the manufacturer show by clear evidence that FDA would have rejected the label change thus made.”

By Wiliam T. Koustas & John R. Fleder –

We recently reported on FDA’s attempt to assert its authority over intrastate commerce through a novel interpretation of “interstate commerce” under the Federal Food, Drug, and Cosmetic Act (“FDCA”).  Regenerative Sciences, Inc. (“Regenerative”) is challenging FDA’s claim that the company’s stem cell procedure, Regenexx, is subject to FDA jurisdiction and regulation under the FDCA and/or the Public Health Service Act (“PHSA”) as an unapproved drug and/or biologic.

The FDCA states that adulterated and misbranded products may not be introduced or delivered for introduction into interstate commerce.  FDCA § 301(a).  In addition, FDA has statutory jurisdiction over products that have been shipped in interstate commerce and thereafter become adulterated.  FDCA § 301(k).  There is absolutely no language in the statute to suggest that FDA has general authority over misbranded or adulterated products that do not move in interstate commerce but where the sale of those products merely “affects” interstate commerce.

Congress has explicitly permitted FDA to assert jurisdiction over certain products that do not move in interstate commerce in very limited circumstances.  Adulterated and misbranded products are subject to FDA’s jurisdiction if they are manufactured in any Territory.  FDCA § 301(g).  “Territory” is defined to include the District of Columbia and any territory or possession of the United States.  FDCA § 201(a)(2).  It is noteworthy that Congress explicitly chose to exclude states from these provisions.

The Supreme Court has noted that the Constitution permits the federal government to assert jurisdiction over products that either travel in, or affect, interstate commerce.  However, these constitutional powers are surely constrained by the relevant statutory language that establishes an agency’s jurisdiction.  In one of its court filings, the Government argues that the Regenexx Procedure is subject to regulation by FDA because it involves interstate commerce, in that Regenerative obtained components from out of state.  That in and of itself is not an unusual argument, but one of the Government’s two arguments involving interstate commerce was unusual, and indeed without any cited legal support.  The Government argues that interstate commerce is substantially affected because individuals traveling to Colorado to have the Regenexx Procedure would “depress the market for out-of-state drugs that are approved by FDA.”

Initially, we thought that this interpretation of interstate commerce was new ground for the FDA.  The Government even fails to cite any judicial precedent for their argument in the brief.  However, additional research revealed that FDA has previously argued that it can regulate products based on their effect on interstate commerce.

In the preamble to the Establishment and Maintenance of Records Under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 rule, 69 Fed. Reg. 71,562 (Dec. 9, 2004), FDA asserts that it has the authority to require food manufacturers to keep certain records even if their food does not enter interstate commerce.  Citing Wickard v. Filburn, 317 U.S. 111 (1942), FDA argues that “given the collective impact on commerce of intrastate manufacturing, processing, packaging, transporting, distributing, receiving, or holding of food in the United States, FDA has concluded that the requirement to establish and maintain records should apply regardless of whether the food enters interstate commerce.”  69 Fed. Reg. at 71572.  This statement indicates that FDA believes that it has the authority to regulate a product that is never introduced or delivered into interstate commerce as long as it has a “collective impact” on interstate commerce.

More recently, in the preamble to the Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements rule, 72 Fed. Reg. 34,751 (June 25, 2007), FDA asserts that it may impose certain cGMP requirements on entities involved with the manufacture of dietary supplements, regardless of whether the process is entirely intrastate, as the collective impact of such entities on interstate commerce is “far from trivial.”  FDA cites both United States v. Lopez, 514 U.S. 549 (1995) and Wickard v. Filburn to try to support its argument.

FDA seems to confuse Congress’ constitutional authority to regulate interstate commerce with FDA’s authority under the FDCA.  While Congress can regulate economic activity that has a substantial effect on interstate commerce, the FDCA generally only permits the FDA to regulate products that travel in interstate commerce.

Congress has shown that it understands this distinction.  Where Congress has wanted agencies to have jurisdiction over matters that “affect” interstate commerce, it has done so explicitly. For example, the Federal Trade Commission Act provides the FTC with the authority to regulate unfair methods of competition and unfair or deceptive acts and practices “in or affecting” interstate commerce.  15 U.S.C. § 45(a)(1) (emphasis added).  The current language was enacted in 1975 after Congress determined that the previous statutory language of “in commerce” unduly restrained the FTC’s authority.  Similarly, Congress could amend the FDCA to provide FDA with jurisdiction over products that merely affect interstate commerce.  Until Congress does so, FDA is restrained by the language in the FDCA.  It cannot expand that authority by administrative fiat, and regulated entities should be vigilant against attempts to persuade courts to the contrary.

By Kurt R. Karst –      

On October 25, 2011, the Federal Trade Commission (“FTC”) announced the release of its annual summary of agreements filed with the Commission during the last fiscal year (Fiscal Year 2011)  – “Agreements Filed with the Federal Trade Commission under the Medicare Prescription Drug, Improvement, and Modernization Act of 2003” – saying that “pharmaceutical companies continued a recent anticompetitive trend of paying potential generic rivals to delay the introduction of lower-cost prescription drug alternatives for American consumers.”  We had an idea the report was coming out soon when we read an editorial in the Washington Post supporting the FTC’s crusade against what they call “pay-for-delay settlements.”  (Contrast the Washington Post’s editorial with one from the Wall Street Journal last year – here.) 
 
According to the FTC, the Commission received 156 final resolutions of patent disputes between a brand and a generic in Fiscal Year 2011.  This is an increase of 43 settlements over the Fiscal Year 2010 figures.  A total of 28 final settlements involving 25 different branded pharmaceutical products “contain both compensation to the generic manufacturer and a restriction on the generic manufacturer’s ability to market its product,” says the FTC.  In addition, 54 of the settlements reportedly involve generics eligible for 180-day exclusivity, and 18 of them “contain both compensation to the generic manufacturer and a restriction on the generic manufacturer’s ability to market its product,” according to the FTC.  Both of the groups of 28 and 18 settlement agreements are tagged by the FTC as “potential pay-for-delay” deals in the handy-dandy table included in the report (below).
Based on the figures provided by the FTC, the Commission concludes that “FY 2011 witnessed the continued trends of (a) record numbers of brands and generics resolving patent litigation prior to a final court decision on the merits and (b) significant numbers of such settlements potentially involving pay-for-delay.” 

Of course, the FTC’s numbers only tell one side of the statistics story.  If, instead of comparing the fiscal year-over-fiscal year “potential pay-for-delay” deal numbers, you compare the “potential pay-for-delay” deals as a percentage of the overall final settlement agreements for each fiscal year, then there is no recent upward trend.  Our friends over at PatentDocs did that last year and here’s what they found – see here.  The Fiscal Year 2011 numbers are the lowest percentages in their respective categories since the FTC began issuing its reports – at 18% in the “Potential Pay-for-Delay” category, and at 11.5% in the “Potential Pay-for-Delay Involving First Filers” category.

The FTC uses its announcement of the latest report to once again express its support for S. 27, the Preserve Access to Affordable Generics Act, which would amend the FTC Act to enact what some have commented would be an effective ban on patent settlement agreements.  The FTC, the Obama Administration (see here, page 42), and the sponsors of S. 27 have urged the Joint Select Committee on Deficit Reduction (i.e., the “Super Committee”) to include the legislation in its deficit reduction plan.

The Generic Pharmaceutical Association (“GPhA”) responded to the FTC report, saying that “the FTC continues to miss the fundamental point: Patent settlements speed up the availability of less costly generic drugs and save money for everyone; banning settlements and forcing drugs makers to continue lengthy litigation with uncertain outcomes will be costly.”

By Carmelina G. Allis –

A billhas been introduced in the U.S. Senate, the “Medical Device Regulatory Improvement Act” (S. 1700) to amend the least burdensome and conflicts of interest provisions in Sections 513 and 712 of the Federal Food, Drug, and Cosmetic Act (the Act), respectively, in order to improve the premarket review process and foster innovation.  These amendments would be a step in the right direction, but are unlikely to achieve the wholesale reform of CDRH that is needed.

The proposed amendments to the least burdensome provisions in Section 513 are intended to lessen the scientific burden imposed upon manufacturers during the PMA approval process.  The amended provision would require the agency to find alternatives to reduce review times, and also consider alternative scientific approaches to evaluate the safety and effectiveness of a device for purposes of approval.  For example, the agency would be required to accept, whenever practicable, alternatives to randomized, controlled clinical trials in support of PMA approval.

It would also require FDA to consider alternative approaches during the review of both 510(k)s and PMAs in order to reduce the “time, effort, and cost of reaching proper resolution” of scientific/regulatory issues.  If the term “cost” refers to monetary cost to the manufacturer, and this proposed bill becomes law, it would be interesting to see how FDA handles this issue.  CDRH does not consider a manufacturer’s product development costs during the device review process (it is not authorized to do so by the Act or its implementing regulations).  And, thus, countless agency’s requests for data are burdensome and costly, and the agency generally overlooks a manufacturer’s request for a more reasonable approach.  This proposed amendment looks promising in that it would require CDRH to take into consideration alternatives in its quest for additional data and weigh in cost before requiring a manufacturer to pursue a particular path.

The proposed bill would also require that the agency not request or accept information that is not relevant to a 510(k) substantial equivalence (SE) determination.  Because this proposed amendment appears to only clarify the scope of the least burdensome provisions, rather than add new meaning to them, we doubt that this amendment will have much practical impact on the 510(k) review process.  FDA’s 510(k) correspondence has carried the “least burdensome” boilerplate since 1997 but it never seems to pose much of a constraint for the agency.

The proposed bill also includes an amendment to Section 712 of the FDC Act, which would require the agency to enter into a contract with an entity experienced in evaluating the management and operating structure of large organizations.  The entity would review the management and regulatory processes at CDRH “to ensure any actions carried out by such Center take into consideration the potential impacts on innovation with respect to medical devices and other products regulated by such Center.”  The entity would be required to submit a report to Congress on its findings and recommendations within a year after the effective date of the contract.

This management consulting review provision might be helpful in bringing about necessary reform at CDRH.  Still, this entity would not be the first one to criticize the management and regulatory processes at CDRH.  In fact, several GAO reports and the most recent IOM report on the 510(k) process have done just that, but there has been no improvement within the Center.  Given this track record, we remain skeptical that this particular provision would improve the status quo in CDRH.

By Ricardo Carvajal –

The 7th Circuit Court of Appeals affirmed a district court’s dismissal of an action alleging consumer fraud in food labeling claims for fiber.  As we noted in a prior posting, Plaintiff alleged that Defendants violated state consumer fraud laws by failing to disclose that their products contain purportedly “non-natural” fibers that provide fewer health benefits than “natural” fibers. 

In its preemption analysis, the court noted that FDC Act § 403A(a)(5) prohibits a state from imposing any food labeling requirement that is not identical to the requirement of section 403(r).  In pertinent part, that section imposes restrictions on nutrient content claims for nutrients required to be included in nutrition labeling under section 403(q), one of which is fiber.  The court found that the labeling of the products challenged by Plaintiff complied with these statutory provisions and with FDA’s implementing regulations.  The court held that the disclaimers demanded by Plaintiff “are not identical to the labeling requirements imposed on such products by federal law, and so they are barred.”

In an added twist that defense counsel may wish to take note of, the court held that Plaintiff failed to state a claim under the Illinois Consumer Fraud and Deceptive Business Practices Act because that law does not apply to “actions or transactions specifically authorized by laws administered by any regulatory body or officer acting under statutory authority of this State or the United States.”

By Kurt R. Karst –      

A recent decision out of the U.S. District Court for the Eastern District of Virginia that Teva Pharmaceuticals USA, Inc.’s (“Teva’s”) generic version of Pfizer Inc.’s (“Pfizer’s”) VIAGRA (sildenafil citrate) Tablets would infringe Orange Book-listed U.S. Patent No. 6,469,012 (“the ‘012” patent), which expires on October 22, 2019, and that the ‘012 patent is valid and enforceable, spawned an interesting Hatch-Waxman dispute between the companies.  Teva is reportedly a first applicant eligible for a period of 180-day exclusivity. 

The court’s August 16, 2011 judgment stated:

IT IS ORDERED AND ADJUDGED that Teva Pharmaceuticals USA, Inc.'s Motion to Dismiss for Lack of Standing is GRANTED IN PART, and Pfizer Ireland Pharmaceuticals Co. is DISMISSED from this litigation; that judgment is entered for Pfizer Inc. and Pfizer Ltd. on the Amended Complaint and Amended Counterclaim, in accordance with the Court’s Opinion and Final Order which found that Pfizer Inc. and Pfizer Ltd. did not commit inequitable conduct in the prosecution of United States Patent No. 6,469,012; that Teva Pharmaceuticals USA, Inc.’s proposed generic equivalent of Viagra would INFRINGE United States Patent No. 6,469,012, and that United States Patent No. 6,469,012 is VALID and ENFORCEABLE.

Shortly after the court entered its judgment, Pfizer filed a motion to amend the judgment to add that the effective date of the approval of Teva’s tentatively approved ANDA No. 077342 shall be no earlier than October 22, 2019 when the ‘012 patent expires.  According to Pfizer, “[t]o give effect to the Opinion and Final Order,” the court should, consistent with 35 U.S.C. § 271(e)(4)(A), amend its judgment to add that the effective date of approval of ANDA No. 77-342 shall be no earlier than the date of the expiration of the ‘012 patent on October 22, 2019.

Under the patent statute at 35 U.S.C. § 271(e)(4), certain remedies are available for “acts of infringement” based on the submission of an ANDA containing a Paragraph IV certification.  Specifically, 35 U.S.C. § 271(e)(4)(A) states that for such acts of infringement, “the court shall order the effective date of any approval of the drug . . . product involved in the infringement to be a date which is not earlier than the date of the expiration of the patent which has been infringed.” 

Teva, which did not consent to Pfizer’s motion, and which has since appealed the court’s decision to the U.S. Court of Appeals for the Federal Circuit, argued in its opposition brief, that the court’s judgment should be amended to include the following provision:

the effective date of the final approval of Teva Pharmaceuticals USA, Inc.’s Abbreviated New Drug Application No. 77-342 shall be no earlier than the date of the expiration of United States Patent No. 6,469,012, or the date of a decision by the United States Court of Appeals for the Federal Circuit that Claims 25 and 26 of United States Patent No. 6,469,012 are invalid or unenforceable, whichever date is earlier.

According to Teva, FDC Act § 505(j)(5)(B)(iii)(II)(aa), which states that “if the judgment of the district court is appealed, the approval shall be made effective on – (AA) the date on which the court of appeals decides that the patent is invalid or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity),” contemplates approval in accordance with Teva’s proposed provision. 

Moreover, Teva states that the company is “entitled to final approval of its ANDA if the [Federal Circuit] decides that Claims 25 and 26 of the ‘012 patent are invalid or cannot be enforced,” and that “[i]f the Federal Circuit invalidates or holds Claims 25 and 26 unenforceable in some other case, there is no reason why Teva should have to delay marketing its proposed sildenafil ANDA product to persuade this Court that the Federal Circuit’s decision should be given effect.” 

Why is Teva concerned?  Because of the failure-to-market 180-day exclusivity forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I), and specifically the “later of” subitem (bb) event.  Under FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA), 180-day exclusivity eligibility can be forfeited on the date that is 75 days after “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” in a patent infringement lawsuit involving the exclusivity-qualifying patent(s) and either a first applicant or any subsequent applicant that has a tentatively approved ANDA for the drug.  “If for any reason, including lack of FDA approval, Teva fails to begin marketing its ANDA product within 75 days of such a Federal Circuit ruling, Teva would forfeit its 180-day period of generic exclusivity,” says the company in its brief.  Pfizer, for its part, says in its reply brief that Teva failed to justify any departure from the court using the language at 35 U.S.C. § 271(e)(4)(A) in an amended judgment.

The court, in its decision granting Pfizer’s motion and denying Teva’s request, says that it was not persuaded that a departure from the statutory language at 35 U.S.C. § 271(e)(4)(A) is warranted. 

Teva points to 21 U.S.C. § 355(j)(5)(B)(iii)(II)(aa) as contemplating an earlier effective date for approval of an ANDA, specifically the date of a subsequent Federal Circuit decision in its favor.  However, 21 U.S.C. § 355(j)(5)(B)(iii)(II) does not seem to be in conflict with 35 U.S.C. § 271(e)(4)(A); indeed, the section goes on to expressly cite 35 U.S.C. § 271(e)(4)(A), stating ‘if the judgment of the district court is not appealed or affirmed, the approval shall be made effective on the date specified by the district court in a court order under [35 U.S.C. § 271(e)(4)(A)].’ . . .  The two statutes seem to be sufficiently harmonized and turn on the outcome of the appeal of the present case.  But 21 U.S.C. § 355(j)(5)(B)(iii)(II) cannot be read to instruct that the court can, let alone should, prospectively impose any effective date for an ANDA under 35 U.S.C. § 271(e)(4)(A) earlier than the one expressly proscribed by statute. [(Emphasis in original)]

While the court notes Teva’s concern about 180-day exclusivity forfeiture, that concern does not, according to the court, provide sufficient reason for the court to depart from the statutory language of 35 U.S.C. § 271(e)(4)(A) – even if the court has discretion to authorize an effective date for ANDA No. 077342 earlier than October 22, 2019.

By Anne K. Walsh –

In what may be a game-changer for drug companies, a court in the District of Columbia has been asked to set forth parameters for a pharmaceutical company that markets its products in a way that the government may consider to be off-label promotion.  Par Pharmaceuticals recently challenged (here and here) FDA’s authority in the off-label promotion arena on First Amendment and Administrative Procedure Act grounds.  Specifically, Par’s action challenges the government’s theories that drugs promoted for unapproved uses are either unapproved “new drugs” based on the statutory definition contained in the Federal Food, Drug, and Cosmetic Act, or “misbranded” drugs, because the drug failed to bear adequate directions for use, sometimes called the “backdoor” new drug charge.   

Par very clearly and accurately describes in its court documents the problems associated with these legal theories, so they are not necessary to reiterate here.  In addition to those challenges, what is unique about Par’s challenge is that it also seeks a declaratory judgment from the court that FDA cannot prosecute Par for making on-label statements about a drug’s approved uses.  Although this seems intuitively logical, Par’s case highlights the overbreadth of FDA’s “intended use” regulations and its authority to regulate speech. 

According to Par, the U.S. Attorney’s Office in the District of New Jersey subpoenaed documents relating to Par’s sales and marketing of its drug, Megace® ES.  Megace® ES is approved only for AIDS patients, to treat anorexia, cachexia or unexplained weight loss (also known as wasting) frequently associated with AIDS patients.  It is more frequently prescribed by physicians, however, for non-AIDS patients who experience wasting, such as cancer and geriatric patients.  Indeed the majority of its sales are to off-label populations.  

In the Complaint, Par details how it purposefully tailored its marketing strategy knowing that the drug was only approved for use by AIDS patients.  Par evaluated the market and decided to talk to doctors in oncology and long-term care settings, not to promote off-label for these patients, but to discuss the on-label treatment of AIDS patients who doctors serve in these settings.  Par determined that these doctors “reasonably may encounter patients suffering from AIDS-related wasting, and thus may have occasion to prescribe Megace® ES for its on-label use.”  Complaint, ¶ 50.  In discussions with Par, the government indicated that Par should have confirmed that there are a “sufficient” number of on-label patients being treated in those settings before Par called on them.  Id. ¶ 71.  Of course as Par correctly notes, there is no guidance provided by the government that defines what is a “sufficient number” to allow Par to have no fear of promoting on-label in those settings.

There are several factors that support a favorable ruling to Par in this action assuming the Court reaches the merits of the dispute.  First, there is practice-based evidence and scientific support of the drug’s efficacy in treating these off-label populations.  Second, there are several authoritative treatment guidelines recommending the off-label use of the drug, including from government agencies like CMS, a sister agency of FDA.  Third, the government determined that the off-label uses are “medically accepted” and reimburses for them from its federal healthcare programs.  Finally, the use of Megace® ES is virtually the standard of care for treating wasting, in AIDS, non-AIDS, geriatric, and oncology patients.  Indeed, this was one of the reasons why it was impossible for Par to develop an appropriate placebo-controlled clinical trial (typically necessary for FDA approval) – as doctors refused to use something other than Megace® ES on their patients.  

This action by Par is just another development in what industry hopes is a restriction on FDA’s authority to prohibit truthful, non-misleading speech.  In the last few months, we have seen the Supreme Court’s decision in IMS Health v. Sorrell, the Citizen Petition filed by the Medical Information Working Group asking FDA for clearer off-label regulations, and supplemental briefs filed in the pending Second Circuit appeal in United States v. Caronia (reported on here).  Because a victory by Par could result in a ruling that certain marketing conduct cannot be prosecuted, many in the industry eagerly await the outcome here.

By Kurt R. Karst –    

Like any good thriller movie that coaxes you into a feeling of finality – right before the surprise twist makes you jump out of your seat – the saga over a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering The Medicines Company’s (“MDCO’s”) ANGIOMAX (bivalirudin) has been a legal thriller for the ages with many surprise twists.  Now there’s a new one . . . . 

As FDA Law Blog readers know, MDCO’s PTE battle has touched all three branches of government throughout the years.  Most recently, Section 37 of the Leahy-Smith America Invents Act (“AIA”) (Pub. Law No. 112-029), titled “Calculation of 60-Day Period for Application of Patent Term Extension” and referred to by some as “The Dog Ate My Homework Act” or the “Medco fix,” amended the PTE statute at 35 U.S.C. § 156(d), and was intended to legislatively resolve MDCO’s PTE battle. 

The inclusion of Section 37 in the AIA was contentious to say the least.  During the Senate’s consideration of the AIA, U.S. Senators Jeff Sessions (R-AL), Tom Coburn (R-OK) and Joe Manchin (D-WV) proposed an amendment to strike Section 37 from the AIA, and sent out a “Dear Colleague” letter urging support for their amendment.  But the amendment failed by a narrow 51-47 vote and Section 37 became law. 

Shortly after the enactment of the AIA, MDCO sent a letter to the U.S. Court of Appeals for the Federal Circuit notifying the Court of the enactment of Section 37 and asserting that it resolves the merits of the ongoing ‘404 patent PTE litigation with APP Pharmaceuticals, LLC (“APP”) (see our previous posts here, here, and here).  APP vigorously disagreed, however, that Section 37 resolved the case, and has argued that Section 37 cannot constitutionally be applied and that Section 37 does not take effect for one year after AIA enactment.  The Federal Circuit ordered MDCO and APP to simultaneously file supplemental briefs addressing the effect of Section 37 of the AIA on the disposition of the case.  Those briefs were filed earlier this week.  Oral argument is scheduled for November 15, 2011.

Now Sens. Sessions and Coburn have reignited their opposition to Section 37.  Earlier this week, they proposed an amendment – SA 812 – to the 2012 Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act (H.R. 2112), intended to effectively nullify Section 37.  SA 812 would add Section 114 to the appropriations bill and states:

Sec. 114. No funds appropriated, or otherwise made available, under this Act may be used by the Director of the United States Patent and Trademark Office to carry out section 37 of the Leahy-Smith America Invents Act (35 U.S.C. 156 note), including the flush sentence added to section 156(d)(1) of title 35, United States Code, by such section 37.

The Sessions/Coburn amendment has received support from the Generic Pharmaceutical Association and Citizens Against Government Waste (“CAGW”).  CAGW sent out a letter to the Senate on October 19th urging support for SA 812.  Other groups may be waiting in the wings to voice their support for the amendment. 

As noted above, the previous amendment failed by a narrow 51-47 vote; however, many of the "nay" votes last time may have been cast to prevent a disruption in the AIA's enactment.  Now separated from patent reform, the vote could change.

We know you’re on the edge of your seats.  Stay tuned for more thrills.

By Kurt R. Karst –   

On October 19, 2011, FDA issued a proposed rule to amend the Agency’s December 29, 1992 (57 Fed. Reg. 62,076) orphan drug regulations.  The proposal is not a whole-scale overhaul of FDA’s orphan drug regulations, but rather a group of amendments “intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since those regulations were issued” and that are based on the Office of Orphan Products Development’s (“OOPD’s”) review of more than 3,350 orphan drug designation requests since December 1992.  FDA’s proposal is the latest development on the orphan drug front.  As we reported last week, the National Organization for Rare Disorders (“NORD”) released a landmark report (authored by Chairman of the NORD Board of Directors and Hyman, Phelps & McNamara, P.C. Director, Frank J. Sasinowski) on the flexibility in FDA’s review of potential treatments for patients with rare diseases.

FDA’s proposed rule addresses 13 specific issues (some of which we touched on earlier this week when we reported on an OOPD Standard Operating Procedures and Policies):

(1)  Demonstration of an appropriate “orphan subset” of persons with a particular disease or condition that otherwise affects 200,000 or more persons in the United States, for the purpose of designating a drug for use in that subset (21 C.F.R. § 316.20(b)(6));

(2)  Eligibility for orphan-drug designation of a drug that is otherwise the same drug for the same orphan indication as a previously approved drug (21 C.F.R. §§ 316.3(b)(3), 316.20(a), and 316.20(b)(5));

(3)  Eligibility for multiple orphan-drug exclusive approvals when a designated orphan drug is separately approved for use in different subsets of the rare disease or condition (21 C.F.R. § 316.31);

(4)  Requirement for demonstrating clinical superiority for the purpose of orphan-drug exclusive approval (21 C.F.R. § 316.3(b)(3)(iii));

(5)  Requirement for submitting the name of the drug in an orphan-drug designation request (21 C.F.R. § 316.20(b)(2));

(6)  Required drug description and scientific rationale in a designation request (21 C.F.R. § 316.20(b)(4));

(7)  Required information in a designation request relating to the sponsor's interest in the drug (21 C.F.R. § 316.20(b)(9));

(8)  Timing of a request for orphan-drug designation (21 C.F.R. § 316.23(a));

(9)  Responding to a deficiency letter from FDA on an orphan-drug designation request (21 C.F.R. § 316.24(a));

(10)  FDA publication of information regarding designated orphan drugs (21 C.F.R. § 316.28);

(11)  FDA recognition of orphan drug exclusive approval (21 C.F.R. § 316.34(c));

(12)  Miscellaneous terminology changes (21 C.F.R. Part 316); and

(13)  OOPD address change (21 C.F.R. § 316.4).    

Below we note some of the proposed changes and clarifications that we think merit special attention.

Demonstration of an “Orphan Subset” of a Disease or Condition.  One element of an orphan drug designation request is to explain the relevant “medically plausible subset” (“MPS”) of individuals (if any) affected by a particular disease or condition that is eligible for a therapy (21 C.F.R. § 316.20(b)(6)).  FDA’s orphan drug regulations do not clearly define the term “medically plausible subset.”  In fact, in the preamble to the 1992 regulations, FDA stated that it “declines to provide examples of medical plausibility or to further develop the definition of [an MPS].  Application of the concept is a matter of judgment based on the specific facts of each case.” 

Recognizing that the term “medically plausible” “has been misinterpreted to mean any medically recognizable or any clinically distinguishable subset of persons with a particular disease or condition,” and that “[i]nappropriate application of the concept of a [MPS] could result in the creation of subsets of non-rare diseases or conditions that are artificially narrow,” FDA proposes to remove the term “medically plausible” in 21 C.F.R. § 316.20(b)(6) “and instead provide a description of how an appropriate subset [(i.e., an ‘orphan subset’)] may be identified for the purpose of orphan-drug designation.”  Specifically, 21 C.F.R. § 316.20(b)(6) is proposed to state:

Where a drug is under development for only a subset of persons with a particular disease or condition that otherwise affects 200,000 or more people, a demonstration that, due to one or more properties of the drug, the remaining persons with such disease or condition would not be appropriate candidates for use of the drug

FDA goes on in the preamble to note that “[w]hen a sponsor has established that the selected population constitutes a non-arbitrary subset, e.g., by describing the scientific or medical basis for limiting the potential use of the drug to that population and demonstrating that such scientific or medical basis is reasonable, the target population is an acceptable orphan subset of persons with the particular disease or condition for the drug of interest.”  FDA also provides some useful examples of what the Agency says are appropriate and inappropriate orphan subsets, and recommends that sponsors ask themselves a few of questions to test whether a subset of patients within a larger disease or condition grouping that has a United States prevalence of 200,000 or more persons can be considered an appropriate orphan subset for purposes of orphan drug designation:

• Is the intended subset artificially restricted in any way with respect to the use of the drug to treat the disease or condition?
• Given that the drug may potentially benefit this particular subset of persons, is there a reasonable scientific or medical basis for believing that the drug would also potentially benefit the remaining population with the non-rare disease or condition or a larger subset of that population?  If not, why not?

Eligibility for Orphan Drug Designation of a Drug That Was Previously Approved for the Orphan Indication.  FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug” (emphasis added).  Over the years, there has been confusion as to how FDA/OOPD interprets the term “orphan drug” in this regulation.  The term is specifically defined at 21 C.F.R. § 316.3(b)(10) to mean “a drug intended for use in a rare disease or condition as defined in section 526 of the act.”  But does this mean that an “orphan drug” is any previously approved drug for a rare disease or condition, regardless of whether or not it was designated and approved as an orphan drug?

FDA states in the proposed rule that “[i]n the absence of a clinical superiority hypothesis, the Agency does not interpret the orphan-drug regulations to permit orphan designation of a drug that is otherwise the same as a drug that is already approved for the orphan use, either where the approved drug received orphan-drug exclusive approval (even after such drug's exclusivity period has run out) or where the approved drug was not previously designated as an orphan drug and thus did not receive orphan exclusive approval” (emphasis added).  Accordingly, FDA proposes to amend certain regulations to delete the word “orphan” in the phrase “approved orphan drug” in order to “clarify that these provisions would be applicable to a drug that is otherwise the same drug as any previously approved drug for the same orphan disease or condition, regardless of whether such drug was designated as an orphan drug” (emphasis in original).

Eligibility for Multiple Orphan-Drug Exclusive Approvals.  For years now, we understand that FDA has adopted a “pie approach” to orphan drug designation, under which a single orphan drug designation can result in multiple periods of orphan drug exclusivity.  That is, an approval for each slice of the pie (i.e., the designation) can result in separate 7-year periods of exclusivity.  As FDA explains in the preamble to the proposed rule:

The scope of orphan exclusive approval for a designated drug is limited to the approved indication or use, even if the underlying orphan designation is broader.  If the sponsor who originally obtained orphan exclusive approval of the drug for only a subset of the orphan disease or condition for which the drug was designated subsequently obtains approval of the drug for one or more additional subsets of that orphan disease or condition, FDA will recognize orphan-drug exclusive approval, as appropriate, for those additional subsets from the date of such additional marketing approval(s).  Before obtaining such additional marketing approval(s), the sponsor in this instance would not need to have obtained additional orphan designation for the additional subset(s) of the orphan disease or condition.

This interpretation is proposed to be included in 21 C.F.R. § 316.31(b).  FDA also notes in the preamble what this interpretation means with respect to clinical superiority and subsetting, stating that:

After approval of the drug for one or more subsets of the orphan disease or condition, a subsequent sponsor may, without submitting a plausible hypothesis of clinical superiority, seek designation of the drug for the subset(s) of the orphan disease or condition for which the drug has not yet been approved.  FDA may designate the drug for use in the remaining subset(s) without requiring a postulation of clinical superiority.  To obtain such a designation, however, the sponsor must demonstrate that, at the time of its designation request, the entire population with the orphan disease or condition, not just the remaining subset(s) of the population, is under the prevalence limit, unless the sponsor can demonstrate that the remaining subset(s) is an orphan subset in accordance with § 316.20(b)(6).

Demonstration of Clinical Superiority.  FDA’s proposal is intended to clarify that merely because FDA/OOPD has granted orphan drug designation based on a plausible hypothesis of clinical superiority does not mean that clinical superiority has been demonstrated and the orphan drug can be approved or approved with a period of 7-year exclusivity.  FDA states in the preamble to the proposed rule that:

It is possible . . . that a sponsor that has obtained designation of its drug on the basis of a hypothesis that the drug will be clinically superior will be unable, upon submission of the marketing application, to demonstrate that the drug is clinically superior to the previously approved drug.  In that case, if the already approved drug has remaining exclusive approval, the subsequent drug would not itself be eligible for approval, because it is the same drug as the drug with exclusive approval.  If the approved drug does not have exclusive approval, the subsequent drug may be approved, but would not itself be eligible for orphan-drug exclusive approval.

FDA also states with respect to the “major contribution to patient care” (the so-called “MC-to-PC”) basis for clinical superiority (see our previous post here) that:

a drug that is otherwise the same drug as a previously approved drug, and for which a clear showing of greater effectiveness or greater safety has not been made, may still be considered clinically superior within the meaning of § 316.3(b)(3)(iii) if it makes a major contribution to patient care.  FDA believes that such clinical superiority is meaningful only when the subsequent drug provides safety or effectiveness comparable to the approved drug.  For example, to claim that a drug makes a major contribution to patient care through a new formulation or a different route of administration, the sponsor must also address whether the change renders the drug less safe or less effective than the approved drug.  (Emphasis added)

Timing of Request for Orphan-Drug Designation.  FDA’s proposal would amend 21 C.F.R. § 316.23(a) to clarify the timing of an orphan drug designation request.  According to FDA, “[i]t is not clear in the current regulatory language that one sponsor’s marketing application would not prevent a different sponsor from submitting a request for orphan designation for the same drug for the same orphan use and that this subsequent sponsor would not have to submit a plausible hypothesis of clinical superiority.” 

The proposed revisions to 21 C.F.R. § 316.23(a) would not only clarify that a sponsor may not submit an orphan drug designation request after the submission of a marketing application for the drug for the rare disease or condition, but also that “submission by a sponsor of a marketing application for the drug for the orphan indication does not prevent another sponsor from submitting a request for orphan designation of the same drug for the same orphan use.”  However, “[o]nce any sponsor’s marketing application for the orphan indication has been approved, with or without orphan exclusive approval, another sponsor may not obtain orphan-drug designation for the same drug and the same orphan indication or use for which the approval was granted absent a plausible hypothesis of clinical superiority.”

Responding to a Deficiency Letter From FDA on an Orphan Drug Designation Request.  Noting that “FDA regulations are currently silent on when sponsors must respond to a deficiency letter from FDA on an orphan-drug designation request,” and that while some sponsors respond promptly to deficiency letters, other sponsors “may take several years or more to respond without sending any interim communication to FDA,” the Agency proposes to amend 21 C.F.R. § 316.24 to require that sponsors respond to a deficiency letter within 1 year after issuance, unless the sponsor requests (in writing) an extension of time to respond within the 1-year period.  “Such a request would specify both the reason(s) for the requested extension and the length of time of the requested extension,” says FDA.  According to FDA, a “repeat request” for an extension may be granted if the sponsor submits a new extension request before expiration of the deadline as originally extended, and if such request states both the reason(s) for the request and the requested length of time of the extension.

In the event a sponsor fails to respond to a deficiency letter, fails to request an extension
of time within a year, or if FDA denies an extension request, the Agency says that it may consider the designation request voluntarily withdrawn.  FDA notes in the proposal that the Agency “will grant all reasonable requests for an extension”; however, FDA goes on to state that:

some deficiencies may be less suitable to extension requests than others.  For example, FDA generally expects that deficiencies involving an inaccurate or incomplete prevalence estimate will be readily addressed within 1 year.  Other types of deficiencies, however, may take longer to address.  For example, deficiencies involving the scientific or medical rationale supporting a designation request for only a subset of persons with a particular disease or condition may require sponsors to conduct research and develop additional data, which may take several years or more.  For the latter types of deficiencies, FDA generally anticipates granting extension requests to allow sponsors to develop necessary supporting data and information.

Electronic or written comments on the proposed rule (Docket No. FDA-2011-N-0583) are due by January 17, 2012.

By Jennifer D. Newberger –

On October 14, 2011, Representative Brian Bilbray (R-CA) introduced H.R. 3203, the “Novel Device Regulatory Relief Act of 2011.”  This bill intends to amend section 513(f) of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to expedite the process for requesting de novo classification of a device.  The de novo review process is a compromise between the 510(k) clearance process and the more rigorous premarket application (“PMA”) approval process, generally reserved for higher risk devices.  It was added to the FDC Act to address novel devices that lack a predicate device but pose only a low to moderate risk, making them ill-suited to the PMA process.

Unfortunately, the current statutory requirements for the de novo process make it difficult and burdensome for both industry and FDA.  The statute currently requires that, before submitting a petition for de novo classification to classify a device into class I or II, the manufacturer must submit a 510(k) notification to FDA and await a determination that the device is not substantially equivalent (“NSE”) and therefore classified into class III, even if the manufacturer knows there is no appropriate predicate. 

Representative Bilbray’s proposal would eliminate this often unnecessary step by allowing a request “without regard to whether such person has received written notice of classification into class III . . . .”  In other words, if a manufacturer knows there is no appropriate predicate for a proposed moderate- to low-risk device, the manufacturer could skip the 510(k) process and submit a de novo petition first.  Of course, it would probably be desirable for the manufacturer to have an understanding with FDA that a de novo petition is the best approach.  Thus, there will be a need for advance discussions.  Nonetheless, this simple change would give FDA more flexibility.

This provision should be non-controversial, and acceptable to both industry and FDA.  As discussed in our previous blog post, FDA recently issued a Draft Guidance revising the de novo classification process in an attempt to make the process more efficient.  Given the current statutory language, however, FDA was constrained to continue to require a 510(k) filing.  Representative Bilbray’s language would do away with this requirement, potentially making the de novo process more appealing to both FDA and industry.

By Cassandra A. Soltis –

Earlier this year, we reported on the Interagency Working Group’s (“IWG’s”) proposed voluntary principles for marketing food to children.  The IWG includes representatives from the Federal Trade Commission (“FTC”), the Centers for Disease Control and Prevention, the Food and Drug Administration, and the United States Department of Agriculture (“USDA”).  As a result of comments the IWG received from stakeholders, it now appears that the proposed voluntary principles will be significantly modified. 

In recent testimony before the House Energy and Commerce Committee’s Subcommittee on Health and Subcommittee on Commerce, Manufacturing, and Trade, the FTC’s David Vladeck, Director of the Bureau of Consumer Protection, stated that consumer and public health advocates “strongly supported the proposal as one that would significantly improve the nutritional profile of foods marketed to children.”  In contrast, the “common theme of industry . . . was that the proposal was simply unworkable and should be withdrawn.”  However, the Council of Better Business Bureau’s Children’s Food and Beverage Advertising Initiative ("CFBAI"), which currently has 17 member companies, did submit its own nutrition principles to the IWG for consideration. 

The “anticipated revisions” to the voluntary principles are apparently intended to “address industry’s concerns” and overlap somewhat with the CFBAI’s nutrition standards.  Some of the changes include revising the marketing activities that fall within the scope of children’s media to those “used most extensively to specifically target children ages 2 to 11,” which would exclude adolescents ages 12 to 17, except for certain in-school marketing activities.  In addition, the criteria for determining whether marketing is directed to children would be modified so that they “are flexible enough to be neither over-inclusive – covering marketing to a general or family audience – nor under-inclusive – leaving out marketing that is clearly targeted to children.”

So why the change of heart?  Perhaps the FTC is having flashbacks from its unsuccessful “Kidvid” rulemaking, in which the Commission’s efforts to ban certain television advertisements directed to children ultimately resulted in Congress passing a law withdrawing the FTC’s authority to regulate advertising to children as unfair.  (The FTC retains the authority to take action against deceptive advertising to children, however.)  In addition, Congress allowed the FTC’s funding to lapse, which caused the agency to temporarily shut down.  (An FTC article provides an excellent overview of the Kidvid matter.)

The proposed revisions described in Mr. Vladeck’s testimony “are recommendations contemplated by the Working Group and have not yet been formally approved by the member agencies.”  The Commission will vote on the IWG’s report, provide it to the Department of Health and Human Services and USDA for final approval, and then submit it to Congress as directed in the accompanying statement to the 2009 Omnibus Appropriations Act.

By Susan J. Matthees –

We recently learned that on August 30, 2011, Philadelphia petitioned FDA pursuant to FDC Act § 403A(b) to request that FDA exempt Philadelphia from federal menu labeling requirements.  As far as we know, this is the first petition for an exemption from federal menu labeling requirements. 

As you may recall, section 4205 of the Patient Protection and Affordable Care Act of 2010 implemented FDC Act §403(q)(5)(H), which requires certain restaurants and vending machines to disclose nutrition information.  The law also amended FDC Act § 403A to preempt any state or local menu labeling requirements not identical to federal menu labeling requirements, unless the state or local government successfully petitions FDA for an exemption.  The city of Philadelphia enacted its own menu labeling requirements in 2008, and in the petition asks FDA for an exemption from FDC Act § 403A so that the city can continue to use its current menu labeling requirements. 

According to the petition, Philadelphia’s labeling requirements are “in large part consistent” with federal requirements, but Philadelphia’s ordinance requires more nutrition information to be displayed directly on the menu than federal law.  Philadelphia’s ordinance requires the amount of calories, sodium, saturated fat, trans fat, and carbohydrates to be listed on the menu, whereas federal law requires only calories to be included on the menu.  Under federal law, information on sodium, saturated fat, trans fat, carbohydrates, and other nutrients must be included in written form and made available upon request.  Philadelphia argues that providing nutrition information on the menu is the “only effective means” of communicating nutrition information to consumers. 

Philadelphia believes that by providing information on calories only, the federal law does not adequately address the city’s “public health crisis.”  The city is particularly concerned about requiring disclosure of the amount of sodium in foods.  According to the petition, Philadelphia County has the highest prevalence of hypertension and cardiovascular disease among the counties that contain one of the 10 largest US cities.  Citing studies detailing harmful effects of excess sodium consumption, Philadelphia argues that disclosing the amount of sodium directly on menus is necessary to reduce sodium consumption and a “vital tool to combat the high rates of hypertension, heart disease, and stroke” in Philadelphia.  Although the city acknowledges mixed success for menu labeling (see our previous post here), the petition cites some studies that have shown that nutrition labeling has a positive impact on consumer’s choices as hope that Philadelphia’s menu labeling requirements will influence consumers to chose lower sodium foods. 

In a clever move, Philadelphia uses FDA’s own initiative to reduce sodium to argue for the city’s menu labeling ordinance.  As we reported last month, FDA and FSIS are seeking information on issues related to reduction of dietary sodium.  Philadelphia offers its menu labeling as an opportunity to study sodium disclosure as a means to reduce sodium consumption.  Because Philadelphia is the only community in the nation that requires sodium information to be included on menus, the city argues that it provides a unique opportunity to study how disclosing information on sodium impacts overall consumption, and therefore should be granted an exemption.

By William T. Koustas –

We have previously reported (here, here, here, and here) on the court struggle in the United States District Court for the District of Columbia (“the Court”) between FDA and Regenerative Sciences, Inc. (“Regenerative”).  Regenerative challenges FDA’s claim that the company’s stem cell procedure is subject to FDA jurisdiction and regulation under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and/or the Public Health Service Act (“PHSA”) as an unapproved drug and/or biologic.  Regenerative has developed a procedure in which stem cells are isolated from a patient’s bone marrow, undergo an expansion in a laboratory and are then returned to the patient’s site of injury to treat musculoskeletal and spinal injuries (“Regenexx Procedure”).  Perhaps most interesting is the Government’s new argument that the Regenexx Procedure is subject to regulation by FDA because it involves interstate commerce.   

After Regenerative’s February 2009 lawsuit against FDA was dismissed, the Government sued Regenerative in June 2010 after FDA issued a Form 483 concerning an inspection of Regenerative’s Colorado facility.  Our previous blog entries on this case have additional discussion on its procedural background.  In our last post on this case in January, we discussed the Government’s motions for summary judgment and to dismiss Regenerative’s counterclaims.  Several documents have been filed in this case since that time, including Regenerative’s brief opposing the Government’s motion to dismiss in April 2011, the Government’s reply brief in support of its motion for summary judgment in August 2011, and Regenerative’s surreply in opposition to the Government’s motion for summary judgment in August 2011.  The Government responded to a show cause order in September 2011, and Regenerative recently filed its own response to that order in October 2011.

In its motion to dismiss, the Government claims that it is not attempting to regulate the practice of medicine, but rather, FDA is regulating the manufacturing of a drug product.  The Government further argues that Regenerative’s claim that the statements regarding minimal manipulation in the preamble of FDA’s HCT/P should have been subject to notice-and-comment rulemaking is without merit since the statements were only in the rule’s preamble and not part of the rule itself.  A fuller discussion of FDA’s HCT/P rule as it pertains to this case can be found in our last blog post.  Regenerative’s filing opposing the Government’s motion to dismiss argues that FDA is indeed attempting to regulate the practice of medicine.  Regenerative asserts that the Government cannot define what is and what is not the practice of medicine when it does not have the jurisdiction to regulate the practice of medicine to begin with and points out that Colorado’s definition of the practice of medicine is much broader than the Government’s definition.  Regenerative also argues that the U.S. Supreme Court has thwarted a prior Government attempt to define the practice of medicine in Gonzales v. Oregon, 546 U.S. 243 (2005).  Regenerative argues that the preamble statements regarding minimal manipulation in FDA’s HCT/P rule are part of the substantive rule and should have been implemented through notice-and-comment rulemaking. 

In its reply brief in support of its motion for summary judgment, the Government reasserts its argument that the cultured stem cells used in the Regenexx Procedure are drugs as defined in the FDCA and therefore subject to FDA approval.  The Government further argues that, although Colorado’s definition of the practice of medicine is fairly broad, it does not address the ability of a physician to produce a drug product which is regulated by FDA.  The Government further reiterates its view that Regenerative’s legal challenges to the HCT/P rule, including whether the statement regarding minimal manipulation should have been subject to notice-and-comment rulemaking, are time barred as we described in our previous blog post. 

The Government also argues that, as a drug, Regenerative’s stem cells are within FDA’s jurisdiction as they affect interstate commerce despite the fact that the Regenexx Procedure is done entirely in Colorado.  First, the Government asserts that the stem cells fall within the scope of interstate commerce since Regenerative obtains “components” to manipulate the stem cells from outside of the state.  Second, and most amazingly, the Government argues that interstate commerce is substantially affected because individuals traveling to Colorado to have the Regenexx Procedure would “depress the market for out-of-state drugs that are approved by FDA.”  This interpretation of interstate commerce appears to be new ground for the FDA.  In fact, it appears to be a novel interpretation of the FDCA, as is evidenced by the Government’s failure to cite any judicial precedent for their argument.  If this interpretation were to be accepted by the Court, we have difficulty envisioning that FDA would admit that any food, drug, device, biologic, or cosmetic product is not subject to FDA’s jurisdiction. 

In its surreply brief opposing the Government’s motion for summary judgment, Regenerative continues to argue that its physicians are engaged in the practice of medicine as defined by Colorado law and therefore outside of the jurisdiction of FDA.  Regenerative’s brief further suggests that FDA does not have jurisdiction to regulate the Regenexx Procedure even if it were considered a drug because it does not substantially affect interstate commerce as the procedure is entirely done in Colorado and does not have a national market.  While the Government seeks to counter this argument by broadly interpreting interstate commerce to include depressing the interstate drug market, Regenerative argues that such a broad interpretation of interstate commerce would allow FDA to regulate a medical procedure based on its ability to depress the interstate drug market.  This, Regenerative asserts, would clearly lead to the FDA regulation of any and all medical procedures and the practice of medicine as a whole.

More recently, the Court issued an order to show cause for the Government to demonstrate why it should not read the definition of device in the FDCA as informing and restricting the definition of drug.  The Court notes that the FDCA defines device as “an article used in the diagnosis, cure, mitigation, treatment or prevention of disease, 21 U.S.C. § 321(h)(2), but which, presumably unlike a drug, ‘does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes’ 21 U.S.C. § 321(h).”  Based on this definition, the Court asked the Government why it should “not interpret the meaning of the word ‘drug’ to include not only an article for use in diagnosis, etc., and intended to affect the structure and function of a patient, but also an article that ‘achieve[s] its primary intended purposes through chemical action’ and which is ‘dependent upon being metabolized for the achievement of its primary intended purposes.’” 

The Government’s memorandum in response to the order to show cause essentially argues that there is nothing in the FDCA, or its legislative history, that suggests the definition of drug be narrowed as contemplated in the show cause order.  The Government asserts that by the FDCA “….implicitly recognizing that drugs often work through chemical or metabolic action and specifying that devices may not work through [such action] is not the same as mandating that all drugs must be shown to work through chemical or metabolic action.”  The Government also claims that the definition of the term drug as described in the show cause order would be contrary to decades of legal precedent.  Regardless, the Government asserts that the Regenexx Procedure works through chemical action, thus making it a drug under the Court’s proposed narrower definition of drug. 

In its response memorandum, Regenerative argues that, contrary to the Government, its review of the legislative history of the definition of device demonstrates that Congress did in fact intend that it “inform and restrict” the definition of drug.  It asserts that the fact that Congress wrote a new definition of device to exempt medical devices from the definition of drug effectively restricts the definition of drug.  As such, Regenerative argues, Congress intended to “inform and restrict” the definition of drug through the definition of device.  Regenerative also pushed back on the Government’s assertion that the Regenexx Procedure works through chemical action thereby causing it to be a drug, noting that there are many medical treatments that consist of living cells that are not considered drugs (e.g., blood transplants, organ transplants, etc.). 

The Government is expected to file a brief to Regenerative’s response to the show cause order by October 24, 2011.

By Kurt R. Karst –      

A Standard Operating Procedures and Policies (“SOPP”) prepared and used by FDA’s Office of Orphan Products Development (“OOPD”) for the review of orphan drug designation requests was recently made public and provides some interesting (and helpful) insight into OOPD’s policies.  Of particular interest are several of the appendicies to the SOPP, including Appendix B (“Scientific Rationale Supporting a Request for Orphan Drug Designation”), Appendix C (“Medically Plausible or Orphan Subsets Supporting a Request for Orphan Drug Designation”), Appendix D (“Lymphoma as the Subject of a Request for Orphan Drug Designation”), and Appendix E (“Recombinant Products and Orphan Drug Designation”).  While we have seen the policies described in the SOPP implemented in product-specific sponsor correspondence (or know them through OOPD designation precedent), never before have we seen them discussed in a more general policy document like the SOPP.

Scientific Rationale Supporting a Request for Orphan Drug Designation – FDA’s orphan drug regulations at 21 C.F.R. § 316.20(b)(4) require that a designation request contain “[a] description of the drug and a discussion of the scientific rationale for the use of the drug for the rare disease or condition, including all data from nonclinical laboratory studies, clinical investigations, and other relevant data that are available to the sponsor, whether positive, negative, or inconclusive.”  FDA may refuse to grant designation on the basis that “[t]here is insufficient information about the drug, or the disease or condition for which it is intended, to establish a medically plausible basis for expecting the drug to be effective in the prevention, diagnosis, or treatment of that disease or condition” (21 C.F.R. § 316.25(a)(2)). 

In describing what constitutes an adequate scientific rationale for the use of the drug for the rare disease or condition when applying for orphan drug designation, the SOPP states that while “OOPD will accept data from clinical investigations as providing the strongest rationale for establishing a medically plausible basis for expecting the drug to be effective in the prevention, diagnosis, or treatment of the disease or condition,” animal data may also be acceptable.  According to OOPD:

[A]s evidence of a medically plausible basis for expecting the drug to be effective in the rare disease under consideration, OOPD requires sponsors seeking orphan drug designation to provide sufficient information about the drug from in vivo studies in a relevant animal model of the disease or from clinical studies in patients with the rare disease or condition treated with the drug.  Please note, the data must be generated from in vivo studies in a relevant animal model of the disease or from clinical studies in patients with the rare disease or condition in which the animals and/or patients are treated with the active moiety that is the subject of the orphan drug designation request.  In the absence of human data and when no animal model of the disease exists, OOPD may consider alternatives that include in vitro data, a description of the mechanism of action of the product, and the pathogenesis of the disease or condition. [(Emphasis in original)]

Medically Plausible or Orphan Subsets Supporting a Request for Orphan Drug Designation – One element of an orphan drug designation request is to explain the relevant “medically plausible subset” (“MPS”) of individuals (if any) affected by a particular disease or condition that is eligible for a therapy (21 C.F.R. § 316.20(b)(6)).  The orphan drug designation process has been designed to ensure that MPSs are groups of patients with special requirements or characteristics that distinguish them from the larger disease grouping.  Although a product may have a beneficial effect on the entire group of individuals with a particular disease or condition, to be designated as an orphan drug, the product must be able to treat a disease or condition that is distinguished in some aspect from the larger disease or condition.  FDA’s orphan drug regulations do not clearly define the term “medically plausible subset.”  In fact, in the preamble to the regulations, FDA states that it “declines to provide examples of medical plausibility or to further develop the definition of [an MPS].  Application of the concept is a matter of judgment based on the specific facts of each case” (57 Fed. Reg. 62,076, 62,081 (Dec. 29, 1992)). 

OOPD’s SOPP takes a stab at defining an MPS:

A "Medically Plausible or Orphan Subset" of a more common disease or condition is defined by some characteristic of the drug or biologic that would limit its use to this subset of the disease or condition and would make the drug or biologic ineffective or too toxic to use in the complement of the subset of the disease or condition.  Examples of such characteristics would include mechanism of action of the drug or biologic or toxicity profile of the drug or biologic.  It is the policy of the Office of Orphan Products Development to apply this definition when faced with a request for orphan drug designation that targets a rare subset of a common disease or condition.

Lymphoma as the Subject of a Request for Orphan Drug Designation – What constitutes the disease or condition when the subject of a request for orphan drug designation is lymphoma?  That’s the question OOPD’s SOPP answers in Appendix D.  “At the crux of the issue,” says OOPD “is the question of ‘What is the disease?’”  The answer to this question has apparently changed over time.

Historically, OOPD has answered this question in different ways as the times have changed: it began with ‘lymphoma’; then was ‘Hodgkin’s disease and non-Hodgkin’s lymphoma” and subsequently progressed to “Hodgkin’s disease, non-Hodgkin’s B-cell lymphoma, non-Hodgkin’s T-cell lymphoma or non-Hodgkin’s null-cell lymphoma.”  With each iteration of OOPD nosology, sponsors were required to meet the statutory prevalence criteria for the disease terms that were put into effect.

As of the effective date of the SOPP – November 9, 2010 – OOPD says that the Office was “at a juncture where further splitting in the disease entities is well recognized by the medical community, and the terms ‘B-cell lymphoma’ and ‘T-cell lymphoma’ are thought not to be ‘diseases’ but rather to be agglomerations of distinct disease entities.”  To cut to the chase, OOPD states that the Office “recognizes the current [World Health Organization] classification of lymphomas as stipulating the diseases of record.” 

Recombinant Products and Orphan Drug Designation – The final appendix to the SOPP delves into the murky area of orphan drug “sameness” and “clinical superiority.”  (Clinical superiority is at the heart of one pending citizen petition – Docket No. FDA-2011-P-0213.)  FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan-drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug.”  FDA’s orphan drug regulations define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways:

(a) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;
(b) greater safety in a substantial portion of the target population; or
(c) demonstration that the drug makes a major contribution to patient care.

With respect to the clinical superiority of recombinant products over tissue-derived products when determinations of orphan drug “sameness” are being considered, OOPD states in the SOPP that:

OOPD will adopt the policy that products of recombinant origin are inherently superior to those of human origin because they are safer regarding person-to-person transmission of infectious agents.  It is recognized that such safety may in fact be only theoretical safety, that is, OOPD would not require evidence of infectious disease transmission with a human-derived product in order to establish the superiority of a corresponding recombinant product.  Rather, it is acknowledged that current understanding may not include all potential agents of human disease; accordingly, this epistemological limitation may prevent the institution of processing procedures that render products free from agents not yet discovered.  This policy, that recombinant products are inherently superior, is a conservative judgment based on a lengthy history of medical iatrogenesis coincident to the use of human-derived products.  But it is acknowledged to be a judgment, and not founded on contemporary data.

The concept of “inherent clinical superiority” has also shown up in other places.  For example, in 1997, FDA determined that BENEFIX (coagulation factor IX) was clinically superior to MONONINE and ALPHANINE (both coagulation factor IX products) based on the fact that “BeneFix™ is inherently less likely to transmit human blood-born viruses and other infectious agents, and is also less likely to transmit animal-derived zoonotic agents.”  

In addition to the policies discussed above, the SOPP provides other helpful information, such as for purposes of documenting cancer prevalence “[t]he Surveillance, Epidemiology, and End Results program (SEER) database maintained by the National Cancer Institute has been adopted as OOPD’s standard source for cancer prevalence information.”  The SOPP also states OOPD’s “3 expert policy” for purposes of documenting disease/condition prevalence when medical literature does not yield prevalence information.  “In the event a search of the medical literature reveals no adequate sources of prevalence of a disease or condition,” says the SOPP, “the sponsor may enlist the statements of three independent experts in the disease in question.  These experts must provide an estimate of the prevalence of the disease or condition with a detailed reasoning or method by which they arrived at their aforementioned estimate.  All experts contacted must be identified by the sponsor if using this method.”