By Riëtte van Laack –

On October 21, 2008, the National Resource Defense Council (“NRDC”) petitioned FDA to issue a regulation to prohibit the use of Bisphenol A (“BPA”) as a food additive.

Currently, BPA is approved as a chemical for use in the production of polycarbonate polymers and epoxy-based enamels and coatings.  See, e.g., 21 C.F.R. §§ 175.300(b)(3)(viii), 177.1440, 177.1580,and 177.2280.  The safety assessments concerning the use of BPA date from the 1960s.  These safety evaluations focused on carcinogenicity and on genetic toxicity as an indicator of carcinogenicity.  However, recent research has raised concerns about the potential effects of BPA on the endocrine system. 

The release, in 2007, of two government sponsored reviews of BPA has resulted in a debate about the safety of residues of BPA in food contact substances.  Based on its review of existing data, the National Toxicology Program (“NTP”) concluded that there was “minimal concern” about the reproductive and developmental effects of BPA. In contrast, in the “Chapel Hill” report, a group of 38 experts raised serious concerns about the safety of BPA.  In August 2008, based on these reports, amendments thereto, and additional sources of information, FDA determined in its draft safety assessment that “an adequate margin of safety exists for BPA at current levels of exposure from food contact uses.” 

NRDC disagrees with FDA’s draft safety assessment, which NRDC claims relied on two-industry funded studies.  According to NRDC, “in light of the data suggesting that BPA is harmful to human health, and in response to well-founded concerns of experts in the field, FDA must prohibit BPA from use in food and food packaging [and] revoke all regulations permitting the use of any food additive that results in BPA becoming a component of food.”

NRDC’s petition was submitted shortly before a subcommittee of the FDA Science Board Advisory Committee released its review of FDA’s draft safety assessment.  The subcommittee also disagreed with FDA’s draft safety assessment and concluded that the margins of safety for BPA are inadequate.  However, the subcommittee indicated that “this does not mean that exposures are not acceptable.”  According to the subcommittee, the acceptability of exposures is a question of policy, and this decision lies with FDA. 

In response to the subcommittee review, FDA acknowledged in a statement the existence of “uncertainties” about BPA and that “additional research would be valuable.”  The Agency is “moving forward with [additional] research to address the potential low dose effects of [BPA].”  FDA’s statement also pointed to “the present consensus among regulatory agencies in the United States, Canada, Europe, and Japan . . . that current levels of exposure to BPA through food packaging do not pose an immediate health risk.”

By Diane B. McColl & Ricardo Carvajal –

On December 15, Cargill issued a press release in which it announced a “broad-based national integrated marketing campaign” to promote its sweetener Truvia™ (Truvia™ is Cargill’s preparation of rebiana, or rebaudioside A, one of the sweetening components that can be extracted from Stevia rebaudiana). According to Cargill, “the tabletop version of Truvia™ natural sweetener is now available nationwide, wherever groceries are sold.”  Previously, Cargill had filed a voluntary GRAS notification with FDA (GRN #253) setting out Cargill’s determination that its rebiana is safe for use as a general purpose sweetener.  FDA has yet to respond to that notification.

Under § 201(s) of the Federal Food, Drug, and Cosmetic Act ("FDC Act"), many food ingredients are not subject to approval and regulation by FDA as food additives if the use of those ingredients in foods is generally recognized, among experts qualified by scientific training and experience to evaluate their safety, as having been adequately shown through scientific procedures or common use in foods, to be safe under the conditions of their intended use.  Self-determination that the use of an ingredient is GRAS can be made independent of FDA, and requires neither FDA approval nor FDA notification.  Use of a self-determined GRAS ingredient carries with it the risk that FDA will disagree with the self-determination of GRAS status and take action against the substance as an unapproved food additive.  For this reason, potential users often demand that ingredient developers voluntarily notify FDA of their GRAS self-determinations.  If FDA has no questions about the notifier’s GRAS determination, FDA issues a letter stating so (a so-called “no questions” letter).  A notifier can accept the risk that FDA will disagree with its notified GRAS determination, and proceed to market without first receiving a “no questions” response letter from the agency. 

In the case of Stevia-derived sweeteners, proceeding to market without a GRAS notice “no questions” letter from FDA may carry some added risks.  As recently as August 2007, FDA issued a warning letter to the manufacturer of a tea product in which the agency took the view that Stevia rebaudiana is an unapproved food additive that renders a food adulterated under FDC Act § 402(a)(2)(C).  Additionally, the Center for Science in the Public Interest ("CSPI") issued its own press release on December 15, the same day as the Cargill press release, in which it contends that additional tests are needed to demonstrate the safety of Stevia and rebaudioside A, and that “FDA should immediately order those products off the market until all the safety testing has been done.”  Also, there is pending before the agency a citizen petition contending that the addition of steviol glycosides (the sweetening components that can be extracted from Stevia) to food is prohibited by FDCA § 301(ll) (see Docket No. FDA-2008-P-0542).

By Ricardo Carvajal & John R. Fleder –

At the invitation of the U.S. Supreme Court, the federal government has recently filed a brief as amicus curiae in the case of Albertson’s, Inc. v. Kanter (No. 07-1327) in which the government argues against preemption of California law.  The case was brought by California consumers of farmed salmon who alleged that grocers engaged in false advertising and unfair and deceptive trade practices (among other things) when they failed to disclose the presence of color additives in their salmon, in alleged violation of California’s Sherman Food, Drug, and Cosmetic Law (“Sherman Law”).  The Sherman Law sets out food labeling requirements that are identical to those imposed under federal law.  Albertson’s argued that federal law preempts the private lawsuit brought by consumers under the Sherman law.  The trial court agreed and dismissed the lawsuit on preemption grounds.  That dismissal was upheld by the California Court of Appeal, but reversed by the California Supreme Court (see out previous post here).  Albertson’s then filed a petition for a writ of certiorari with the U.S. Supreme Court, which prompted a request by the Court for the Solicitor General’s views on the matter.

In part, the government’s brief argues that the language of FDC Act § 403A “strongly suggests” that States are free to adopt requirements identical to federal requirements, and notes that NLEA section 6(c)(1) explicitly limits the preemptive effect of the NLEA.  The federal government further argues that nothing in § 403A suggests Congressional intent to “limit the States’ authority to prescribe the remedies for violations of the state requirements permitted by [section 403A].”  For support, the brief draws on the Court’s prior holdings interpreting other FDC Act statutory provisions in Medtronic, Inc. v. Lohr, Riegel v. Medtronic, Inc., and Bates v. Dow Agroscience LLC.

The government also argues in its brief that the California action is not preempted by FDC Act § 310, which provides that proceedings for enforcement, or to restrain violations, of the FDC Act must be by and in the name of the U.S. (with the exception of certain actions brought by States in conformance with certain procedural requirements).  According to the government, “[a]ctions to enforce state laws that impose requirements identical to those under the FDCA are not actions to enforce the FDCA itself.”  The government’s brief further argues that this section does not preempt state law claims that “parallel” FDC Act requirements.  Moreover, the federal government stated that even when state-law claims are predicated on violations of the FDC Act, they remain state-law claims that are not preempted by federal law.

The accolades keep rolling on in . . . .  

USPharmD has named the FDA Law Blog one of the “Top 50 Medical Ethics Blogs.”  According to them, we will help you “[s]tay on top of current legal issues in the medical field.”  And all this time we were just trying to spell the big words correctly.

The USPharmD top blogs list is the second such list we’ve made in the past few months.  In September, RNCentral.com named FDA Law Blog to their “100 Best Health Care Policy Blogs.”

By Ricardo Carvajal –  

According to a recently-issued Letter to Manufacturers, FDA “feels it is imperative to remind its constituents that front-of-package symbols can at times constitute nutrient content claims” that are subject to FDA’s regulatory requirements at 21 C.F.R. 101.13 and Subpart D of Part 101.  A nutrient content claim is one that expressly or impliedly characterizes the level of a nutrient in a food (e.g., low fat, 100 calories).  Manufacturers are making increasing use of front-of-package symbols to convey information about the nutritional attributes of their products in a simplified, consumer-friendly format.  FDA has been aware of the trend, and held a public hearing on the subject in 2007.  But it appears that some manufacturers have been making express or implied nutrient content claims without adhering to the regulatory requirements that attach to such claims.  FDA states that it “will notify manufacturers when we see any front-of-package symbols that are explicit or implied nutrient content claims that are not consistent with current requirements or where such front-of-package symbols are used in a manner that is false or misleading.”  Although not noted in FDA's letter, it is permissible to include a statement in labeling about the amount or percentage of a nutrient present in a food if the conditions specified in 21 C.F.R. 101.13(i) are met. 

By Kurt R. Karst –      

Earlier today, by a five-to-four vote, the U.S. Supreme Court ruled against preemption in Altria Group, Inc. Good, the so-called “light cigarette” case.  Background on the case is available via the SCOTUS Wiki. 

The respondents in the case (i.e., Good et al) alleged that Altria violated the Maine Unfair Trade Practices Act by fraudulently advertising their cigarettes as “light” and “low in tar and nicotine.”  The U.S. District Court for the District of Maine dismissed the lawsuit on preemption grounds, finding the Maine law preempted by the Federal Cigarette Labeling and Advertising Act (“FCLAA”).  In August 2007, however, the U.S. Court of Appeals for the First Circuit reinstated the lawsuit, holding that the FCLAA neither expressly nor impliedly preempts the respondents’ fraud claim.  In ruling that neither the FCLAA, nor actions in this field by the Federal Trade Commission in Commission dating back to 1966 preempted respondents’ state law fraud claim, the Supreme Court has effectively cleared the way for smokers to file lawsuits to challenge deceptive cigarette marketing. 

This ruling could have an impact on the FDA preemption cases now before the Court; namely that small case everyone is watching – Wyeth v. Levine.

By Kurt R. Karst –      

We previously reported on concerns as to whether a company submitting an ANDA (or a 505(b)(2) application) containing the results of an in vivo bioequivalence study must certify on Form FDA 3674 that new Public Health Service Act (“PHS Act”) § 402(j), as added by Title VIII of the FDA Amendments Act (“FDAAA”), applies and that in vivo bioequivalence studies  have been registered at ClinicalTrials.gov.  Specifically, it has been unclear whether an in vivo bioequivalence study is an “applicable drug clinical trial” subject to the PHS Act § 402(j) databank registration requirements.  PHS Act § 402(j)(1)(A) defines an “applicable drug clinical trial” to mean “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .” (emphasis added).   In September 2008, the Generic Pharmaceutical Association (“GPhA”) sent a letter to Representative John Dingell (D-MI) expressing concern “that FDA will incorrectly interpret the statute to include bioequivalence studies as ‘applicable drug clinical trials,’” and strongly urging that Congress “amend the definition of ‘applicable drug clinical trial’ at PHS Act § 402(j)(1)(A)(iii) to specifically exclude bioequivalence studies.”

Earlier this month, a draft document was posted on the ClinicalTrials.gov FDAAA website elaborating on the applicability of the FDAAA Title VIII requirements to bioequivalence studies.  (The draft guidance also discusses the term “applicable clinical trial” generally as it applies to drugs – including biological products – and medical devices, and the term “responsible party” for purposes of the entity or individual responsible for registering and submitting clinical trial information to the clinical trials registry data bank.)  According to the draft guidance:

In the agency’s view, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) is considered to be a controlled clinical investigation. In this case, the control generally would be the previously approved drug product.

Although a bioequivalence study is a controlled clinical investigation, the draft guidance goes on to note that:

Under certain circumstances, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) will be considered to be a Phase 1 clinical investigation under 21 CFR § 312.21 for purposes of determining whether a particular clinical trial is an “applicable drug clinical trial” under Title VIII of PL 110‐85 (section 402(j)(1)(A)(iii) of the PHS Act).  Although Phase 1 clinical investigations are generally designed to fit sequentially within the development plan for a particular drug, and to develop the data that will support beginning Phase 2 studies, 21 CFR § 312.21(a) does not limit Phase 1 trials to that situation.  Bioequivalence or comparative bioavailability studies that fall within the scope of the studies described in 21 CFR § 320.24(b)(1), (2), and (3) share many of the characteristics of Phase 1 clinical investigations as described in 21 CFR § 312.21(a), and therefore will be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85. However, bioequivalence or comparative bioavailability trials that fall within the scope of 21 CFR § 320.24(b)(4) do not share the characteristics of Phase 1 trials as described in 21 CFR § 312.21(a), and thus would not be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85. [(emphasis added)]

Bioequivalence studies that fall within the scope of 21 CFR § 320.24(b)(4) and that are not exempt from reporting on ClinicalTrials.gov are generally clinical endpoint studies.  According to an FDA Manual of Policies and Procedures, such studies are typically “applied to dosage forms intended to deliver the active moiety locally, forms that are not intended to be absorbed, or drug products for which traditional pharmacokinetic studies are not feasible,” such as drug products in topical dosage forms. 

Although the draft guidance posted on the ClinicalTrials.gov FDAAA website would exempt most bioequivalence studies from reporting under federal requirements, under a Maine law that is still in effect (and that might not be preempted for a few years), a “covered clinical trial,” which includes a bioequivalence study, initiated on or after October 15, 2002 must be reported.  Under the Maine law and its implementing regulations, bioequivalence studies must be registered and the results posted if the generic drug is approved by FDA and is or has been “dispensed, administered, delivered or promoted in Maine.”

By Anne Marie Murphy –

We have previously reported on the Consumer Product Safety Improvement Act of 2008 (“CPSIA”) (here, here, and here), which makes a number of changes to the laws enforced by the Consumer Product Safety Commission (“CPSC”).  Section 102(a)(1) of the CPSIA amends the Consumer Product Safety Act (“CPSA”) to require each importer or domestic manufacturer of any product that is subject to any CPSC rule, ban, standard, or regulation to issue a certificate that the product complies with such CPSC requirements.  The certificate must be “based on a test of each product or upon a reasonable testing program.”  This certification applies to drugs and dietary supplements that require child-resistant packaging (“CRP”) under the Poison Prevention Packaging Act (“PPPA”).

Yesterday, the CPSC posted on its website new Frequently Asked Questions (“FAQs”) that address the certification as it applies to PPPA products.  The FAQs confirmed the following:

• The CPSC does not regulate drugs, including drugs intended for children, because such products are excluded from the definition of “consumer product” under the CPSA.  The CPSC does, however, regulate CRP for those products that are subject to the PPPA.

• The importer of a PPPA-regulated product already in CRP or the domestic party that packages a PPPA-regulated substance in CRP must issue the general conformity certificate.

• The child resistance and senior friendly testing data obtained with the procedures described at 16 C.F.R. § 1700.20 may be relied upon as the “reasonable testing program” to support the certification.  There is no expiration date for such testing, and the testing need not be repeated unless the packaging is changed.

• There is no requirement to provide certification for the following types of shipments:  bulk drug product provided to pharmacies; empty vials and caps; and clinical trial drugs provided to physicians. 
   

By Jeffrey N. Wasserstein, Alan M. Kirschenbaum & Bryon F. Powell –

On December 10, 2008, the Massachusetts Department of Public Health (Department) issued proposed regulations pursuant to Mass. Gen. L. § 111N, which requires the Department to promulgate regulations that adopt a standard marketing code of conduct (the Code) for all prescription pharmaceutical and medical device manufacturers.  The law also requires the Department to establish a public database of payments by such companies to health care practitioners, to collect fees associated with marketing cost disclosure, and to enforce the law’s marketing requirements.  We previously reported on the enactment of this statute (here and here).

The Department issued a unified Code that covers both pharmaceutical and medical device manufacturers.  However, recognizing the differences between the PhRMA Code and the AdvaMed Code, the Code includes some provisions that are applicable only to pharmaceutical manufacturers, and other provisions applicable only to device manufacturers (such as reimbursement for certain training costs, discussed below).  The Code mirrors the PhRMA Code to some extent, while also including specific prohibitions and permissions required by the statute. 

The Code’s discussion of specific marketing practices includes tight restrictions regarding the provision of meals, support for CME, and other payments to health care practitioners.  While the restrictions are similar to those in the revised PhRMA Code, which we previously reported on, there are some differences.  Notably, the PhRMA Code limits the in-office/in-hospital restriction on meals to health care professionals to sales representatives and their immediate supervisors.  Other business people may provide meals out of the office or hospital on occasion, and meals may be provided outside the office or hospital in connection with a health care speaker provided by the company.  The Code does not mirror the PhRMA Code in this respect and limits all meals to in-office or in-hospital.  Another difference is that the Massachusetts Code apparently prohibits funding of unaccredited CME programs, whereas the PhRMA and AdvaMed Codes permit such funding.  Yet another difference between the Code and industry standards is that the Code permits reimbursement for certain medical device training costs, provided the costs of the training are specified in the purchase agreement for the device.  The AdvaMed Code permits device companies to train health care professionals on medical devices even whether or not such training is provided for in a purchase agreement.  

Manufacturer/practitioner interactions permitted by the Code include, among other things, payments for genuine research projects or clinical trials; product samples or evaluation units; normal price concessions, such as rebates and discounts; provision of reimbursement-related information; and medication for patient assistance programs.  The proposed regulations also address the use of prescriber-identifiable data, in a manner similar to the PhRMA Code. 

The Code also requires companies to: adopt and comply with the Code by July 1, 2009; adopt a training program to ensure compliance with the Code; conduct annual audits to ensure compliance with the Code; adopt policies and procedures for investigating noncompliance; appoint a compliance officer responsible for compliance with the Code; submit a description of the training program, the company’s investigation policies, and the contact information for the compliance officer; certify annually that the company has conducted an annual audit and is in compliance with the Code; and submit an annual disclosure report, described more fully below.

Under the Code’s disclosure requirements, manufacturers must annually report all payments of at least $50 made “in connection with the company’s sales and marketing activities.”  The Department proposed a $2,000 fee to be paid by reporting manufacturers to fund the disclosure program.  The first disclosure report is due July 1, 2010, covering the period of July 1, 2009 through December 31, 2009. 

The Massachusetts Public Health Council  discussed the proposed regulations at its December 10th public hearing.  Public hearings regarding the proposed regulations will also be held in Boston on January 9, 2009 and in Worcester on January 12, 2009.  Comments are due by February 10, 2009. 

By Cassandra A. Soltis –

FDA has posted on its web site two revised draft guidance documents (here and here) concerning the labeling requirements of dietary supplements and over-the-counter (OTC) drugs under the Dietary Supplement and Nonprescription Drug Consumer Protection Act of 2006.  That Act requires the labels of dietary supplements and OTC drugs other than those approved through the NDA process to bear the domestic phone number or domestic address of the “responsible person” so that consumers can report serious adverse events. 

In its draft guidance documents issued in December 2007, FDA indicated that by “domestic address,” Congress meant the full address, which includes the street address or P.O. box.  However, Hyman, Phelps & McNamara, P.C. and industry trade associations disputed this narrow interpretation of “domestic address” in comments on the guidance documents, arguing that FDA’s current “place of business” requirement for the labels of dietary supplements and OTC drugs satisfies the “domestic address” requirement of the new law, provided that the place of business is domestic, not foreign.  FDA also stated in its December 2007 guidance that it would not begin enforcing the labeling requirements until January 1, 2009.

In notices to be issued in the Federal Register on December 11, 2008, FDA announces that the December 2008 revised draft guidance documents change the enforcement date to January 1, 2010, “[b]ecause the agency is still in the process of finalizing the guidance” documents.  Nevertheless, even if the final guidance documents continue to interpret “domestic address” as including either the street address or P.O. box, FDA’s interpretation is not binding on either FDA or industry.  As FDA’s own regulation makes clear, “[g]uidance documents do not establish legally enforceable rights or responsibilities” and “do not legally bind the public or FDA.”  21 C.F.R. § 10.115(d)(1). 

By Susan J. Matthees—

FDA and the Department of Health and Human Services Office for Human Research Protections (OHRP) recently announced the availability of two guidance documents intended to help investigators, researchers, sponsors, and IRBs understand how data already collected may be used after a subject discontinues participation in a clinical trial.                                                             

FDA’s guidance document, “Guidance for Sponsors, Clinical Investigators, and IRBs Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials,” explains that under the existing regulatory scheme, if a subject withdraws from a study, the data collected on that subject up to the point of withdrawal generally must remain in the study database.  FDA states that “[c]omplete removal of data, possibly in a non-random or informative way, raises great concerns about the validity of a study.”  However, once a subject withdraws, an investigator may only continue to gather data with the subject’s permission.  The “investigator may ask a subject who is withdrawing whether the subject wishes to provide continued follow-up and further data,” distinguishing with the subject the “study-related interventions and continued follow up of associated clinical outcome information.”  The subject must agree and provide informed consent before the investigator can continue to gather data. 
 
If the subject does not give permissions to the investigator to collect further data, the investigator may not access the subject’s medical record.  But, the guidance document makes clear that the investigator may consult public records, including death records, to obtain follow-up data.   
 
OHRP’s draft guidance document, “Guidance on Important Considerations for When Participation of Human Subjects in Research is Discontinued,” does not discuss whether an investigator should consult public records to obtain follow-up data.  However, like FDA’s guidance document, OHRP’s draft guidance document states that an investigator may continue to analyze data already collected from a subject even after the subject withdraws from participation in the research.  OHRP’s draft guidance document also provides details on both the meaning of “participation” and the types of data that can be collected.   

The OHRP draft guidance states that OHRP “interprets subject participation” to mean any of the following activities:  interviewing the patient, taking a blood sample, administering a drug, “collecting individually identifiable private information . . . collecting individually identifiable biological specimens” from the subject, or “using or testing individually identifiable biological specimens already collected by the investigator (e.g., performing a genetic test on a tissue specimen already collected from a subject).”  OHRP does not consider the following activities to be subject participation:  “[a]ny continued analysis by the investigator of individually identifiable private information about the subject that was obtained by the investigator prior to the subject’s decision to discontinue participation in a study” or “continued analysis . . . of data that was derived by an  investigator through a previous use or test of a subject’s individually identifiable biological specimens prior to the subject’s decision to discontinue participation.” 

The OHRP guidance document also recommends that whenever a subject decides to discontinue participation, the investigator document the circumstances.  The investigator should specify “[w]hether the discontinuation of the subject’s participation results from a decision by the subject or by the investigator,” whether the discontinuation is full or partial, and “[t]he reason for the discontinuation.”  
 

By Susan J. Matthees –

FDA recently announced the availability of a new draft guidance document on the types of information FDA recommends be included in a complete submission for the evaluation of proprietary names for prescription drug products, biologics, and nonprescription drug products that are the subject of an IND, NDA, ANDA, or BLA.  FDA agreed to publish the draft guidance as part of the Agency’s performance goals under PDUFA IV.  FDA’s Center for Biologics Evaluation and Research ("CBER”) also published a manual of standard operating procedures and policies specific to CBER-regulated product proprietary names.  

FDA’s primary concern for proprietary names for drugs and biologics is safety.  An Institute of Medicine (“IOM”) report from 2006 encouraged FDA to address potential safety issues presented by the labeling and nomenclature of drugs and biologics.  The IOM and FDA have both expressed concerns about medical errors that could be attributed to sound-alike or look-alike names.  Thus, FDA states in the guidance document that the Agency’s “safety review of a proposed proprietary name focuses on the prevention of medication errors,” and that the agency will review names to determine whether they sound or look similar to the names of drugs already being marketed.  Additional factors that FDA believes could lead to confusion include the proposed indication, dosage form, route and frequency of administration, strength, unit of measure, dosage units, recommended dose, typical quantity or volume, product packaging, storage conditions, and patient and prescriber population. 
 
The guidance recommends that each submission contain general information, including the primary and an alternate propriety name, the intended pronunciation of the proposed name, the derivation of the name, the intended meaning of any proposed modifiers (e.g., “Lo” or “XR”), and the pharmacological/therapeutic category of the product.  All submissions should also contain information about product dispensing and delivery, including the likely environment for dispensing and use and, if applicable, a model and instructions for the product delivery system or device (e.g., a transdermal patch or inhaler) and/or the measuring device for dispensing the product (e.g., a calibrated dosing cup).  In addition, FDA “encourages applicants to include any assessments of the proprietary name, packaging, and/or labeling that were conducted or commissioned by the applicant or sponsor,” but the agency will “not consider a submission incomplete” if this information is not provided.
 
Submissions for products that have proposed labels and labeling should include the proposed labeling “in color and reflecting the presentation that will be used in the marketplace.”  In addition, the submission should include the container labels and labeling.  The guidance document explains that FDA will evaluate the container labels and labeling and consider the appearance and visibility of critical information, including whether it is prominently displayed, obscured by a logo, or is similar in appearance to the labels or labeling of a different drug or dosage. 
 
If a product does not have proposed labeling, FDA recommends that the submission include the following information: the established name of the drug, prescription status, dosage forms, product strengths, proposed indications for use, routes of administration, usual dosage, frequency of administration, dosing interval, maximum daily dose, dosing in specific populations, instructions for use, storage requirements, and information describing how the product will be supplied and packaged. 
 

By Bryon F. Powell –

On November 26, 2008, the Massachusetts Department of Public Health delayed plans to propose emergency regulations that would implement the state’s recently enacted pharmaceutical and device marketing law at a December 10 meeting of the Public Health Council.  A pair of hearings will be held in January 2009 to address issues surrounding the law with the earliest possible vote on proposed regulations taking place in February.  We previously reported on the enactment of Senate Bill 2863.

By Kurt R. Karst –      

Late last week while those of us in the U.S. were still digesting our turkey dinners, FDA issued a draft guidance document describing the Agency’s current thinking on the implementation of § 4(b)(1) of the Q1 Program Supplemental Funding Act (Pub. Law No. 110-379) (“the Q1 Act”).  Specifically, FDA’s draft guidance addresses when sponsors of NDAs for “old” antibiotics must submit patent information to FDA for Orange Book listing under the transition rules of the Q1 Act.  The draft guidance does not address FDA’s interpretation of the scope of, and procedural requirements associated with FDC Act § 505(v). 

As we previously reported (here and here), the Q1 Act, which was enacted on October 8, 2008, amended the FDC Act to add new § 505(v) – “Antibiotic Drugs Submitted Before November 21, 1997” – to create Hatch-Waxman benefits for “old” antibiotics.  The Q1 Act includes three “transition provisions.”  Those provisions: (1) require antibiotic drug NDA sponsors to submit to FDA for Orange Book listing information on applicable patents within 60 days of enactment of the Q1 Act; (2) require FDA to list those patents in the Orange Book not later than 90 days after the enactment of the Q1 Act; and (3) create “fist applicant” status (for 180-day exclusivity purposes) for each ANDA applicant that not later than 120 dates after enactment of the Q1 Act amends a pending application to contain a Paragraph IV certification to a newly listed antibiotic drug patent. 

To date, few patents have been submitted to FDA for Orange Book listing.  The first “old” antibiotic patents were listed on October 24, 2008 for MOXATAG (amoxicillin).  Since then, other patents have been listed for ZMAX (azithromycin), and NEORAL (cyslosporine).  We understand that other patents covering “old” antibiotic drug products will soon be added to the Orange Book before the 60-day deadline for Orange Book patent listing expires later this week.

FDA’s draft guidance reminds NDA sponsors of the fast-approaching deadline:

Section 4(b)(1) of the Q1 Act requires the submission of patent information to FDA “not later than sixty days after enactment of [the Q1 Act].”  Sixty days after enactment falls on Sunday, December 7, 2008.  Therefore, to be in compliance with this provision, sponsors must submit the patent information on or before the weekday preceding December 7, 2008, that is, on or before December 5, 2008.  [(emphasis added)]

FDA’s draft guidance also clarifies who must submit the patent information to FDA under §  4(b)(1) of the Q1 Act:

The sponsor of an NDA approved on or before October 7, 2008, for a drug (including a combination drug) containing an antibiotic drug that was the subject of an application approved under section 507 of the FD&C Act (as in effect before November 21, 1997) must submit this patent information.  [(emphasis added)]

One of the reasons so few patents covering “old” antibiotics have been submitted to FDA for Orange Book listing might be due to a misunderstanding of the applicability of the transition provisions.  Some have speculated that the transition provisions might apply only to NDAs for “old” antibiotics approved after October 8, 2008 when the Q1 Act was enacted.  According to FDA, this is not the case:

The application of section 4(b)(1) of the Q1 Act set forth in this guidance gives meaning to both section 505(v) of the FD&C Act, as added by section 4(a) of the Q1 Act, and the legislation’s transitional rules at section 4(b).  Section 4(b)(3) of the Q1 Act contemplates submission of patent certifications by applicants of pending ANDAs that reference drugs for which patent information must be listed under section 4(b)(1).  By statute, ANDAs may reference only already approved drugs.  See 21 U.S.C. 355(j)(2)(A). Therefore, the drugs referenced by these pending ANDAs (that is, drugs for which patent information was submitted under section 4(b)(1) of the Q1 Act) must be drugs that were approved on or before October 7, 2008.  This approach is further supported by the requirement that FDA must, upon receipt of the patent information required to be submitted under 4(b)(1) of the Q1 Act, publish the information in the electronic version of FDA’s Approved Drug Products with Therapeutic Equivalents (the Orange Book).  Per section 505(j)(7) of the FD&C Act, the Orange Book includes only information about approved drugs.  See section (4)(b)(2) of the Q1 Act. 

By Kurt R. Karst -     

On November 25, 2008, FDA granted in full a citizen petition (petition supplements are available here and here) submitted by Osmotica Pharmaceutical Corp. earlier this year requesting that FDA determine that any company with a pending Abbreviated New Drug Application ("ANDA") for a proposed Venlafaxine HCl Extended-Release Tablets drug product, and in particular Sun Pharmaceutical Industries Ltd. ("Sun"), be required to submit to FDA a new ANDA citing Osmotica's approved Venlafaxine HCl Extended-Release Tablets drug product as the Reference Listed Drug ("RLD"), and that FDA require any such ANDA applicant to conduct new bioequivalence studies comparing its proposed drug product to Osmotica's approved drug product.  FDA's 26-page decision: (1) affirms FDA's longstanding "RLD Change Policy," which requires a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the Agency approves an application for the drug product covered by the suitability petition; (2) affirms FDA's "RLD Choice Policy," under which a generic applicant must choose the most pharmaceutically equivalent listed drug as the RLD; and (3) and implements FDC Act § 505(j)(2)(D)(i), which was added to the statute in 2003 by the Medicare Prescription Drug, Improvement, and Modernization Act ("MMA") and precludes an applicant with a pending ANDA from amending that application to change RLD.  It is the first citizen petition covered under FDC Act § 505(q) that FDA has granted in full - see the FDA Law Blog FDC Act § 505(q) Citizen Petition Tracker.

Osmotica's May 30, 2008 citizen petition concerns FDA's May 20, 2008 approval of Osmotica's 505(b)(2) application (NDA #22-104) for Venlafaxine HCl Extended-Release Tablets, and FDA's March 30, 2005 decision approving a suitability petition submitted pursuant to FDC Act § 505(j)(2)(C) for a dosage form change from Venlafaxine HCl Extended-Release Capsules (i.e., Wyeth's EFFEXOR XR) to Venlafaxine HCl Extended-Release Tablets.  Sun had submitted an ANDA to FDA pursuant to FDA's suitability petition decision seeking approval of Venlafaxine HCl Extended-Release Tablets – pharmaceutically the same drug product FDA approved under Osmotica's NDA.

Under FDA's RLD Choice Policy, a generic applicant should refer to the approved pharmaceutical equivalent designated by FDA as the RLD as it basis for ANDA submission.  As FDA explained in a 2004 citizen petition response (page 9, note 13):

if a tablet and a capsule are approved for the same moiety with patents listed for the tablet and none listed for the capsule, an ANDA applicant seeking approval for a tablet should cite the approved tablet as the [RLD].  It should not circumvent the patents on the tablet by citing the capsule as the [RLD] and filing a suitability petition under [FDC Act § 505(j)(2)(C)] and 21 CFR 314.93 seeking to change to a tablet dosage form.

Under FDA's longstanding RLD Change Policy, the Agency has required a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the Agency approved an application for the drug product covered by the suitability petition.  For example, after FDA approved NDAs for Carboplatin Injection drug products that were also the subject of pending ANDAs submitted pursuant to an approved suitability petition, the Agency required generic applicants to change RLD.  FDA has also required generic applicants to take the same action in an Rx-to-OTC switch scenario, where the Agency approved a new NDA for an OTC drug product – thus creating a new RLD listed in the Orange Book to which generic applicant must cite.

FDA's RLD Change Policy became particularly important with the enactment of the MMA in 2003.  The MMA amended the FDC Act to add § 505(j)(2)(D)(i), which states: "[a]n applicant may not amend or supplement an [ANDA] to seek approval of a drug referring to a different listed drug from the listed drug identified in the application as submitted to [FDA]."  A similar provision was added to FDC Act § 505(b)(4)(A) with respect to 505(b)(2) applications.  That provision states: "[a]n applicant may not amend or supplement [a 505(b)(2) application] to seek approval of a drug that is a different drug than the drug identified in the application as submitted to [FDA]."  Thus, given FDA's RLD Change and Choice Policies, a generic applicant must cite the most appropriate RLD, and must change RLD (for a pending application) when a pharmaceutically equivalent listed drug is approved.  However, the MMA precludes an ANDA applicant with a pending application from changing RLD.  Instead, Osmotica argued in its citizen petition that a new application must be submitted citing the appropriate RLD, and such application must contain the required bioequivalence data comparing the proposed generic drug to the new RLD (in this case, Osmotica's approved Venlafaxine HCl Extended-Release Tablets drug product).

In October 2004, FDA issued a draft guidance document discussing, among other things, FDC Act § 505(j)(2)(D)(i).  FDA's draft guidance document states, in relevant part:

All changes that would have the effect of seeking approval for a drug product different from the listed drug cited in the initial submission (e.g., different active ingredient, dosage form, route of administration) should be made in a new application.  When the Orange Book identifies as a separate listed drug a product with the characteristics (e.g., active ingredient, dosage form, route of administration) for which the applicant is seeking approval, the applicant should submit a separate ANDA referencing the corresponding listed drug.  The applicant should not submit a supplement or amendment to its pending or approved application to seek approval for such a change.
     
In the Federal Register notice announcing the availability of the draft guidance, FDA stated:

A situation that is not considered in this guidance is that where a pending ANDA was submitted referencing a [suitability] petition approved under [FDC Act § 505(j)(2)(C)], and another application is approved for the product described in the petition before the pending ANDA is approved.  FDA has not completed its analysis of this situation, and therefore the draft guidance does not cover it.

Despite the apparent uncertainty in 2004, however, FDA has completed its analysis and has determined that a generic applicant with a pending ANDA subject to an approved suitability petition must submit a new ANDA citing the appropriate RLD when the drug product described in the approved suitability petition is approved under an NDA.  FDA's petition response states:     

our requirement that an applicant with a pending ANDA subject to an approved suitability petition change the RLD upon FDA approval of an NDA for the same drug product described in the approved suitability petition reflects the Agency's judgment that considerations regarding an ANDA's limited reliance on an approved suitability petition are outweighed by the need for a clear determination of therapeutic equivalence for a generic drug product and protection of intellectual property rights accorded an NDA holder. . . .

[T]his approach reduces the potentially confusing proliferation of pharmaceutically equivalent drug products that have not demonstrated therapeutic equivalence, and ensures that ANDAs for venlafaxine HCl extended-release tablets will be therapeutically equivalent and thus substitutable for the RLD, Osmotica's venlafaxine HCl extended-release tablets. . . .

FDA's policy of requiring all pending ANDA applicants to change their basis for ANDA submission upon approval of an NDA for the same drug product described in the suitability petition is intended to ensure that ANDA applicants do not circumvent the patent certification requirements of section 505(j)(2)(A)(vii)-(viii) of the Act through the suitability petition process.  In addition, our policy would appropriately protect any marketing exclusivity that has been granted to the newly-approved RLD.

In the case of Sun's pending ANDA for Venlafaxine HCl Extended-Release Tablets, FDA determined that:

an ANDA for venlafaxine HCl extended-release tablets submitted based upon an approved suitability petition that was pending at the time of approval of Osmotica's NDA 22-104 and that seeks approval for a pharmaceutically equivalent drug product must be withdrawn, as the ANA is required to reference the corresponding approved strengths of Osmotica's venlafaxine HCl extended-release tablets as its RLD, and section 505(j)(2)(D)(i) of the Act precludes such a change from being submitted as an amendment to an ANDA.  If Sun or any other applicant wishes to pursue approval of an ANDA for venlafaxine HCl extended-release tablets, it must submit a new ANDA containing data and information required by section 505(j) of the Act for approval (including, but not limited to, a demonstration of bioequivalence to the RLD, Osmotica's venlafaxine HCl extended-release tablets).

FDA's citizen petition response also applies to 505(b)(2) applications pursuant to FDC Act § 505(b)(4)(A).  FDA states in the context that "[o]ur interpretation of the MMA provisions related to the Hatch-Waxman Amendments upholds the legislative balance of facilitating the availability of generic drug products that meet the statutory requirements for approval while protecting innovator intellectual property rights (and allowing for an early resolution of any patent infringement litigation)" that:

We note that our interpretation of § 505(b)(4)(A) of the Act, also added by the MMA, for 505(b)(2) applications is influenced by and intended to be consistent with section 505(j)(2)(D)(i) regarding ANDAs.  Accordingly, a 505(b)(2) applicant may not amend or supplement a 505(b)(2) application to seek approval of a drug that relies on the Agency's finding of safety and/or effectiveness for a drug that is different from the drug identified in a previous submission of the application.

The importance of FDA's citizen petition response cannot be overstated.  It has significant implications – and creates significant risk – for generic companies that rely on the suitability petition process.  And for 505(b)(2) applicants, it also creates a risk of application resubmission and underscores the importance of carefully choosing the appropriate listed drug(s).