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).

By John A. Gilbert

On December 4 and 5, FDLI will hold a conference on Regulation of Controlled Substances: Balancing Medical Need and Diversion Control.  The conference will focus on issues related to drug scheduling and regulation of controlled substances and List I chemicals and provide information on new initiatives to ensure medical availability of these drugs while reducing diversion.  John Gilbert of HPM will be speaking at the conference along with other government and industry representatives.  More information on the conference can be found at: http://www.fdli.org/conf/446/index.html.

By James P. Ellison

In a November 10, 2008 response posted on November 24, 2008, FDA denied an April 27, 2005 Citizen Petition challenging a March 29, 2005 Interim Final Rule increasing Color Additive Certification Fees as violating the FDC Act and the Administrative Procedure Act (APA), because notice and comment rulemaking was required under the law.
 
FDA's response rejected the argument by the International Association of Color Manufacturers that notice and comment rulemaking was required, citing the APA's "contrary to public interest" exception to the general rule requiring notice and comment rulemaking.

While the question of whether FDA should proceed with an interim final rule, a direct final rule, a direct final rule in tandem with a proposed rule, or simply a proposed rule–in this case specifically or in connection with rulemakings generally–raises potentially interesting APA questions, one cannot help but feel that the writing was on the wall in connection with this issue as the increased fees have been in effect for over 3 and 1/2 years.  Those who are intrigued by agency decisions concerning publication of rules may want to stay tuned to see how FDA proceeds in connection with its next Color Additive Certification Fee increase, which given the delay in responding to this Citizen Petition, may be just around the corner.

By Cassandra A. Soltis

The Federal Trade Commission (FTC) is seeking comments on proposed revisions to its Guides Concerning the Use of Endorsements and Testimonials in Advertising.  The Guides, although advisory in nature, set forth the principles the FTC will follow in reviewing endorsements and testimonials and provide examples that illustrate the principles set forth therein.

The proposed revisions have taken into consideration the comments the agency received in response to its January 2007 notice concerning the results of consumer research on consumer endorsements and related issues.  Among other things, the Commission is proposing to make clear in the Guides that advertisers can be held liable for any false or unsubstantiated statements made by endorsers or for not disclosing any material connections between themselves and the endorsers.  In addition, the proposed revisions would provide that endorsers, including expert endorsers and celebrities, may be held liable for their statements. 

Several new examples are proposed to be added to the Guides.  One example will demonstrate how advertisers may be liable for using bloggers to promote their products and how bloggers themselves may be held liable.  Another will make clear that experts must have the level of expertise that the advertisement suggests.  Yet another example will illustrate the FTC’s expectation that celebrities disclose their financial connection to any product they endorse during routine interviews because consumers do not expect celebrities to be paid for what appear to be genuine, unplanned discussions of a product. 

The proposed revisions are expected to be published in the Federal Register soon, but they can currently be viewed through the FTC’s website at http://www.ftc.gov/opa/2008/11/endorsements.shtm.  Comments on the revisions are due by January 30, 2009.

By William T. Koustas & Kurt R. Karst –

We previously reported that the Federal Trade Commission (“FTC”) is planning a Roundtable on Follow-on Biologics (“FOBs”) to be held on November 21, 2008 in Room 432 at FTC Headquarters in Washington, D.C.  The Roundtable was first announced earlier this year in the Federal Register.  In that notice, the FTC requested comment on two sets of questions concerning regulatory exclusivities and FOB competition, and patent dispute resolution issues.  Comments responding to the FTC’s notice are available here.  Discussion at the Roundtable will likely aid the FTC as it drafts a report analyzing the potential impacts on the marketplace of FOBs, which the FTC reportedly plans to issue in spring 2009.

On November 18, 2008, the FTC issued a press release detailing the scope and providing an agenda for the November 21, 2008 Roundtable.  The Roundtable is scheduled to begin with remarks from FTC Commissioner Pamela Jones Harbour, who recently gave a speech on the FTC’s perspectives on FOBs, followed by a presentation on FOBs by FDA’s Rachel Behrman.  The FTC’s press release notes that the session will the be broken out into panel discussions on the following five issues: “the price and market share effect of entry of both biosimilar and biogeneric drugs, the likely competitive effects of reference product regulatory exclusivity, biotechnology patent issues, the likely competitive effects of follow-on biologic regulatory incentives, and the patent resolution process.”

The panel session regarding the effects of entry by biosimilar and biogeneric products will specifically address how the competition between FOBs and innovator products will affect reimbursement by private and public payers.  The second panel, related to competitive effects of reference products and regulatory exclusivity, will focus on the benefits and drawbacks of FOB non-patent market exclusivity for innovator companies and follow-on applicants.  The third panel on biotechnology patent issues will discuss the differences between patents on biologics and small molecule drugs with specific emphasis on claim drafting, Patent and Trademark Office approval, judicial review, and how patent and non-patent market exclusivity affect business planning.  The fourth panel on the competitive effects of FOBs and regulatory incentives is scheduled to center on whether Hatch-Waxman-like statutory exclusivity incentives are needed to promote the growth of FOBs.  Finally, the patent dispute resolution panel will consider the different ways to structure a system to resolve patent disputes between innovator companies and follow-on competitors using case study. 

The Roundtable is free and open to the public without the need for pre-registration.  Only a photo ID is necessary to enter the FTC Headquarters.  A live webcast will be available on the day of the Roundtable. 

The issue of non-patent FOB market exclusivity has been hotly debated in Congress and by scholars.  Recent papers by the American Enterprise Institute’s Alex Brill and Duke University Fuqua School of Business Professor Henry Grabowski (both of whom are scheduled to present at the Roundtable) have taken different views about the appropriate period of such exclusivity, assuming FOBs can overcome the scientific, statutory, and regulatory hurdles currently in place.

By James R. Phelps & Kurt R. Karst –      

On November 17, 2008, Representatives John Dingell (D-MI), Chairman of the Committee on Energy and Commerce, and Bart Stupak (D-MI), Chairman of the Subcommittee on Oversight and Investigations of the U.S. House of Representatives, announced their most recent investigation of FDA – “whether managers within the [FDA] Center for Devices and Radiological Health (CDRH) knowingly corrupted the scientific review process and approved or cleared medical device applications in gross violation of laws and regulations designed to assure the safety and effectiveness of medical devices.”  The investigation was prompted by an October 14, 2008 letter written on behalf of a group of CDRH scientists and physicians who allege that CDRH managers have “corrupted the scientific review of medical devices.” 

The October 14, 2008 letter to Chairman Dingell is quite remarkable and includes several serious allegations.  According to the letter:

This misconduct reaches the highest levels of CDRH management including the Center Director and the Director of the Office of Device Evaluation (ODE) . . . .  To avoid accountability, these managers at CDRH have ordered, intimidated and coerced FDA experts to modify their scientific reviews, conclusions and recommendations in violation of the law. Furthermore, these managers have also ordered, intimidated and coerced FDA experts to make safety and effectiveness determinations that are not in accordance with scientific regulatory requirements, to use unsound evaluation methods, and accept clinical and technical data that is not scientifically valid nor obtained in accordance with legal requirements, such as obtaining proper informed consent from human subjects.  These same managers have knowingly avoided and failed to properly document the basis of their decisions in official Agency records.

Under the banner of regulatory “precedent,” managers at CDRH have demanded that physicians and scientists review regulatory submissions employing methods, and accepting evidence and conclusions, that are not scientifically proven and clinically validated. These demands appear to be based on the misguided notion that because flawed methods, evidence and conclusions were used or accepted in the recent or even the remote past, we must continue to blindly and knowingly accept these flawed methods, evidence and conclusions and continue to use them as the basis for regulatory recommendations. Such invalid regulatory “precedent” goes against current scientific and clinical evidence. Rather than remedy past regulatory or scientific errors after they come to light, and rather than applying the best and latest scientific knowledge and methodology, these managers at CDRH knowingly continue to make the same regulatory and scientific mistakes over and over again. Rather than recall, re-evaluate or otherwise deal with potentially unsafe or ineffective devices that are already on the market, these managers at CDRH continue to approve more devices of the same kind in a non-transparent and non-scientific manner. This is especially true of the 510(k) program but also applies to the PMA program as well as the advice and guidance given to manufacturers before they make regulatory submissions. The practices described above represent an unwarranted risk to public health and a silent danger that may only be recognized after many years.

The October 14, 2008 letter reportedly follows up on a similar letter sent by some CDRH scientists to FDA’s Assistant Commissioner for Integrity and Accountability on May 31, 2008.  In a November 17, 2008 letter from Reps. Dingell and Stupak to FDA Commissioner von Eschenbach, the Representatives: (1) express concern that “no action has been taken to address the serious concerns raised by CDRH scientists or the retaliatory behavior of CDRH managers toward those concerned FDA employees;” (2)  remind FDA officials that it is a violation of Federal law to retaliate against whistleblowers and to interfere with a congressional inquiry; and (3) request a briefing by FDA no later than December 1, 2008 of what actions have been or will be taken to respond to the allegations raised in the October 14, 2008 letter. 

Managing FDA is an excruciatingly difficult task.  One of the principal reasons this is so is laid bare in the letters discussed above.  At this stage, it is impossible to know what will happen to the CDRH personnel involved.  Do the complainants have a better grasp of good scientific methodologies than the senior people at CDRH?  Will they be viewed as heroic whistleblowers or back-stabbing knaves?  We may never learn.

We can, however, foresee yet another season of congressional activity – grillings by Hill staff and maybe hearings.  The one easily predictable consequence of all this is that FDA, and especially CDRH, will for some time to come be in a defensive mode.  When this happens, history teaches that FDA reviews will reach a new level of difficulty.  The affected personnel will be distracted to attend to the allegations.  The managers will have a heightened interest in making judgments that no one – not even the worst informed employee – can criticize. 

Will the enhanced rigidity of the approval system that occurs as Congress sorts out FDA’s personnel issues give the public access to new technologies in an appropriate time frame?  Time will tell.