By Kurt R. Karst –      

At a September 24th Senate Judiciary Committee Executive Business Meeting, Senator Herb Kohl’s (D-WI) substitute amendment to S. 369, the Preserve Access to Affordable Generics Act, was adopted by unanimous consent.  As we previously reported, the amendment makes significant changes to the version of S. 369 Sen. Kohl introduced earlier this year. 

The new version of S. 369 would amend the Federal Trade Commission Act to permit the FTC to “initiate a proceeding to enforce the provisions of [new Sec. 28] against the parties to any agreement resolving or settling, on a final or interim basis, a patent infringement claim, in connection with the sale of a drug product.”  In such a proceeding, “an agreement shall be presumed to have anticompetitive effects and be unlawful if – (i) an ANDA filer receives anything of value; and (ii) the ANDA filer agrees to limit or forego research, development, manufacturing, marketing, or sales of the ANDA product for any period of time.”  However, the presumption of anticompetitive effects “shall not apply if the parties to such agreement demonstrate by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.”  Several “competitive factors” must be taken into consideration to determine whether the procompetitive benefits of the agreement outweigh its anticompetitive effects, including “the length of time remaining until the end of the life of the relevant patent, compared with the agreed upon entry date for the ANDA product,” “the value to consumers of the competition from the ANDA product allowed under the agreement,” and “the revenue the ANDA filer would have received by winning the patent litigation.”

In terms of penalties, the Kohl Amendment states that “[e]ach person, partnership or corporation that violates or assists in the violation of this section shall forfeit and pay to the United States a civil penalty of not more than 3 times the gross revenue of the NDA holder from sales of the drug product that is the subject of the patent infringement claim for the period of the violation, starting with the date of the agreement.”  Although the bill would generally apply to agreements “irrespective of whether such agreements are entered into before, on, or after the date of enactment of this Act,” the penalties provisions would “not apply to agreements entered into before the date of enactment of this Act.”

By Kurt R. Karst –     

Many thanks to all of those who participated in our little Hatch-Waxman trivia contest.  Although no single person was able to correctly answer all of the questions, just about all of them were correctly answered through your collective knowledge.  The answers are provided below.  As a reward, we are posting the first edition (1980) of the Orange Book.  Enjoy!

Q1: Who said “So, when you add it all up, this bill will provide regulatory relief, increased competition, economy in government, and best of all, the American people will save money, and yet receive the best medicine that pharmaceutical science can provide”?

A: President Ronald Reagan on September 24, 1984, in the Rose Garden upon signing Hatch-Waxman into law.

Q2:   Why is the “Orange Book” cover Orange?

A: The festive color was chosen by the "father of the Orange Book," Don Hare, because it was first published around Halloween.     

Q3:   Who was the following exchange between? 

THE COURT:  The [Federal Food, Drug, and Cosmetic Act] itself uses the term “strength.”  It references the drug with respect to which the certification is made.  The certification will mention the listed drug which includes the strength; correct?

ATTORNEY:  That’s correct, Your Honor.

THE COURT:  All right.  There’s a special place in Hell where they torture people who write things like this.  For 14 years I was on the Rules Committee of Maryland’s Court of Appeals that didn’t have as many subsections as this, so I would flunk the person who gave me this as a draft rule.  I would say this is 50 rules.

Anyway, I wanted to wander into the right place of this endless section.  When I first went to Westlaw and said, just give me section 355, it had to tell me it was going to be 85 pages.  I said, no, no, no, no.  Let’s try (j), and I get this huge thing here.

ATTORNEY:  Well I hope that our brief lays out the precise subsections, Your Honor.  I believe it does.  But that is the sum of my argument, unless the court has any further questions.

THE COURT:  No.  You’ve been very helpful.  I’m glad to have somebody here who knows what they’re talking about.

ATTORNEY:  So am I, Your Honor.  It’s just not me.  Thank you.

THE COURT:  Thank you.   

A:   Judge Roger W. Titus, U.S. District Court for the District of Maryland, and Gerald C. Kell from the Department of Justice (December 21, 2006) in Biovail Corporation. v. FDA.

Q4: What is the date on which patent information was first listed in the Orange Book covering an old antibiotic drug product?  

A:  October 24, 2008, the Electronic Orange Book listed information on three patents covering MiddleBrook Pharmaceuticals’ MOXATAG (amoxicillin extended-release) Tablets – specifically, U.S. Patent Nos. 6,544,555, 6,669,948, and 6,723,341. 

Q5: Both the 5th and 6th editions of the Orange Book carry a 1985 date on their covers.  The 7th edition of the Orange Book lists 1987 on its cover.  Why is there no edition with a 1986 date on its cover? 

A: Between the 6th and 7th editions of the Orange book, FDA transitioned from a Fiscal Year to a Calendar Year publication schedule.  The 6th edition has 16 cumulative supplements rather than the usual 12 because of the transition.

Q6: What is the difference between a New Chemical Entity and a New Molecular entity? 

A: An NCE is a drug that contains no active moiety that has been approved by FDA in any other application submitted under FDC Act § 505(b).  An NME is a drug that contains an active moiety that has never been approved by FDA or marketed in the U.S. 

Q7: What was the period of stay of ANDA approval Congress contemplated (and stated in the House Report) after a timely filed lawsuit arising from a Paragraph IV certification notification?  (It was not 30 months.)

A: 18 months

Q8: How many Directors has the Office of Generic Drugs had since passage of Hatch-Waxman?

A: Four.  Marvin Seiff, Roger Williams, Doug Sporn, and Gary Buehler.

Q9: What generic drug was at issue in Mova Pharm. Corp. v. Shalala?

A: Micronized glyburide

Q10: Who said about a provision of Hatch-Waxman that : “[O]ne must admit that while the provision more naturally means what respondent suggests, it is somewhat difficult to understand why anyone would want it to mean that.”

A:  Justice Scalia in Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661, 679 (1990) (referring to the “Bolar Amendment” provision of the Patent Code enacted in Title II).

Q11:   What drug was at issue in Roche v. Bolar?

A: DALMANE (flurazepam)

Q12: How many years of exclusivity was granted to an NCE approved between January 1, 1982 and September 24, 1984?

A: 10 years (Question 13 answered this question).

Q13: What prescription NSAID drug got the benefit of this 10 year period?

A: FELDANE (piroxicam)

Q14: How many patent term extensions has PTO issued –  fewer than 500 or more than 500? 

A: More than 500 (about 556)

Q15: And for a total of how many years of extension – fewer than 1500 years or more  than 1500 years?

A: More than 1500 years (about 1,510 years)

Q16: What is the shortest patent term extension granted?

A: 20 days

Q17: What was the last provision of Hatch-Waxman to be negotiated?  And for whom was it a deal-breaker?

A: Filing an ANDA containing a paragraph IV certification at the end of four years of the five year new chemical entity exclusivity period.  Senator Howard Metzenbaum (D-OH).

Q18: What was the first drug approved in a “paper NDA?”

A: Furosemide injection

Q19: Who have been FDA’s Chief Counsels since Hatch-Waxman was enacted?

A: Tom Scarlett, Margaret Ann Porter, Dan Troy, Sheldon Bradshaw, Jerry Masoudi, Mike Landa (acting)

Q20: Who was Paul Parkman?  And what was his most famous letter?

A: Deputy Director and then Acting Director of FDA’s Center for Drugs and Biologics.  He is famous for his April 1987 letter discussing 505(b)(2) applications.  The following additional information was provided by one of our readers:

Paul Parkman, who is still alive, had a very distinguished career prior to becoming Director of CBER. He was in the Bureau of Biologics (name of the center prior to CBER) Division of Virology, where he discovered a way to grow rubella virus in vitro for the first time, and developed the first rubella vaccine. During the 1950s, Weller, Enders, and Robbins had developed a way to grow viruses in cell culture for the first time, but for many years no one could succeed in growing rubella virus. Parkman figured out a way to detect growth of rubella virus in cell culture by showing it interfered with the growth of another marker virus. Based on this discovery, he worked with his boss, Harry Meyer (later a director of what still later became CBER) to create and test a rubella vaccine. For this work, he and Meyer received a major award and the two of them had their photograph on the cover of Time Magazine in the 1960s.

By Kurt R. Karst –      

Late yesterday (Sept. 22nd), Wyeth Pharmaceuticals (“Wyeth”) sued FDA in the U.S. District Court for the District of Columbia over the Agency’s recent decision to approve two ANDAs for generic versions of ZOSYN (piperacillin sodium; tazobactam sodium) Injection.  Both ANDAs are owned by Orchid Healthcare (“Orchid”) and were approved (here and here) on September 15, 2009 following FDA’s decision on several related citizen petitions.  As we previously reported, FDA’s decision to grant petitions submitted by generic manufacturers (and largely deny a Wyeth petition) and approve ANDAs reaffirmed an Agency policy that FDA will, in the context of discontinued drug product formulations, waive its so-called “exception excipient regulations” to permit the receipt and approval of an ANDA for a drug product containing a so-called “non-exception excipient” change from the Reference Listed Drug.

By way of background, in September 2005, FDA approved an NDA supplement for a new formulation of ZOSYN containing edetate disodium dihydrate (“EDTA”) and citric acid monohydrate, which reportedly function in the drug product as a chelator (a non-exception excipient) and a buffer, respectively.  Several petitions were submitted to FDA requesting that the Agency: (1) determine that the formulation of ZOSYN originally approved by FDA was not discontinued for safety or efficacy reasons; and (2) accept ANDAs for generic versions of ZOSYN duplicating the discontinued formulations (i.e., without EDTA and citric acid).  FDA granted the petitions in its September 15th response, and commented that “experience with Wyeth's original Zosyn formulation and FDA’s recent analysis has shown that the inactive ingredients in the ANDA for piperacilin and tazobaetam for injection duplicating the original Zosyn formulation are safe. . . .”   Wyeth contended in its own citizen petition that the new formulation of ZOSYN was essential to its safe use – specifically that EDTA and citric acid are essential to the safe co-administration of ZOSYN with Lactated Ringers Solution (“LRS”) – and that ANDAs should not be approved with the discontinued formulation.  Alternatively, Wyeth requested that FDA require any generic appliant whose drug could not safely be co-administered with LRS to implement a Risk Management Action Plan (“RiskMAP”) “to ensure that healthcare professionals were aware of and understood the [product] differences.”

Wyeth’s September 22nd complaint challenges FDA’s petition decision and ANDA approval decisions as a violation of the Administrative Procedure Act, as well as violations of FDA’s ANDA exception excipient regulations (21 C.F.R. § 314.94(a)(9)(iii); 21 C.F.R. § 314.127(a)(8)(ii)(A)) and the statutory and regulatory same labeling requirement (FDC Act § 505(j)(2)(A)(v); 21 C.F.R. § 314.94(a)(8)(iv)).  According to Wyeth’s complaint:

FDA’s decision to approve a generic formulation that lacks two inactive ingredients that are essential to the safe co-administration of Zosyn with LRS was wrong as a matter of fact and law.  That decision was based on an impermissibly narrow view of generic drug safety, which focused only on the intrinsic safety of the product under the labeled conditions for use and ignored the risks of confusion and medication error that could result in the product being used in a manner contrary to the labeled warnings.  Given the evident purpose of the Hatch-Waxman Act and the related body of law governing generic approvals, statutory and regulatory requirements that products be the “same” can only be waived where the evidence demonstrates not only that the differences do not undermine the intrinsic safety of the generic product viewed in isolation, but also that they will not compromise patient health and safety under the likely conditions of actual use by clinicians.  The evidence is directly to the contrary with respect to the approved generic formulation. 

Wyeth also filed a Motion for a Preliminary Injunction or a Temporary Restraining Order (and a supporting Memorandum of Points and Authorities) that would, if granted, require FDA to withdraw or suspend the Orchid ANDA approvals.  Wyeth is seeking a hearing on or before Friday, September 25th.

Wyeth’s lawsuit – filed on the first day of Fall 2009 – follows a rather active summer in which FDA was sued several times, including over generic drug approvals for ELOXATIN (oxaliplatin) and PROGRAF (tacrolimus).

UPDATE:

• US court denies Wyeth bid to halt Zosyn generic-India's Orchid (Reuters).
• A copy of the district court's September 24th Memorandum Opinion is available here.

By Kurt R. Karst –     

September 24, 2009 is the 25th anniversary of the enactment of the Drug Price Competition and Patent Term Restoration Act (Public Law No. 98-417) – commonly known as “Hatch-Waxman” or “Waxman-Hatch” depending on when you became familiar with the law.  To celebrate, we dredged Hatch-Waxman history to come up with some trivia questions (and also used some questions asked earlier this week at the Food and Drug Law Institute’s 25th anniversary reception).  Think you know Hatch-Waxman?  Then take our quiz below.  Anyone who is able to correctly answer all of the questions will receive an electronic copy of the first edition (1980) of the Orange Book.  We will update this post late on Thursday (Sept. 24th) with the answers.  (You can e-mail me your answers at kkarst@hpm.com)

Q1: Who said “So, when you add it all up, this bill will provide regulatory relief, increased competition, economy in government, and best of all, the American people will save money, and yet receive the best medicine that pharmaceutical science can provide”?

A: 

Q2:   Why is the “Orange Book” cover Orange?

A:      

Q3:   Who was the following exchange between? 

THE COURT:  The [Federal Food, Drug, and Cosmetic Act] itself uses the term “strength.”  It references the drug with respect to which the certification is made.  The certification will mention the listed drug which includes the strength; correct?

ATTORNEY:  That’s correct, Your Honor.

THE COURT:  All right.  There’s a special place in Hell where they torture people who write things like this.  For 14 years I was on the Rules Committee of Maryland’s Court of Appeals that didn’t have as many subsections as this, so I would flunk the person who gave me this as a draft rule.  I would say this is 50 rules.

Anyway, I wanted to wander into the right place of this endless section.  When I first went to Westlaw and said, just give me section 355, it had to tell me it was going to be 85 pages.  I said, no, no, no, no.  Let’s try (j), and I get this huge thing here.

ATTORNEY:  Well I hope that our brief lays out the precise subsections, Your Honor.  I believe it does.  But that is the sum of my argument, unless the court has any further questions.

THE COURT:  No.  You’ve been very helpful.  I’m glad to have somebody here who knows what they’re talking about.

ATTORNEY:  So am I, Your Honor.  It’s just not me.  Thank you.

THE COURT:  Thank you.   

A:

Q4: What is the date on which patent information was first listed in the Orange Book covering an old antibiotic drug product?  

A: 

Q5: Both the 5th and 6th editions of the Orange Book carry a 1985 date on their covers.  The 7th edition of the Orange Book lists 1987 on its cover.  Why is there no edition with a 1986 date on its cover? 

A: 

Q6: What is the difference between a New Chemical Entity and a New Molecular entity? 

A: 

Q7: What was the period of stay of ANDA approval Congress contemplated (and stated in the House Report) after a timely filed lawsuit arising from a Paragraph IV certification notification?  (It was not 30 months.)

A: 

Q8: How many Directors has the Office of Generic Drugs had since passage of Hatch-Waxman?

A: 

Q9: What generic drug was at issue in Mova Pharm. Corp. v. Shalala?

A: 

Q10: Who said about a provision of Hatch-Waxman that : “[O]ne must admit that while the provision more naturally means what respondent suggests, it is somewhat difficult to understand why anyone would want it to mean that.”

A:  

Q11:   What drug was at issue in Roche v. Bolar?

A: 

Q12: How many years of exclusivity was granted to an NCE approved between January 1, 1982 and September 24, 1984?

A: 

Q13: What prescription NSAID drug got the benefit of this 10 year period?

A: 

Q14: How many patent term extensions has PTO issued –  fewer than 500 or more than 500? 

A: 

Q15: And for a total of how many years of extension – fewer than 1500 years or more  than 1500 years?

A: 

Q16: What is the shortest patent term extension granted?

A: 

Q17: What was the last provision of Hatch-Waxman to be negotiated?  And for whom was it a deal-breaker?

A: 

Q18: What was the first drug approved in a “paper NDA?”

A: 

Q19: Who have been FDA’s Chief Counsels since Hatch-Waxman was enacted?

A: 

Q20: Who was Paul Parkman?  And what was his most famous letter?

A: 

By David B. Clissold & Ricardo Carvajal –

As we discussed in a prior post, the FDC Act’s  ban on "characterizing flavors" in cigarettes took effect on September 22, 2009.  FDA marked the occasion by issuing a press release that highlights the effects of those cigarettes on youth, and by publishing an advisory to parents on “the serious risks associated with flavored tobacco products.”  According to that advisory, such products “[a]ppeal to kids,. . .[d]isguise the bad taste of tobacco,. . . [a]re just as addictive as regular tobacco products,. . . [and] [h]ave the same harmful health effects as regular tobacco products.”  Parents and other consumers are encouraged to submit an electronic report of the availability of a flavored cigarette that identifies the product and the date and location of purchase.  Consumers are also given the option of mailing packages, advertisements, or labels to the Center for Tobacco Products.  A Federal Register notice announcing the ban is scheduled to publish on September 25.

Perhaps not coincidentally, FDA has denied a citizen petition submitted by retailers that asked FDA to exercise enforcement discretion with respect to cigarettes that are not "expressly labeled" as containing fruit, candy, herb, or spice flavoring as a "characterizing flavor" of the product or its smoke, and to issue a regulation that defines a standard for flavored cigarettes.  In its denial letter, FDA noted that decisions regarding the exercise of enforcement discretion fall outside the scope of the citizen petition process.  Furthermore, FDA refused to issue the requested regulation on the ground that FDC Act section 907(a)(1) "provides sufficient clarity as to the definition of 'characterizing flavor.'"

By Alan M. Kirschenbaum –

The Senate Finance Committee began today to mark up its healthcare reform bill, the America’s Healthy Future Act of 2009.  In a previous post, we provided an outline of the provisions of the Chairman’s Mark that would specifically affect drug and device reimbursement, discounting, fees, and reporting.  Several of these provisions were amended today, including the following (page numbers refer to the Committee’s Modifications list):

• In one of three amendments favorable to generic drugs, the Medicaid Federal Upper Limit (FUL) provision of the Mark, which set the FUL at 175% of the weighted average of the AMPs of the therapeutically equivalent multiple source drugs, was amended to say “no less than 175%.”  Presumably, this would permit CMS to set a higher FUL if the agency deemed it appropriate, but there is no hint in the Mark of when a higher FUL might be warranted.  (p. 14)

• Another new provision favorable to generics would amend the civil monetary penalty against federal health care program beneficiary inducements (42 U.S.C. § 1320a-7a(a)(5)), which currently prohibits waivers of coinsurance except in cases of financial need.  The amendment would exempt sponsors of Medicare Part D plans to allow them to waive copayments for first fills of generic drugs as an incentive for Part D beneficiaries to try generics.  (p. 28)

• Another new provision would require the Comptroller General to review state laws that have a negative impact on generic drug utilization in federal programs due to restrictions such as limits on pharmacists’ ability to substitute generics, or carve-outs of certain classes of drugs from generic substitution.  (p. 14)

• The provision of the Mark that would impose Medicaid rebates on drugs dispensed by Medicaid managed care organizations was amended to exclude drugs purchased through the 340B program.  (p. 14)

• The provision that would have made prescription drug coverage mandatory for all Medicaid beneficiaries was stricken.  (p. 14)

The Senate Finance Committee will continue its mark-up tomorrow and hopes to conclude it by Sunday evening.

Meanwhile, in the House, the Energy and Commerce Committee will begin its second mark-up of its healthcare reform bill, H.R. 3200 (see our earlier post on this bill), and has released a list of amendments it will be considering.  One of these appears similar to the amendment described above that would exclude 340B drugs dispensed by Medicaid managed care organizations from Medicaid Rebate liability.  Others include an amendment to enhance compliance by manufacturers and covered entities under the 340B program, and a change that would appear, based on the brief description, to narrow the preemption provisions of the physician payments sunshine section of the bill.

We will continue to report on these bills as they work their way through Congress.

By Kurt R. Karst –      

Over the past several weeks there has been growing chatter about FDA’s Document Archiving, Reporting and Regulatory Tracking System (“DARRTS”) and how its implementation might affect generic drugs.  DARRTS is a Center for Drug Evaluation and Research (“CDER”) information technology platform developed to replace many of CDER’s core tracking systems, including those for ANDAs.  Earlier this year, FDA issued a Manual of Policies and Procedures (“MaPP”) – MaPP 6700.4 – on the use of DARRTS for systematically tracking post-market drug safety issues, which explains that “[u]ltimately, [DARRTS] will be the archival system of record for new drug applications (NDAs), biologics license applications (BLAs), and abbreviated new drug applications (ANDAs) . . . .”  Another MaPP, issued in April 2009 – MaPP 5210.3 – discusses the use of DARRTS in the Office of Generic Drugs’ (“OGD’s”) documentation of bioequivalence study reviewer productivity.

As DARRTS implementation moves forward, we understand that it will be used to, among other things, drive ANDA review priority based on a points system.  Point values may be assigned to an ANDA based on an overview of patent certifications and when an application may be eligible for final approval or tentative approval, as well as once a particular OGD review component (e.g., chemistry or bioequivalence) is completed.  The greater the number of points, the higher the application moves in the review queue.  The intent of using this new point system is reportedly to make more efficient use of OGD’s resources so that those applications that can or should be approved sooner than others will be prioritized over applications that might not be approved for several years (e.g., because an ANDA contains a Paragraph III Certification to a patent that expires in many years). 

Another effect of DARRTS implementation will be to create a new application numbering system.  For decades, FDA has used a numeric system that easily identifies an application as an NDA or ANDA.  For example, applications with a 20,000 or 50,000 series number are NDAs, and applications with a 70,000 or 90,000 series number are ANDAs.  Under DARRTS, however, all submissions will now be numbered sequentially beginning with 200,000 regardless of application type.  This change was recently criticized in a docket submission from a former FDA official:

The usefulness of being able to identify the type of application ANDA or NDA from the application number cannot be overstated.  This will no longer be possible unless this is reevaluated and changed by FDA.  The IT folks at FDA should serve the programs and cater to program needs not the other way around.  This is vital historical information and is very useful to industry to be able to quickly identify NDA or ANDA filings for planning, patent and other purposes.  The transparency has now been lost on this issue.

There is still much that is unknown about how DARRTS will be rolled out in OGD.  Perhaps FDA will explain these changes at an upcoming conference or in an announcement. 

By Carrie S. Martin –

On September 21, 2009, FDA announced in a Federal Register notice that the Agency plans to hold a public hearing to discuss issues regarding the promotion of FDA-regulated products – specifically prescription drugs, prescription biologics, and medical devices – via the Internet and social media.  Many in industry feel that guidance from FDA on this issue is long overdue.  

The meeting is intended to help FDA form its policy on the promotional of these products using the Internet and social media tools.  Of particular interest to the Agency is how “Web 2.0” can be used to promote products in a truthful, non-misleading, and balanced manner to both consumers and health care professionals (“HCPs”).  Web 2.0 includes new web development and design that facilitates interactive information sharing, such as social-networking sites (e.g., Facebook, Sermo), video-sharing sites (e.g., YouTube), wikis (e.g., Wikipedia), podcasts, blogs, and micro-blogs (e.g., Twitter).  The hearing will not address nonprescription drug promotion.

FDA invites comments on the “general concept” of Internet promotion, any particular aspect of Internet promotion, and the following questions: 

(1)    For what online communications are manufacturers, packers, or distributors accountable?  More specifically: 

• What criteria should be applied to determine when third-party communications are subject to substantive influence by companies that market products related to the communications/discussions?
• When should third-party discussions be treated as being performed by, or on behalf of, the companies that market the product?
• How should companies disclose their involvement or influence over discussions or material?
• Are there different considerations that should be weighed depending on the specific social media platform that is used or based on the intended audience?
• What is the experience to date with company communications being altered by third-parties? 

(2)    How can manufacturers, packers, or distributors fulfill regulatory requirements (e.g., fair balance) in their Internet and social media promotion, especially when some tools have space limitations or allow for real-time communications?  More specifically: 

• How should product information be presented to ensure that the user has access to a balanced presentation of risks and benefits?
• Are there data to support whether different types or formats of presentations have an impact on the public health?
• Are there ways to address regulatory concerns associated with space limitations or tools that allow for real-time communications to present product information?
• How should companies address the potential volume of information shared on various social media sites with regard to real-time information that is continuously posted and regulatory requirements to submit promotional materials to FDA as applicable?

(3)    What parameters should apply to the posting of corrective information on Web sites controlled by third-parties?  More specifically:

• Is there any data or research on how companies have approached these issues?
• Are there any criteria that could be used to determine how to correct misinformation on a Web site outside a company’s control?
• Should the parameters differentiate the prominence of the third-party site, its intended audience, its intended purpose, and/or the author of the information on the site?

(4)    When is the use of the links appropriate?  More specifically:

• What are appropriate techniques regarding the use of links (including between various social media tools) and is there data about whether or not users find these approaches to be misleading?
• Should parameters be established for links to and from Web sites?
• Is there data regarding how often users click on different categories of links (e.g., banner ads, sponsored links, organic search result links) to get additional information about products?

(5)    Questions specific to Internet adverse event reporting, including:

• How are entities with post-marketing reporting responsibilities using the Internet and social media tools to monitor adverse event information?
• How is adverse event information from these sources being received, reviewed, and processed?
• What challenges are presented in handling adverse event information from these sources?
• What uncertainties are there regarding what should be reported from these sources to meet FDA adverse event reporting obligations?

The meeting is scheduled for November 12 and 13, 2009 (8 a.m. to 5 p.m. each day) at the National Transportation Safety Board Conference Center in Washington, D.C.  Registration is required and must be submitted by October 9, 2009.  Participation will be determined on a first-come, first-served basis. 

To register or submit written comments, use the following address:  Division of Dockets Management (HFA305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, Maryland 20852.  Electronic registration and comments may be submitted via www.regulations.gov.  FDA will accept public comments through February 28, 2010. 

By Kurt R. Karst –      

A few months ago after FDA’s approval of an NDA for the Pancreatic Enzyme Product (“PEP”) CREON (pancrelipase) (amylase; lipase; protease) we queried whether FDA might apply a presumption in favor of New Chemical Entity (“NCE”) status for all PEPs, such that each drug would be granted a 5-year period of exclusivity.  There seemed to be good reason to conclude that FDA would presume NCE status for each PEP; however, it was not until earlier this week that FDA made public its exclusivity decision.

FDA stated its “presumption in favor of NCE status” policy in 2005 in the context of the Agency’s approval of various non-recombinant hyaluronidase drug products.  In the case of hyaluronidase, uncertainty arose from the fact that such drug products are complex proteins that are not fully characterized.  FDA stated that:

Generally, if the Agency has insufficient information to know whether a product contains a previously approved active moiety, the applicant would be required to submit an NDA containing substantial clinical safety and efficacy data.  These data requirements could reasonably be expected to be comparable to those that would be needed for approval of an NCE.  Under the presumption, if it is not known whether a product contains a previously approved active moiety, the product also would be treated as an NCE for marketing exclusivity purposes, and, accordingly, granted 5-year exclusivity.  [(emphasis added)]

In the case of PEPs, FDA had previously stated that given their complexity “it is unlikely that currently available physiochemical and biological analytical tools would be able to demonstrate that the active ingredients in [PEPs] from two different manufacturers are the same.”  So, when FDA approved another PEP in August 2009 – ZENPEP (pancrelipase) (amylase; lipase; protease) – it stood to reason that FDA determined that both recently approved PEPS – CREON and ZENPEP – would each be granted 5 year exclusivity in accordance with FDA’s “presumption in favor of NCE status” policy.  But it was not until FDA published its latest Orange Book Cumulative Supplement (pages A-32-33) that the decision to grant NCE exclusivity with respect to each product became public. 

There are still pending at FDA a couple of decisions concerning NCE exclusivity, including for VERAMYST (fluticasone furoate) Nasal Spray and VYVANSE (lisdexamfetamine dimesylate) Capsules.  FDA is expected to issue a ruling concerning VYVANSE later this month.

By Alan M. Kirschenbaum –

Today the Senate Finance Committee (“SFC”) released the Chairman’s Mark of the “America’s Healthy Future Act of 2009,” which currently is scheduled for Committee mark up next Tuesday, September 22.  Among the various health reform proposals in the House and Senate, the Senate Finance Committee bill is viewed as the approach most likely to succeed.  Although health care reform will substantially benefit drug and device manufacturers by increasing the insured population, the bills also seek to extract discounts from manufacturers to help pay for reform.  The SFC Chairman’s Mark is no kinder to manufacturers in this regard than the health care reform bill reported out of the House Energy and Commerce Committee on July 31, which was the subject of an earlier post. 

Both the SFC Chairman’s Mark and the House bill would increase the minimum Medicaid rebate, though the Mark would increase it more than the House bill, and, unlike the House bill, would impose increases on non-innovator as well as innovator drugs.  Other, more minor tweaks to the Medicaid Rebate Program are similar.  Both would change the Federal Upper Limit methodology, though the FULs in the Senate version would be higher.  Both bills would also require drug manufacturers to fund a 50 percent discount on drugs purchased by Medicare Part D beneficiaries in the coverage gap.  Both bills contain physician payment “sunshine” provisions, though the reporting requirements under the House bill are more extensive.  The major differences in regard to payments extracted from manufacturers are that the House bill would require drug manufacturer rebates for dual eligibles, while the SFC Chairman’s Mark would not.  On the other hand, the Mark would impose aggregate annual “sector” fees of $2.3 billion and $4 billion on the drug and device industries, respectively, to fund Medicare, while the House bill does not contain such fees.

You will find a summary of the drug- and device-related provisions of the SFC Chairman’s Mark here.  Please note that this summary only addresses provisions of the Mark that would most directly affect drug and device manufacturers.  There are many other aspects of this bill that would have an indirect but considerable impact on drug and device manufacturers.

The health care reform debate in Congress is fluid.  The Senate Finance Committee bill could change substantially in mark-up, or it might not be reported out of Committee at all.  The House Energy and Commerce Committee bill faces similar uncertainty as it goes to a potential second mark-up and to the House floor.  We will be following these developments closely and reporting on the aspects that most directly affect drug and device manufacturers.

By Kurt R. Karst –      

On September 15, 2009, FDA issued its long-awaited decision responding to several citizen petitions submitted in 2005 and 2006 (available here, here, here, and here) concerning the approval of ANDAs for generic versions of Wyeth Pharmaceuticals’ ZOSYN (piperacillin sodium; tazobactam sodium) Injection.  FDA’s decision to grant the petitions (and largely deny a Wyeth petition) and approve ANDAs reaffirms an Agency policy that FDA will, in the context of discontinued drug product formulations, waive its so-called “exception excipient regulations” to permit the receipt and approval of an ANDA for a drug product containing a so-called “non-exception excipient” change from the Reference Listed Drug (“RLD”).
 
FDC Act § 505(j)(4)(H) states that FDA must approve an ANDA unless, among other things:

information submitted in the application or any other information available to [FDA] shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.

FDA’s regulations implementing FDC Act § 505(j)(4)(H), generally, are found in the Agency’s ANDA content and format regulations at 21 C.F.R. 314.94.  Pertinent regulations on inactive ingredient changes for certain types of generic drug products are set forth in 21 C.F.R. § 314.94(a)(9).  FDA’s regulations for parenteral drug products at 21 C.F.R. § 314.94(a)(9)(iii) state:

Generally, a drug product intended for parenteral use shall contain the same inactive ingredients and in the same concentration as the [RLD] identified by the applicant under paragraph (a)(3) of this section.  However, an applicant may seek approval of a drug product that differs from the reference listed drug in preservative, buffer, or antioxidant provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product.

Preservative, buffer, and antioxidant changes in generic parenteral drug products are referred to as “exception excipients,” which may qualitatively or quantatively differ from the RLD formulation.  Other regulations at § 314.94(a)(9)(iv) identify exception excipients for generic ophthalmic and otic drug products (i.e., preservative, buffer, substance to adjust tonicity, and thickening agent).  Excipients not identified in these regulations are referred to as “non-exception excipients.”  These regulations find their parallel in 21 C.F.R. § 314.127(a)(8)(ii), which addresses the grounds for an FDA refusal to approve an ANDA for a parenteral, ophthalmic, or otic drug product.  For example, 21 C.F.R. § 314.127(a)(8)(ii)(B) states: “FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the [ANDA] unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the same concentration as the listed drug. . . .”

Notwithstanding FDA’s exception excipient regulations, the Agency has, on occasion, but only in very limited circumstances, waived its exception excipient regulations to permit the receipt and approval of an ANDA for a drug product containing a non-exception excipient change from the RLD.  Specifically, FDA has granted waivers under 21 C.F.R. § 314.99(b), which states that a generic applicant “may ask FDA to waive . . . any requirement that applies to the applicant under §§ 314.92 through 314.99.”  FDA can grant such a waiver if the Agency finds: “(1) the applicant’s compliance with the requirement is unnecessary for the agency to evaluate the application or compliance cannot be achieved; (2) the applicant’s alternative submission satisfies the requirement; or (3) the applicant’s submission otherwise justifies a waiver.”  21 C.F.R. § 314.90(b).

FDA has historically granted § 314.99(b) waivers when an ANDA applicant seeks approval to market a drug product containing a non-exception excipient used in a discontinued RLD formulation that is not used in the currently-marketed RLD formulation.  For example, in 2005, FDA granted a petition permitting generic applicants seeking approval to market generic SANDOSTATIN (octreotide acetate) Injection to substitute a different tonicity agent (a non-exception excipient change) and buffer system because “the inactive ingredients (including the buffer system and tonicity agent) used in the discontinued formulation of Sandostatin do not make that formulation unsafe. . . [and because] the discontinued formulation of Sandostatin is no less safe and effective than the new formulation.” 

FDA’s ZOSYN petition decision is in the same vein as the SANDOSTATIN petition response.  In September 2005, FDA approved an NDA supplement for a new formulation of ZOSYN containing edetate disodium dihydrate (“EDTA”) and citric acid monohydrate, which reportedly function in the drug product as a chelator (a non-exception excipient) and a buffer, respectively.  Several petitions were submitted to FDA requesting that the Agency: (1) determine that the formulation of ZOSYN originally approved by FDA was not discontinued for safety or efficacy reasons; and (2) accept ANDAs for generic versions of ZOSYN duplicating the discontinued formulations (i.e., without EDTA and citric acid).  In granting these petitions, FDA stated:

The Agency may rely on § 314.99(b) (21 CFR 314.99(b)) to grant a waiver of the regulation requirement – that the ANDA and NDA formulations contain the same inactive ingredients in the same concentrations as the RLD, with limited exceptions for preservatives, buffers, and antioxidants – insofar as the statutory requirement regarding safety of inactive ingredients has been met. . . .  FDA may approve ANDAs for piperacilin and tazobactam for injection duplicating the original Zosyn formulation.  Such ANDAs would differ from the reformulated Zosyn with respect to the inactive ingredient EDTA, which is not a preservative, buffer, or antioxidant.  Here, experience with Wyeth's original Zosyn formulation and FDA’s recent analysis has shown that the inactive ingredients in the ANDA for piperacilin and tazobaetam for injection duplicating the original Zosyn formulation are safe. . . .  Because the original Zosyn formulation clearly meets the statutory safety standard with respect to inactive ingredients, the Agency may rely on § 314.99(b) to grant a waiver of the regulation requirement that the ANDA formulation contain the same inactive ingredients in the same concentration with the limited exceptions for preservatives, buffers, and antioxidants.

It is also noteworthy that ZOSYN contains an old antibiotic drug and is subject to § 4 of the “QI Program Supplemental Funding Act of 2008” (the “QI Act”).  The QI Act was enacted on October 8, 2008 and amended the FDC Act to add new § 505(v) – “Antibiotic Drugs Submitted Before November 21, 1997” – to create Hatch-Waxman benefits for old antibiotics.  Under a transition provision included in the QI Act, NDA holders and patent owners can list patents in the Orange Book, and generic applicants can qualify for 180-day exclusivity.  Shortly after the enactment of the QI Act, a patent was listed in the Orange Book covering ZOSYN.  Those generic applicants who timely amended their pending ANDAs for generic ZOSYN to include a Paragraph IV Certification to that patent are eligible for shared 180-day exclusivity.

By Ricardo Carvajal –

FDA has issued a letter to the tobacco industry offering a reminder that, under the standard for cigarettes in FDCA section 907(a)(1)(A), a cigarette or any of its component parts may not contain “an artificial or natural flavor (other than tobacco or menthol) or an herb or spice, including strawberry, grape, orange, clove, cinnamon, pineapple, vanilla, coconut, licorice, cocoa, chocolate, cherry, or coffee, that is a characterizing flavor of the tobacco product or tobacco smoke.”  That prohibition on "characterizing flavors" takes effect on September 22, 2009, and any cigarette that violates the prohibition is adulterated and subject to seizure.  FDA has not explained what makes a flavor a "characterizing flavor."  However, those responsible for the violation may be subject to injunction, civil penalties, and criminal prosecution.  The letter states that FDA “intends to use the full range of enforcement tools within the Agency’s authority to ensure compliance with the new requirement.”

The standard for cigarettes applies to any tobacco product that meets the following definition:

(3) CIGARETTE.—The term “cigarette”—
(A) means a product that—
(i) is a tobacco product; and
(ii) meets the definition of the term “cigarette” in section 3(1) of the Federal Cigarette Labeling and Advertising Act [("FCLAA")]; and

(B) includes tobacco, in any form, that is functional in the product, which, because of its appearance, the type of tobacco used in the filler, or its packaging and labeling, is likely to be offered to, or purchased by, consumers as a cigarette or as roll-your-own tobacco.

Section 3(1) of the FCLAA defines a cigarette as “(A) any roll of tobacco wrapped in paper or in any substance not containing tobacco, and (B) any roll of tobacco wrapped in any substance containing tobacco which, because of its appearance, the type of tobacco used in the filler, or its packaging and labeling, is likely to be offered to, or purchased by, consumers as a cigarette described in subparagraph (A).”

The letter states that FDA will consider products that meet these criteria to be cigarettes, “even if they are not labeled as ‘cigarettes’ or are labeled as cigars or as some other product.”  This would seem to indicate that some manufacturers that have been reported to be revamping their flavored cigarette offerings to try to work around the prohibition may be in FDA's crosshairs.

By Kurt R. Karst –
 
At a September 10, 2009 Senate Judiciary Committee Executive Business Meeting, Senator Herb Kohl (D-WI) stated his plans to pursue a substitute amendment to S. 369, the Preserve Access to Affordable Generics Act, that would make significant changes to the proposed legislation.  (A webcast of the Executive Business Meeting is available here.  See minutes 46-49 for Sen. Kohl’s remarks.) 

Under the version of S. 369 Sen. Kohl introduced in February 2009, it would be unlawful for a person, in connection with the sale of a drug product, to be a party to any agreement resolving or settling a patent infringement claim in which a generic applicant receives anything of value, and for a generic applicant to agree not to research, develop, manufacture, market, or sell the generic product for any period.  Sen. Kohl’s substitute amendment would largely reverse course, permitting reverse payments between brand and generic companies if such companies can prove that the deals are “pro-competitive.”  The Federal Trade Commission (“FTC”) would reportedly have to challenge the deals and the burden would be on the companies to prove in court that the agreements are pro-competitive; however, it is unclear what evidence would be needed to prove pro-competitiveness.   In addition, we understand that Sen. Kohl’s substitute amendment would allow the FTC to levy fines of up to three times the revenue of the brand name drug in question if the agreement is found to be unlawful. 

Although the Senate Judiciary Committee was originally scheduled to vote on Sen. Kohl’s substitute amendment at the September 10th Executive Business Meeting, we understand that some Committee members requested an additional week to study the amendment, and that Sen. Orrin Hatch (R-UT) has written a letter to Sen. Kohl expressing his concerns about the proposal.  The Committee is scheduled to further consider – and likely vote on – the measure at its September 17th Executive Business Meeting.

If Sen. Kohl’s substitute amendment is passed, it will be at odds with the reverse payment provision added to the House Energy and Commerce Committee’s version of H.R. 3200, the America’s Affordable Health Choices Act, earlier this summer.  As we previously reported, in late July, the Committee passed by voice vote an amendment to H.R. 3200 sponsored by Rep. Bobby Rush (D-IL) that would prohibit reverse payment settlements between generic and brand-name drug companies.

By Ricardo Carvajal –

USDA’s Food Safety and Inspection Service (“FSIS”) has released a prepublication version of an Advanced Notice of Proposed Rulemaking (“ANPRM”) that seeks additional public input on the conditions under which FSIS should permit use of the claim “natural” in the labeling of meat and poultry products (FSIS has authority to review and approve labeling prior to marketing of such products).  FSIS previously signaled its intent to issue a proposed rule.  However, in response to a prior Federal Register notice and a public hearing that addressed the use of “natural” in labeling, USDA received over 12,000 comments that expressed a wide range of views.  In addition, FSIS  received several petitions requesting that FSIS adopt particular interpretations of “natural.”  The evident lack of any consensus on the meaning of “natural” has prompted FSIS to seek another round of comment.

In its ANPRM, FSIS asks for comment on numerous issues, including: whether FSIS should establish a definition of “natural” by regulation or maintain a more flexible definition by policy;  whether multi-functional ingredients (e.g., ingredients that may have both flavoring and antimicrobial effects) can properly be labeled as “natural;” whether the use of recently developed processing methods should be permitted for “natural” products; whether “enhancement” (i.e., addition of marinades/flavoring/tenderizing solutions) should be permitted in “natural” products; whether conditions under which animals are raised should be considered (the Agricultural Marketing Service currently permits use of the claim “naturally raised”); and whether there should be a single Federal definition of “natural” (currently FSIS and FDA maintain separate policies).  In addition, FSIS makes clear that it continues to consider the use of carbon monoxide in modified atmosphere packaging systems to be incompatible with a “natural” claim, and requests comment on that issue.

By Cassandra A. Soltis –

Regrow your hair.  Cure cancer.  Obtain a photographic memory.  These are just some of the claims that Kevin Trudeau, infomercial marketer extraordinaire, has made for various products over the years.  The Federal Trade Commission (“FTC”) is all-too-familiar with Mr. Trudeau and his promotional tactics: since 1998, Trudeau has entered into several Orders with the Agency that collectively made him: promise he would not misrepresent the benefits of any product without competent and reliable evidence; submit infomercials to the FTC before they are televised; and stop marketing Coral Calcium as a cure for cancer or from advertising any products in infomercials, except to promote his publications, provided he did not refer to any other product he was marketing.     

His troubles with the FTC resurfaced in 2007, when he began promoting his book The Weight Loss Cure “They” Don’t Want You To Know About.  The FTC brought civil contempt proceedings against Mr. Trudeau, arguing that he had violated a 2004 Consent Order’s command that he not misrepresent the content of his book.  FTC v. Trudeau, No. 08-4249, 2009 U.S. App. LEXIS 19318, at *11 (7th Cir. Aug. 27, 2009).  Trudeau countered that he was merely quoting what he wrote in the book.  However, the district court disagreed, finding that Trudeau could not cherry-pick certain phrases which “did not accurately portray the book’s overall content.”  Id. at *12.  The court found Trudeau in contempt of court, required that he pay $37.6 million, and banned him for three years from appearing in infomercials.  

Trudeau appealed to the court of appeals.  On August 27, 2009, the United States Court of Appeals for the 7th Circuit agreed with the district court’s contempt finding, stating that Trudeau “clearly misrepresented [his] book’s content.”  Id. at *3.

However, the Court of Appeals rejected the district court’s monetary sanction because the district court’s order did not indicate “how the court arrived at the figure it did, whether the award will be used to reimburse consumers, and what happens if there’s money left over after all reimbursements are paid.”  Id. at *38. 

In addition, the Court ruled that the district court had erred in the manner in which it had imposed sanctions.  It found that although the case was labeled as civil contempt, the district court had actually imposed a remedy that appeared to be a criminal contempt sanction, without providing certain constitutional safeguards that apply in criminal cases. 

The Court also found the infomercial ban to be improper because the ban was to last for three years, regardless of what Trudeau did in the future.  Id. at *63-65.   

If history is any indication, the courts have not seen the last of Kevin Trudeau.