By William T. Koustas –

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

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

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

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

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

By David B. Clissold & Ricardo Carvajal –

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

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

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

By Jeff Wasserstein –

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

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

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

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

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

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

FDA’s Definition of Combination Products

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

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

A combination product can be created either:

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

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

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

Which Current Good Manufacturing (CGMP) Regulations Apply?

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

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

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

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

The Proposed Rule

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

By Douglas B. Farquhar –     

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

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

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

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

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.