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:
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:
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:
(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:
(3) What parameters should apply to the posting of corrective information on Web sites controlled by third-parties? More specifically:
(4) When is the use of the links appropriate? More specifically:
(5) Questions specific to Internet adverse event reporting, including:
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.
