On March 21, 2008, the California EPA Office of Environmental Health Hazard Assessment (“OEHHA”) announced a workshop scheduled for April 18, 2008 to seek public input on the potential regulation of nutrients, such as vitamins and minerals, under Proposition 65 (the Safe Drinking Water and Toxic Enforcement Act of 1986, Health and Safety Code § 25249.5, et. seq.). Proposition 65 requires that the state publish and maintain a list of chemicals known to cause cancer or birth defects or other reproductive harm. The list now includes approximately 775 chemicals. If a chemical is on the list, then a product that contains that chemical must carry a specified warning statement unless the exposure poses no significant risk of cancer or is significantly below levels observed to cause birth defects or other reproductive harm. If exposure falls below OEHHA’s “safe harbor number” for that chemical, then no warning is required.

OEHHA’s workshop announcement states that “certain chemicals or compounds such as vitamins and minerals are necessary to promote human health or to ensure the healthy growth of food crops,” but that “[e]xcessive exposures to these same chemicals or compounds can cause cancer or adverse reproductive effects.”  OEHHA asserts that it is “seeking a way to balance the need for these nutrients with the necessity for providing Proposition 65 warnings for exposures to listed chemicals in foods.”

OEHHA has drafted language for a possible regulation. That language would exempt from the definition of “exposure” the consumption of a listed chemical in food if the person “causing the exposure” can show that the chemical is a nutrient that is “beneficial to human health,” and that the total amount of the chemical consumed in a food does not exceed the Recommended Daily Allowance (“RDA”) established by the Food and Nutrition Board of the Institute of Medicine (“IOM”).  If no RDA is established, then the total amount cannot exceed 20% of the Tolerable Upper Intake established by the IOM. A chemical would be considered “beneficial to human health” only if a daily value or allowance has been established by the IOM.

At least three points are notable about OEHHA’s proposal. First is the use of RDA’s as thresholds for determining whether an “exposure” has occurred. This is, to say the least, a novel use of RDA’s. Second is the notion that a nutrient is “beneficial to human health” only if a daily value or allowance has been established by the IOM. What of nutrients that have clearly established health benefits but have yet to make it into IOM’s Dietary Reference Intake Tables? Finally, there is the prospect that dietary supplements and conventional foods that comply with the applicable safety standards and labeling requirements in the Federal Food, Drug, and Cosmetic Act will nonetheless be made to bear a warning label in the state of California.

In a limited sense, California is not breaking new ground. Vitamin A already is included in the Proposition 65 list of chemicals. But the potential breadth of OEHHA’s proposal is such that it is impossible to not recall the long and painful history of FDA’s attempts to regulate the sale of articles containing “excessive” levels of vitamins and minerals. Decades of aborted rulemakings, protracted litigation, and legislative activity resulted in FDA’s virtual retreat from a playing field that proved formidably hostile. It’s hard to imagine that OEHHA has any interest in a reprisal of that experience – the state agency is prudently “requesting input from stakeholders in the enforcement and business communities, as well as other members of the public, concerning issues that may arise if OEHHA proceeds with such a regulatory proposal.” No doubt, OEHHA will get an earful. 

By Ricardo Carvajal, A. Wes Siegner, and Brian J. Donato

Earlier today, FDA issued a Federal Register notice notifying holders of applications for certain prescription drug products approved under FDC Act § 505(b) (NDA) or § 505(j) (ANDA) and biological products licensed under § 351 of the Public Health Service Act that they will be deemed to have in effect an approved Risk Evaluation and Mitigation Strategy (“REMS”) under the recently-enacted FDA Amendments Act (“FDAAA”).  FDA also made available a “Questions and Answers” document explaining the Federal Register notice and discussing, among other things, when a decision will be made for a specific application that a REMS is needed. 

FDAAA was signed into law on September 27, 2007.  Title IX, Subtitle A of FDAAA created new FDC Act § 505-1, which authorizes FDA to require applicants submitting a marketing application for a prescription drug or biological product to submit and implement a REMS if the Agency determines that such a mechanism is necessary to ensure that the benefits of the product outweigh its risks.  Certain products approved prior to the effective date of FDAAA are, under FDAAA § 909(b)(1), deemed to have a REMS in effect “if there are in effect on the effective date of this Act elements to assure safe use — (A) required under [FDA’s accelerated approval restricted distribution regulations at 21 C.F.R. § 314.520 or § 601.42]; or (B) otherwise agreed to by the applicant and the Secretary [of Health and Human Services] for such drug.”  New FDC Act § 505-1(f)(3) states that “elements to ensure safe use” include the following:

(A) health care providers who prescribe the drug have particular training or experience, or are specially certified (the opportunity to obtain such training or certification with respect to the drug shall be available to any willing provider from a frontier area in a widely available training or certification method (including an on-line course or via mail) as approved by the Secretary at reasonable cost to the provider);

(B) pharmacies, practitioners, or health care settings that dispense the drug are specially certified (the opportunity to obtain such certification shall be available to any willing provider from a frontier area);

(C) the drug be dispensed to patients only in certain health care settings, such as hospitals;

(D) the drug be dispensed to patients with evidence or other documentation of safe-use conditions, such as laboratory test results;

(E) each patient using the drug be subject to certain monitoring; or

(F) each patient using the drug be enrolled in a registry.

FDAAA § 909 took effect earlier this week, on March 25, 2008.  Under FDAAA § 909(b)(3) and today’s Federal Register notice, sponsors of products with “deemed REMS” applications must submit a proposed REMS to FDA by September 21, 2008.  “Such proposed strategy is subject to [FDC Act § 505-1] as if included in such application at the time of submission of the application to the Secretary.”

FDA’s Federal Register notice identifies 16 products (subject to 28 approved or licensed applications) approved prior to the effective date of FDAAA Title IX with “elements to assure safe use.”  According to FDA’s notice, “[a] drug will not be deemed to have a REMS if it has only a Medication Guide, patient package insert, and/or communication plan.” However, the Agency also states in its “Questions and Answers” document that “[i]n the future, a product with only a new or revised Medication Guide (without elements to assure safe use) will be under a REMS that will include a timetable for assessment of the REMS.”  The Agency requests that members of the public notify FDA if they are aware of products that should have a “deemed REMS” in effect, and also requests that application holders who do not believe their product should be on the list submit a letter to the Agency with justification as to why its product was improperly listed.

FDA is reportedly working on an interim guidance document that will describe the content and format of a proposed REMS and provide a template and a model REMS.  Violations of REMS are subject to stiff civil monetary penalties.  Under FDAAA, the penalties may not exceed $250,000 per violation, or $1 million for all violations adjudicated in a single proceeding.

Also earlier today, Dr. Douglas C. Throckmorton, Deputy Director of FDA’s Center for Drug Evaluation and Research, commented during a presentation concerning FDAAA implementation at the Food and Drug Law Institute’s Annual Conference here in Washington, D.C. that FDA will use its REMS authority “judiciously,” as there is a “targeted use” per FDAAA.  “Too many [REMS] would increase confusion in the system, [and] could increase errors and decrease [product] availability,” according to Dr. Throckmorton.

By Kurt R. Karst    

FDA and the University of Rhode Island College of Pharmacy will co-sponsor an interactive forum from June 30 through July 1, 2008 at the Hyatt Regency in Bethesda, Maryland on how and how not to communicate with FDA’s Office of Generic Drugs (“OGD”).  Forum presenters will also address how the legal landscape for generic drug companies has changed over the past few years following the enactment of the Medicare Modernization Act (“MMA”) in December 2003. A copy of the forum brochure is available here.  Forum presenters include an all-star cast from FDA, including OGD Director Gary J. Buehler and FDA’s Associate Chief Counsel for Drugs, Elizabeth H. Dickinson.  Hyman, Phelps & McNamara, P.C.’s Robert A. Dormer will present on post-MMA FDA decisions and related communications concerning 180-day generic drug exclusivity and other issues.

Last week, the Pennsylvania Court of Common Pleas of Philadelphia County (the lowest court of general jurisdiction in Pennsylvania) ruled in Clark v. Pfizer, Inc., Case No. 1819 (June Term 2004) – a class action lawsuit in which the plaintiffs allege that Parke-Davis (then a Warner-Lambert and now a Pfizer subsidiary) fraudulently promoted the anticonvulsant drug product NEURONTIN (gabapentin) for “off-label” uses (i.e., uses not approved by FDA) – that drug companies may have a legal obligation to class members for the money spent on generic versions of the drug product.  The class action lawsuit, brought on behalf of a certified class of persons “who purchased Neurontin, or its generic equivalent, gabapentin, in the Commonwealth of Pennsylvania” for unapproved uses, stems from a May 2004 agreement in which Warner-Lambert pled guilty to charges of illegally marketing NEURONTIN for off-label uses and paid $430 million to resolve federal charges.  NEURONTIN is approved in capsule, tablet, and oral solution dosage forms for the treatment of partial seizures associated with epilepsy and for the management of post-herpetic neuralgia.

The complaint (amended) in the lawsuit alleges that Gregory Clark and other plaintiffs were prescribed NEURONTIN for off-label uses (e.g., knee pain and bipolar disorder) “as a direct result of defendant’s active marketing and promotion of Neurontin for unapproved uses,” and that “plaintiffs and the class members sustained injuries, including ascertainable economic losses, by purchasing Neurontin” “as a direct and proximate result of [such] marketing and promotional schemes.”  The complaint includes several counts, including misrepresentation, negligence, negligence per se, breach of express warranty, and violations of the Pennsylvania unfair trade practices and consumer protection law. 

Judge Mark I. Bernstein’s March 14, 2008 ruling on Pfizer’s Motion for Partial Summary Judgment let stand the class action claims of negligent misrepresentation, negligence, and intentional misrepresentation regarding generic NEURONTIN manufactured by third-party drug companies.  “The legal question presented by this Motion for Partial Summary Judgment is whether under Pennsylvania Law, a drug company which negligently or intentionally perpetrates a fraud upon the medical community may be held responsible for sums paid to other drug manufacturers because of their misrepresentations,” Judge Bernstein states in his opinion. Assuming that the plaintiffs can prove their allegations at trial, “[u]nder Pennsylvania law, a defendant may be liable for misrepresentation to foreseeable plaintiffs even without any direct relations between the parties.”  According to the opinion:

Given the presumption that plaintiffs will be able to factually prove their allegations, the question presented becomes whether under Pennsylvania law, defendants owed any duty for which they can be held liable to purchasers of the drug because defendants had reason to anticipate those individuals would be induced to act.  The sale of generic Gabapentin for non-approved uses was not only foreseeable and predictable, but in fact predicted.  A heavily and successfully marketed drug will, at the time exclusive rights to the formulation have passed, be copied and sold by competitors as a generic equivalent.  The medical literature which plaintiffs claim was manipulated by defendants’, often referred to the generic chemical name rather than the defendants’ brand name.  When generic drugs become available they are often required by law or insurance companies to be prescribed as a substitute unless a physician specifically designates a brand name drug. . . . Defendants themselves estimated that Neurontin would lose between 65 and 95 percent of its market once its patents had expired.  Accordingly, defendant Pfizer proposed manufacturing its own “authorized” generic, to keep a portion of that market.  The significant increased sale of generic Gabapentin was a foreseeable result of defendants actions in marketing Neurontin for “off-label” use. 

The Pennsylvania court’s decision is contrary to other court decisions, which have found that the manufacturer of a brand name (i.e., innovator) drug product does not have a duty to those persons who purchase generic versions of the drug.  For example, the U.S. Court of Appeals for the Fourth Circuit held in 1994 in Foster v. American Home Products Corp., 29 F.3d 165 (4th Cir. 1994), that an innovator drug manufacturer does not owe a legal duty to a consumer of a generic drug.  Indeed, the U.S. District Court for the Eastern District of Pennsylvania stated in dicta in its May 2006 opinion in Colacicco v. Apotex, Inc., 432 F. Supp. 2d 514 (E.D.P.A. 2006) (which is on appeal to the U.S. Court of Appeals for the Third Circuit), that “name brand drug manufacturer does not owe a legal duty to consumers of a generic equivalent of its drug . . . .”  Nevertheless Judge Bernstein, citing the Pennsylvania Supreme Court’s 5-part test in Althaus v. Cohen, 756 A.2d 1166 (Pa. 2000), for determining whether a duty exists as discussed, determined that a duty existed for Pfizer. 

Judge Bernstein’s opinion also opines on the Colacicco case with respect to preemption of state law and takes a stab at FDA’s current pro-preemption policy on drug labeling.

Giving excessive deference to [FDA’s] reinterpretation of the Statute and the Regulations it administers as to preemption, the Colacicco Court found state claims preempted.  While taking the opposite position for many years, in 2006 the FDA promulgated a “preemption preamble” [(see pages 3933-36)] which for the first time stated that FDA labeling requirements did not represent a minimal safety standard, but did in fact “establish both ‘floor’ and ‘ceiling’.”  Although it might be said that this preamble was a politically motivated legal opinion about statutory construction and not one of “agency expertise,” in the field of Pharmaceuticals, the Colacicco Court found that the “FDA has acted within its authority and this Court must respect its expert judgment that an October 2003 warning label other than approved by the FDA would have been in direct actual conflict with Federal law.”  In contradiction, it is plaintiff herein who supports the FDA in the proposition that in violation of Federal law, defendants unlawfully manipulated scientific “truth” to convince by misrepresentation the entire medical community of the proposition that Gabapentin could be therapeutically used for indications never approved by the FDA.

While State Courts respect the reasoning of Federal Courts particularly when interpreting Federal law issues of nationwide import which impact upon Federal-State relations, the right of each sovereign State to protect its citizens is a matter of State law interpretation protected by the 10th Amendment to the United States Constitution.  As a Pennsylvania Trial Court, this Court is obligated to enforce state law until such time as the Supreme Court of the United States having actual authority determines that state law has been preempted.

Additional information on Clark v. Pfizer, Inc. is available from The Legal Intelligencer.

By Kurt R. Karst    

Earlier this month, we reported on a lawsuit filed by Teva Pharmaceuticals USA against FDA in the U.S. District Court for the District of Columbia concerning the relisting of U.S. Patent #5,158,952 (“the ‘952 patent”) in the Orange Book covering Janssen Phaemaceutica’s RISPERDAL (risperidone) Tablets.  The lawsuit was filed after FDA denied Teva’s citizen petition requesting that FDA relist the ‘952 patent and confirm the company’s eligibility for 180-day exclusivity based on its Paragraph IV certification to the patent. 

FDA states in its petition response that according to the Agency’s records, the ‘952 patent was delisted before Teva submitted ANDA #76-228 to FDA in August 2001, and that as a result, the delisting was proper and Teva is not eligible for 180-day exclusivity.  Teva had argued in its petition that because the “official Orange Book” (that is, the printed edition of the Orange Book) listed the ‘952 patent when the company submitted its ANDA to FDA, “FDA’s putative delisting of the ‘952 patent did not become effective until January 2002 when the official Orange Book reflected the delisting of that patent.”  Teva’s complaint and motion for preliminary injunction requests that the court enter an injunction compelling FDA to relist the ‘952 patent and restore the company’s Paragraph IV certification, declare that Teva is entitled to 180-day exclusivity, and enjoin FDA from granting final approval to other ANDAs for generic RISPERDAL during Teva’s 180-day exclusivity period.  The Orange Book currently lists one patent covering RISPERDAL, U.S. Patent #4,804,663, which expired on December 29, 2007, but that is covered by a period of pediatric exclusivity expiring on June 29, 2008. 

On March 14, 2008, FDA submitted its memorandum opposing Teva’s motion for a preliminary injunction.  According to FDA, “[t]here are numerous reasons to deny Teva’s request.”  In response to Teva’s argument that the printed version of the Orange Book is the official version of the publication and that the delisting of the ‘952 patent did not become effective until the official Orange Book reflected the delisting of the ‘952 patent in January 2002, FDA argues that “Teva’s contention is meritless.  Contrary to Teva’s arguments, neither the FDCA nor FDA regulation limit FDA’s publication of patent information to a paper version or preclude FDA from listing that information on its web site.”  FDA’s brief also opposes Teva’s request based on arguments that the company cannot show irreparable harm in the event Teva is denied injunctive relief, and that Teva has not shown that an injunction would serve the public interest.  FDA also takes issue with Teva’s “years-long delay” in raising the issue with FDA and states that “Teva’s lengthy delay . . . severely undermines its request for equitable relief, especially its allegations of irreparable harm.” 

On March 11, 2008, Mylan Pharmaceuticals Inc., which has a pending ANDA for Risperidone Tablets, submitted a motion to enter the case as an intervenor-defendant and a proposed answer.  According to Mylan’s motion, the company’s “final approval and market entry are at risk of being substantially delayed” because of Teva’s lawsuit, and as such, the court should permit Mylan to intervene “to ensure that its interests are protected.”  On March 20, 2008, the court granted Mylan’s motion to intervene.  Mylan is expected to file its brief in intervention later this week (by March 26th).  Teva’s reply brief is due by April 1, 2008.  Oral argument is scheduled for April 4, 2008. 

We will continue to update you on this interesting case as we learn more information. 

By Kurt R. Karst    

Last year, in our post titled “180-Day Exclusivity Forfeiture – A Zen Moment,” we reported on a case in which FDA took a stance with respect to the forfeiture of 180-day exclusivity eligibility that is reminiscent of the old “if a tree falls in the woods and nobody is there” enigma.  That case concerned Sandoz’s ANDA #76-969 for Metoprolol Succinate Extended-Release Tablets, 25mg, which was submitted to FDA in December 2003.  Sandoz was a “first applicant” eligible for 180-day exclusivity based on its Paragraph IV certification to a patent listed in the Orange Book covering the Reference Listed Drug (“RLD”), TOPROL-XL. 

In July 2006, FDA granted full approval for the 25mg drug product, but noted that Sandoz failed to obtain tentative approval within 30 months after the date on which the ANDA was filed, and might therefore not be eligible for 180-day exclusivity.  Under FDC Act § 505(j)(D)(5)(i)(IV), as amended by the Medicare Modernization Act:

The first applicant [forfeits 180-day exclusivity eligibility if the applicant] fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

Ultimately, FDA punted on the issue, and stated in the ANDA approval letter that “the agency is not making a formal determination at this time of Sandoz’s eligibility for 180-day generic drug exclusivity.  It will do so only if another applicant becomes eligible for approval within 180 days after Sandoz begins commercial marketing Metoprolol Succinate Extended-Release Tablets USP, 25 mg.” 

Over the past several weeks, FDA has been faced with two similar situations concerning FDC Act § 505(j)(D)(5)(i)(IV).  In one case FDA used language similar to that stated in the Sandoz ANDA approval letter.  In another case FDA made clear its determination that 180-day exclusivity eligibility was forfeited.

In the case of Perrigo R&D Co.’s ANDA #77-355 for a generic version of PEPCID COMPLETE (famotidine, 10mg; calcium carbonate, 800mg; magnesium hydroxide, 165 mg) Chewable Tablets, Perrigo was a “first applicant” based on the company’s Paragraph IV certification to 3 Orange Book-listed patents.  The ANDA was submitted to FDA in October 2004.  According to FDA’s February 2008 approval letter, “Perrigo failed to obtain tentative approval of this ANDA within 30 months of the date on which the ANDA was filed . . . .  However, the agency is not making a formal determination at this time of Perrigo’s eligibility for 180-day generic drug exclusivity.  It will so only if another applicant becomes eligible for approval within 180-days after Perrigo begins commercial marketing” of the drug product approved under ANDA #77-355. 

In the case of Watson Laboratories, Inc’s ANDA #77-219 for a generic version of CAMPTOSAR (irinotecan HCl) Injection, 20mg/mL, Watson was the first applicant to submit a submit a substantially complete ANDA with a Paragraph IV certification to an Orange Book-listed patent covering CAMPTOSAR.  As such, the company was eligible for 180-day exclusivity.  Watson submitted ANDA #77-219 to FDA in July 2004, and FDA tentatively approved the application in May 2007 – about 34 months after the date on which the application was filed.  In contrast to the two previous cases cited above, FDA’s February 20, 2008 approval letter to Watson states:

The ANDA filing date plus 30 months was January 26, 2007; therefore, this ANDA was not granted tentative approval within the 30-month period described in section 505(j)(D)(5)(i)(IV).  We also have determined that the requirements for approval of this ANDA were not changed or reviewed after your ANDA was filed . . . .  We therefore conclude that the 180-day exclusivity period . . . for Irinotecan Hydrochloride Injection, 20 mg/mL, was forfeited by Watson. 

FDA’s decision that Watson forfeited 180-day exclusivity eligibility was almost certainly prompted by the fact that several generic applicants that would have been subject to Watson’s 180-day exclusivity were pending and ready for approval.  Indeed, on February 27, 2008, just a few days after approving Watson’s ANDA, FDA approved 7 ANDAs for generic Irinotecan HCl Injection drug products.

FDA’s decision in the Watson case should put to rest any speculation based on the Agency’s previous letters that FDA will determine that a “first applicant” has not forfeited 180-day exclusivity eligibility if tentative approval was not granted within 30 months of the date on which the ANDA was filed and there are other ANDAs in the approval queue. 

By Kurt R. Karst    

Hyman, Phelps & McNamara, P.C. (“HPM”) is pleased to announce that Ricardo Carvajal has joined the firm as Of Counsel.  From 2002 to 2007, Mr. Carvajal served as Associate Chief Counsel in FDA’s Office of Chief Counsel, where he handled issues concerning foods (including conventional foods, bioengineered foods, dietary supplements, functional foods, and food additives), labeling compliance (such as the use of health, nutrient content, structure/function, and disease claims), Good Manufacturing Practices, and the Hazard Analysis and Critical Control Point regulations.  Mr. Carvajal has particular expertise in the regulation of products derived through biotechnology and nanotechnology, and in the regulation of allergens.  Mr. Carvajal has also worked on matters involving drugs, devices, and other products regulated by the FDA.  Mr. Carvajal received an M.S. in Biology from the University of Michigan, and his law degree from Northwestern University School of Law.  He is an active member of the Food and Drug Law Institute, the Institute of Food Technologists, and the American Bar Association.

Last month, we reported on the U.S. Supreme Court’s 8-1 decision in Riegel v. Medtronic, in which the Court provided a definitive decision preempting state tort law claims for medical devices subject to an approved Premarket Approval Application.  Immediately after the decision was issued, some members of Congress threatened to introduce legislation that would have the effect of overturning the Riegel decision.  Representative Henry Waxman (D-CA) vowed that Congress will “pass legislation as quickly as possible to fix this nonsensical situation,” and House Energy and Commerce Health Subcommittee Chair Rep. Frank Pallone (D-NJ) stated that the Riegel decision “shows why it is more necessary than ever for Congress to step in and restore the protections that patients are entitled to if they are the victim of a life-altering accident caused by a medical device.” 

A 2-page draft bill, styled as the “Medical Device Safety Act of 2008,” is being circulated on Capitol Hill.  The bill (apparently originating from Rep. Pallone) would amend § 521 of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to add a new subsection, titled “No Effect on Liability Under State Law,” which states: “Nothing in this section shall be construed to modify or otherwise affect any action for damages or the liability of any person under the law of any State.” If enacted, the amendment would apply to any civil action pending or filed on the date of the enactment of the Medical Device Safety Act of 2008.  Furthermore, the bill, if enacted, would be retroactive to the enactment of the Medical Device Amendments of 1976, which added FDC Act § 521.

By Kurt R. Karst    

Last Friday, Representatives Anna Eshoo (D-CA) and Joe Barton (R-TX) announced the introduction of H.R. 5629, the “Pathway for Biosimilars Act.”  We previously reported on a draft version of the bill circulated on Capitol Hill in February 2008.  H.R. 5629 will be referred to the House Energy and Commerce Committee where it will presumably be scheduled for a hearing or mark-up session later this year.

Much of H.R. 5629 is similar to the draft version.  The bill would amend § 351 of the Public Health Service Act (“PHS Act”) to permit the submission of an application for licensure of a biogeneric that includes, among other things, information demonstrating that the biogeneric is biosimilar to a reference product based on analytical studies, animal studies, and a clinical study or studies sufficient to demonstrate the safety and efficacy of the biosimilar product.  While the draft version would have permitted the Department of Health and Human Services Secretary (“Secretary”) to waive only analytical and animal studies (if determined to be unnecessary), H.R. 5629 also permits the Secretary to waive clinical studies (again, if determined to be unnecessary).

As with the draft version, H.R. 5629 provides the sponsor of the first biogeneric determined to be interchangeable with a reference product with a 24-month period of market exclusivity.  Innovator companies would get a period of 12-year exclusivity after initial licensure that may be increased to 14 years if during the 8-year period following licensure of the reference product, the Secretary approves a supplement for a “medically significant new indication” that would be a “significant improvement” compared to marketed products.  The 12-year or 14-year exclusivity periods may be extended by 6 months by pediatric exclusivity.  As is currently the law for pediatric exclusivity applicable to drugs under § 505A of the Federal Food, Drug, and Cosmetic Act (“FDC Act”), H.R. 5629 states that pediatric exclusivity would not apply to a biological product unless FDA determines no later than 9 months prior to the expiration of market exclusivity that pediatric studies submitted to the Agency in response to a Pediatric Written Request meet the terms of the request.  Other provisions in FDC Act § 505A would also apply to biologics under H.R. 5629.

New to H.R. 5629 is a provision stating that an application for a biological product must be submitted under PHS Act § 351, except that “an application for a biological product may be submitted under [FDC Act § 505] if  – (A) such biological product is in a product class for which a biological product in such product class is the subject of an application approved under [FDC Act § 505] not later than the enactment of [the Pathway for Biosimilars Act]; and (B) such application” was submitted to FDA before the enactment of the Pathway for Biosimilars Act or is submitted to FDA not later than 10 years after enactment.  This exception provision is limited so that “if there is another biological product approved under [PHS Act § 351(a)] that could be a reference product with respect to such application” (that is, if such application were submitted under new PHS Act § 351(k) for a biosimilar), then the application may not be submitted under FDC Act § 505.  If enacted, H.R. 5629 would also deem an application for a biological product approved under FDC Act § 505 to be a license under PHS Act § 351 on the date that is 10 years after the enactment of the Pathway for Biosimilars Act.

FDA Law Blog will continue to follow H.R. 5629 as it makes its way through the legislative gauntlet. 

By Kurt R. Karst    

There is a rather memorable (and hilarious) scene from the movie “Good Morning, Vietnam” in which Robin Williams (playing the role of Airman First Class and disc jockey Adrian Cronauer) questions an Army lieutenant about a 1965 press conference to be given by former Vice President Richard Nixon: “Excuse me, sir.  Seeing as how the VP is such a VIP, shouldn’t we keep the PC on the QT?  ‘Cause if it leaks to the VC he could end up MIA, and then we’d all be put out in KP.”

Although the use of acronyms in the military is ubiquitous and probably not matched in any other sector, the healthcare sector probably comes in a close second.  It not uncommon to read legal memoranda, court documents, or agreements in which a single sentence contains 5 or more acronyms.  Consider the following:  “FDA’s ANDA regulations implementing the FDCA provide that a PE drug product must be shown to be BE to the RLD covered under an approved NDA in order to obtain an AB rating in the OB.”  Translated: “The Food and Drug Administration’s Abbreviated New Drug Application regulations implementing the Federal Food, Drug, and Cosmetic Act provide that a pharmaceutically equivalent drug product must be shown to be bioequivalent to the Reference Listed Drug covered under an approved New Drug Application in order to obtain a substitutable rating in the Orange Book.” 

For those of us who need a guide to wade through the various FDA-related acronyms, FDA has created an Acronyms and Abbreviations Database, beginning with “A-V” (arteriovenous) and ending with “YTD” (year to date).  The database is not complete; however, visitors to FDA’s website may suggest new entries.  (How about “AAD” – Acronyms and Abbreviations Database?)

Click here for previous FDA Law Blog “Lighter Side” posts.

By Kurt R. Karst    

Under the Hatch-Waxman Act, certain patents related to products regulated by FDA are eligible for extension if patent life was lost during a period when the product was undergoing regulatory review.  The “regulatory review period” is composed of a “testing phase” and a “review phase.”  For a medical device subject to an approved Premarket Approval Application (“PMA”), the Patent Term Extension (“PTE”) statute at 35 U.S.C. § 156(g)(3)(B) states that the “testing phase” begins on “the date a clinical investigation on humans involving the device was begun and [ends] on the date [a PMA] was initially submitted with respect to the device.”  The “review phase” is the period between PMA submission and approval.  A patent term may be extended for a period of time that is the sum of one-half of the time in the “testing phase,” plus all the time in the “review phase.”  The “regulatory review period” must be reduced by any time that the applicant “did not act with due diligence.”  The total (calculated) regulatory review period may not exceed 5 years, and the extended patent term may not exceed 14 years after the date of PMA approval.  FDA’s regulations implementing the PTE statute are located at 21 C.F.R. Part 60.

In March 2004, FDA approved a PMA for Boston Scientific Corp.’s TAXUS™ Express 2™ Paclitaxel-Eluting Coronary Stent System (Monorail and Over-the-Wire).  In May 2004, Angiotech Pharmaceuticals, Inc. (“Angiotech”), which owns U.S. Patent #5,716,981 (“the ‘981 patent”) covering the TAXUS device, submitted a PTE application to the U.S. Patent and Trademark Office (“PTO”) requesting that the Office extend the ‘981 patent.  Angiotech calculated the maximum eligible PTE for the ‘981 patent to be 807 days.  This number is based on a testing period beginning on October 12, 2000, which is the initiation date of the first clinical trial involving the TAXUS device conducted in Germany, and a review period ending on March 4, 2004 when FDA approved the TAXUS PMA. 

In July 2006, FDA issued a Federal Register notice in in which the Agency determined the maximum eligible PTE for the ‘981 patent to be 716 days.  FDA’s PTE calculation was based on a testing period beginning on March 21, 2002 (and not October 12, 2000 as Angiotech claimed), when FDA records showed that the applicable Investigational Device Exemption (“IDE”) was determined to be substantially complete for permitting clinical studies to have begun, and a review period ending on March 4, 2004 with PMA approval.  On April 3, 2007, the PTO issued a notice of final determination to Angiotech stating that the PTE date would be calculated based on the March 21, 2002 IDE date and the March 4, 2004 approval date. Angiotech was given the option of filing a request for reconsideration of PTO’s determination. 

On May 3, 2007, Angiotech filed a request for reconsideration challenging the PTE determination.  Angiotech argued that the testing phase should have begun on October 12, 2000 when the first clinical trial was initiated in Germany, and not on the March 21, 2002 IDE date.  In referring to FDA’s decision that the testing phase began on March 21, 2002 instead of October 12, 2000, Angiotech’s request for reconsideration states that “[t]he apparent basis for this determination is [FDA’s] regulation governing calculation of the regulatory review period.  Although the statue mandates that the regulatory review period be deemed to commence ‘on the date a clinical investigation on humans involving the device was begun,’ 35 U.S.C. 156(g)(3)(B)(i), FDA’s regulation [at 21 C.F.R. § 60.22(c)(1)] imposes additional criteria.” 

Specifically, FDA’s regulatory review period determinations regulation at 21 C.F.R. § 60.22(c)(1) states:

[A] clinical investigation is considered to begin on whichever of the following dates applies:

(i) If an [IDE] is required, the effective date of the exemption. 

(ii) If an IDE is not required, but institutional review board (IRB) approval under [FDC Act § 520(g)(3)] is required, the IRB approval date.

(iii) If neither an IDE nor IRB approval is required, the date on which the device is first used with human subjects as part of a clinical investigation to be filed with FDA to secure premarket approval of the device.

According to Angiotech, FDA’s regulation is contrary to the plain meaning of 35 U.S.C. 156(g)(3)(B)(i).  “The statute directs that the PTE be based on a regulatory review period commencing ‘on the date a clinical investigation on humans involving the device was begun with no additional requirement,” states Angiotech. “The imposition of additional statutory requirements is contrary to the plain meaning of the statute.” 

Angiotech notes that “Congress made clear in the broader context of the PTE provisions that it intended to distinguish the testing phase of the [regulatory] review period based on the commencement of a clinical investigation from a [regulatory] review period based on the effective date of a statutory investigational exemption under the FDCA.”  In support of its argument, the company notes that in contrast to the device PTE provision, the drug PTE provision in 35 U.S.C. 156 specifically states that the testing phase begins on the effective date of an Investigational New Drug Application.  With respect to the PTO’s ability to reconsider FDA’s determination the request for reconsideration states that although “Congress directed that FDA determine the review period for the PTO, it is appropriate for the PTO to consider and to determine – with FDA – whether the terms of the PTE were established on extra-statutory, and unlawful, criteria.”

In late December 2007, the PTO denied Angiotech’s request.  Instead of addressing the difference between the PTE statute and FDA’s PTE regulations, however, the PTO defers to FDA’s authority over regulatory review period determinations.  Under 35 U.S.C. § 156(d)(2)(A), “[n]ot later than 30 days after the receipt of a [PTE] application by the [PTO], [FDA] shall review the dates contained in the application . . . and determine the applicable regulatory review period.”  Citing the statute and judicial precedent, the PTO concludes that “the statute thus plainly mandates the FDA to determine the regulatory review period,” and that the Office “has no authority to change or redetermine the regulatory review period determined by the FDA. . . .”

It is unclear whether Angiotech will fight on with the PTO in court, or perhaps raise the issue with FDA in a citizen petition or in informal communication. 

By Kurt R. Karst    

Hyman, Phelps & McNamara, P.C. (“HPM”) is happy to announce that 4 of the firm’s attorneys have been named Super Lawyers in the Washington, D.C., area.  The March 2008 edition of Washington, D.C. Super Lawyers identifies 17 Super Lawyers from the Food and Drug Bar.  HPM snagged 4 of the slots – more than any other firm!  Congrats go to HPM’s James R. Phelps, Paul M. Hyman, Robert A. Dormer, and Douglas B. Farquhar.

Earlier today, FDA announced that Dr. Janet Woodcock was appointed as the permanent director of FDA’s Center for Drug Evaluation and Research (“CDER”).  The CDER directorship is a position familiar to Dr. Woodcock.  She served as CDER Director from 1994 to 2005.  Dr. Woodcock’s most recent position at FDA was as the Agency’s Chief Medical Officer and Deputy Commissioner.  She also served as Acting CDER Director since October 2007.  Over the past several years Dr. Woodcock played a leading role in FDA’s “Critical Path” Initiative, which is designed to improve the scientific basis for medical product development, and spearheaded the Agency’s pharmacogenomics initiative, among other things.

In April 2007, we reported on a complaint filed by a group of non-profit organizations (including the Association of American Physicians & Surgeons, Concerned Women for America, Family Research Council, and Safe Drugs For Women) against FDA (and later Duramed Pharmaceuticals, Inc.) in the U.S. District Court for the District of Columbia requesting that the court, among other things, vacate FDA’s August 24, 2006 approval of a supplemental NDA (“sNDA”) for Duramed’s emergency contraceptive PLAN B (levonorgestrel) Tablets, 0.75mg.  FDA’s August 24, 2006 approval permitted Over-the-Counter (“OTC”) use of PLAN B in women 18 years and older and maintained prescription status for women 17 years old and younger. 

After FDA and Duramed filed motions to dismiss the case based primarily on a lack of standing, the Plaintiffs amended their complaint in an attempt to cure any deficiencies.  The amended complaint includes 8 counts:

(1) that the FDA’s approval was unlawful because the SNDA failed to demonstrate that Plan B was safe for OTC use by consumers age 18 and older;

(2) that the FDA’s approval violated the [Federal Food, Drug and Cosmetic Act (“FDCA”)] by allowing Plan B to be marketed as both a prescription and an OTC drug;

(3) that the FDA’s age-based decision violated the FDCA;

(4) that the FDA has created a “third class” of drugs in violation of the FDCA;

(5) that the FDA violated the [Administrative Procedure Act (“APA”)] by failing to conduct a rulemaking;

(6) that the FDA violated the FDCA by failing to conduct a rulemaking;

(7) that the [FDA was] improperly influenced by political pressure; and

(8) that the FDA is not authorized to impose administrative exhaustion requirements.

FDA and Duramed filed motions to dismiss the amended complaint (available here and here) arguing that the Plaintiffs lacked standing to bring any claim and that that they failed to exhaust their administrative remedies, and objecting to the Plaintiffs’ legal theories with respect to counts 2, 4, 5, and 6 of the amended complaint.  “Although plaintiffs have alleged numerous standing theories on behalf of women, physicians, and pharmacists within their membership, and the organizations themselves, their allegations are insufficient to establish the elements of standing on behalf of any of these subgroups or individuals,” states FDA’s memorandum in support of the Agency’s motion to dismiss. “Similarly, plaintiffs have failed to allege a cause of action within the Court’s jurisdiction.  There is no right under the FDCA or APA for members of the general public to challenge or participate in a drug application proceeding.  Plaintiffs have also failed to exhaust administrative remedies as required by FDA regulations . . . .”

On March 4, 2008, Judge John Bates granted FDA’s/Duramed’s motion to dismiss.  In the memorandum opinion accompanying the dismissal order, Judge Bates ruled that the court has no jurisdiction to entertain the amended complaint because of the plaintiffs’ lack of standing to assert the claims in the complaint, and because the plaintiffs also failed to exhaust their administrative remedies, thereby further rendering the action nonjusticiable. 

With respect to standing, the plaintiffs challenging FDA articulated a representational standing argument in their court papers based on several alleged injuries flowing from FDA’s August 24, 2006 PLAN B approval.  The court did not buy the argument and stated that “Plaintiffs have failed to establish standing because they lack a sufficient personal stake in the outcome of the litigation so as to warrant the invocation of federal-court jurisdiction.” 

On the issue of failure to exhaust administrative remedies raised by FDA and Duramed in their motions to dismiss, the court noted that “[t]his threshold issue presents a more difficult question.”  The plaintiffs argued in their court papers, among other things, that 21 C.F.R. § 10.45(e), which permits “interested persons” to, under certain circumstances, “request judicial review of a final decision of the [FDA] Commissioner in the courts without first petitioning the Commissioner for reconsideration or for a stay of action,” allowed them to proceed to court without first presenting their arguments to FDA, because the Agency’s PLAN B sNDA approval was final agency action.  The court ultimately disagreed: “Although plaintiffs’ interpretation of the regulatory requirements has some surface appeal, it would allow ‘interested parties’ to bypass the administrative remedies and would undermine the entire regulatory process” (internal quotations omitted).

It is unclear whether the organizations challenging FDA’s PLAN B approval will appeal the district court decision or will first exhaust their administrative remedies at FDA – or perhaps abandon all hope of vacating the PLAN B approval.  Stay tuned!

By Kurt R. Karst    

On February 29, 2008, Judge Stadtmueller of the United States District Court for the Eastern District of Wisconsin dismissed a lawsuit brought by Schering-Plough Healthcare Products, Inc. (“Schering”) against three manufacturers of prescription polyethylene glycol 3350 (“PEG”), a laxative drug product.  In its lawsuit, Schering sought to use the Lanham Act, 15 U.S.C. § 1125, (along with state law claims) to privately enforce the Federal Food, Drug, and Cosmetic Act (“FDC Act”).  The court, following the reasoning of many other courts, held that Schering could not do so and dismissed the case.  Hyman, Phelps & McNamara, P.C., represented one of the defendants in the case. 

In October 2006, FDA approved Schering’s New Drug Application (“NDA”) (#22-015) to switch the company’s PEG product, MIRALAX, from prescription to Over-the-Counter (“OTC”) use – a so-called “Rx-to-OTC switch.”  MIRALAX was first approved in February 1999 under NDA #20-698 for prescription use only.  Schering began marketing OTC MIRALAX in early 2007.  Schering received 3 years of market exclusivity for the Rx-to-OTC switch. 

Prior to Schering’s switch, FDA had approved three Abbreviated New Drug Applications (“ANDAs”) for prescription PEG drug products.  Those three manufacturers had used prescription MIRALAX as their reference listed drug (“RLD”) in their ANDA submissions.

Following FDA’s approval of Schering’s OTC switch NDA, an Agency employee sent letters to the three generic manufacturers of prescription PEG products expressing the views that: (1) the FDC Act prohibits simultaneous prescription and OTC marketing of the same drug; and (2) the generic manufacturers’ prescription products were misbranded because they were labeled as “Rx only.”  FDA did not attempt to withdraw ANDA approval, however.

Schering brought suit alleging that the labeling of the generic prescription PEG products was false and misleading under the Lanham Act and Wisconsin law because the products’ labeling contained the statements “prescription only” and “Rx only.”   Schering sought partial summary judgment as to liability under the theory that the generic manufacturers’ prescription labeling was “literally false,” a claim, that if proven, establishes liability under the Lanham Act, even in the absence of a showing of consumer confusion.  The defendants opposed Schering’s motion for partial summary judgment, arguing that their labeling was not false, but in fact true and required by FDA, and that the terms “prescription only” and “Rx only” referred to each of their own products, and not to all PEG products.  The court found the defendants’ arguments persuasive and denied Schering’s motion for partial summary judgment.

Additionally, the defendants sought dismissal of Schering’s complaint on the grounds that it constituted an attempt to privately enforce the FDC Act in an area where FDA had not definitively interpreted the law.  The court agreed with the defendants, and dismissed the complaint.  In so deciding, the court rejected Schering’s argument that FDA opined on the defendants’ labeling because FDA employees had sent letters to the defendants.  Following established precedent, and FDA’s own regulations, the court reasoned that the letters did not constitute an official FDA determination.

By James P. Ellison