Hyman, Phelps & McNamara, P.C. is very pleased to announce that Jeffrey K. Shapiro has joined the firm as a director. Prior to joining the firm, Mr. Shapiro was a partner at Hogan & Hartson. Mr. Shapiro’s practice focuses primarily on assisting medical device and diagnostic manufacturers in complying with FDA regulatory requirements. Mr. Shapiro assists clients with obtaining premarket clearance or approval and compliance with postmarket requirements, such as labeling and advertising, the quality system regulation, adverse event reporting requirements, the regulation of in vitro diagnostic assays and analyte specific reagents, and responding to Form 483s and Warning Letters. He has extensive experience in FDA regulatory aspects of mergers and acquisitions, supplier contracts, and filings with the U.S. Securities and Exchange Commission. Mr. Shapiro frequently advises clients in combination product and product jurisdiction matters. For many years, he has assisted clients in addressing FDA’s evolving regulation of human and cellular based tissue products, along with state licensure requirements in that area. Mr. Shapiro is the co-editor of “Promotion of Biomedical Products,” a textbook on FDA’s regulation of promotion and advertising, and is also the co-author of the book, “Combination Products: How to Develop the Optimal Strategic Path for Approval.” He has authored numerous articles.

On April 20, 2007, Arnold & Porter submitted a citizen petition and a petition for stay of action on behalf of Medicis Pharmaceutical Corp. asking FDA to change the Agency’s policy with respect to Hatch-Waxman patent and exclusivity benefits for combination drugs containing a so-called “old” antibiotic.  “Old” antibiotics are antibiotic active ingredients (and derivatives of such ingredients) included in an application submitted to FDA for review prior to November 21, 1997, the date of enactment of the 1997 FDA Modernization Act (“FDAMA”).  The Medicis petitions concern the company’s combination drug product ZIANA (clindamycin phosphate; tretinoin) Gel, which the Agency approved in November 2006 for the treatment of acne vulgaris, and which contains the “old” antibiotic clindamycin. FDA’s decision on the Medicis petitions will determine whether such combination drugs are eligible for Hatch-Waxman patent and non-patent marketing exclusivities.

The Medicis citizen petition asks that FDA:

1. . . . .reconsider, as a matter of policy, its current position that any combination drug that has, as one of its active ingredients, a pre-1997 antibiotic ingredient is denied the incentives of market exclusivity and patent listing in that FDA reverse that position[; and]

2. . . . list the patent submitted for the Medicis product Zianaä and acknowledge the 3-year period of market exclusivity earned by that product.

The Medicis petition for stay of action asks that FDA:

1.  prevent the approval of any ANDA or Section 505(b)(2) application referencing the Zianaä NDA during the 3-year [period] of market exclusivity that would be earned by the Zianaä application if the citizen petition is granted, and

2.  provisionally list the patent submitted by Medicis for Zianaä in the Orange Book.

FDA’s policy on patent and exclusivity benefits for combination drugs containing “old,” pre-FDAMA antibiotics stems from the Hatch-Waxman Act, which excluded antibiotic drugs approved under FDC Act § 507 from such benefits. 

FDAMA repealed FDC Act § 507 and required all NDAs for antibiotic drugs to be submitted under FDC Act § 505.  FDAMA included a transition provision declaring that an antibiotic application approved under § 507 before the enactment of FDAMA would be considered to be an application submitted, filed, and approved under FDC Act § 505. 

Congress created an exception to this transition provision.  FDAMA § 125(d)(2) exempts certain antibiotic applications for antibiotic drugs from those provisions of § 505 that provide patent listing, patent certification, and marketing exclusivity.  Specifically, FDAMA § 125(d)(2) exempts an antibiotic application from Hatch-Waxman benefits when “the drug that is the subject of the application contains an antibiotic drug and the antibiotic drug was the subject of an application” received by FDA under § 507 of the FDC Act before the enactment of FDAMA (i.e., November 21, 1997). 

Thus, applications for antibiotic drugs received by FDA prior to November 21, 1997, and applications submitted to FDA subsequent to November 21, 1997 for drugs that contain an antibiotic drug that was the subject of an application received by FDA prior to November 21, 1997 are within the FDAMA § 125(d)(2) exemption and are not eligible for Hatch-Waxman benefits.  Applications for antibiotic drugs not subject to the FDAMA § 125(d)(2) exemption are eligible for Hatch-Waxman benefits.  A 1998 FDA guidance document explains the effects of FDAMA § 125 in greater detail. 

On January 24, 2000, FDA published proposed regulations in the Federal Register that include a list of “old,” pre-FDAMA antibiotic drugs not subject to Hatch-Waxman benefits.  The list includes clindamycin.  FDA has not yet promulgated final regulations.  In addition to the specific chemical substances listed, the list also includes “‘any derivative’ of any such [listed] substance, such as a salt or ester of the [listed] substance.”

The Medicis petitions claim that FDA’s interpretation of FDAMA § 125(d)(2) “requires unwarranted verbal gymnastics with respect to the meaning of ‘drug,’” and that it:

is not a sensible way to read a statute.  Instead, Congress clearly intended the reference to “contains” to follow the normal understanding of the term: when one asks “what does a combination of tretinoin and clindamycin contain,” the answer is “tretinoin and clindamycin,” not “clindamycin” . . . .  Thus, the drug product is in common parlance the active ingredient or ingredients it contains.  If the word “contains” is read as intended to mean “is,” the statute then parses: the statutory incentives are not available when the drug product that is the subject of the application is an antibiotic drug product and that antibiotic drug product was the subject of an application for marketing under Section 507 on the FDAMA effective date.

If FDA grants the Medicis petitions, it is unclear how the Agency might retroactively apply its decision to approved marketing application for combination drugs containing an “old” antibiotic previously denied Hatch-Waxman benefits.

On April 20, 2007, FDA’s Division of Drug Marketing, Advertising, and Communications (“DDMAC”) issued a Warning Letter to Alcon Laboratories, Inc. concerning the company’s promotion of CIPRODEX (ciprofloxacin, 0.3%; dexamethasone, 0.1%) Sterile Otic Suspension in a retail sell sheet and a sales aid.  FDA approved CIPRODEX in 2003 for the treatment of acute otitis media and acute otitis externa in certain pediatric patients. 

According to DDMAC’s Warning Letter:

Both the retail sell sheet and sales aid omit material facts about Ciprodex, including important risk information and limits to Ciprodex’s indication; the sales aid also makes numerous unsubstantiated superiority claims. Therefore, the materials misbrand the drug in violation of the [FDC Act], 21 U.S.C. §§352(a) and 321(n). These violations are concerning from a public health perspective because they suggest that Ciprodex is safer or more effective than has been demonstrated, and they encourage use in circumstances other than those for which the drug has been shown to be safe and effective.

DDMAC found that the main page of the retail sell sheet contains efficacy claims for CIPRODEX, but no risk information.  Further, “the retail sell sheet claims Ciprodex is ‘approved for the treatment of acute otitis media with tympanostomy tubes and acute otitis externa.’ This claim misleadingly broadens the drug’s indication by failing to reveal, for example, that it is only approved for use in the treatment of certain susceptible isolates of the designated microorganisms causing acute otitis media and acute otitis externa infections.”

DDMAC’s Warning Letter also cites Alcon’s sales aid for making several unsubstantiated CIPRODEX superiority claims over CORTISPORIN (neomycin, 0.35%; polymyxin B, 10,000 IU/mL; hydrocortisone, 1%) Otic, including that:

• CIPRODEX superiority claims about cure rates are not valid, as the referenced study found no significant difference in cure rates between the two drugs (although there were numerical differences);
• Comparisons of the two drugs in the area of pain relief are considered inappropriate because the references cited do not prespecify this comparison as a study endpoint;
• Claims about superior efficacy as an anti-inflammatory are not substantiated, as the study did not demonstrate a significant difference between the drug at three of the four time points studied;
• Claims that CIPRODEX has a lower rate of treatment failures are not supported by references, because this was not a prespecified analysis in the references and the results are not consistent across studies; and
• Claims about superior safety are not substantiated, because the claims exaggerate the risk of CORTISPORIN and are based on results found in experimental conditions that did not mimic clinical usage.

The Warning Letter also cites as an “omission of material fact” the failure of the sales aid to present a warning of skin rash and hypersensitivity associated with CIPRODEX.

DDMAC’s Warning Letter to Alcon is yet another indication that the Division, due to limited resources, will continue to focus its enforcement efforts on marketing materials that have the potential to most adversely affect the public health.  That is, those materials that omit or minimize risk information, and those materials that use misleading (comparative) safety and efficacy claims.  In 2006, of the 22 Warning Letters issued by DDMAC, only one did not cite the omission or minimization of risk as a violation. 

Earlier this year, FDA proposed the creation of a user fee system to fund the review of direct-to-consumer advertisements.  If implemented as part of the reauthorization of the Prescription Drug User Fee Act (“PDUFA IV”), it is possible that DDMAC will have the resources to broaden the Division’s enforcement focus.

RELATED READING:

• Washington Legal Foundation FDA/DDMAC Watch
• April 17, 2007 FDA Testimony Before House Subcommittee on PDUFA IV

By Dara Katcher Levy

On April 13, 2007, the U.S. Court of Appeals for the District of Columbia ruled in Moms Against Mercury v. FDA that the court lacks subject matter jurisdiction to decide whether FDA should classify “pre-amendment” Encapsulated Amalgam Alloy and Dental Mercury (“EAADM”) devices.  The Petitioners, four organizations representing the economic, health, and environmental interests of their members and the public generally, and five individuals, contend that FDA’s decision not to classify EAADM violates the FDC Act.  They petitioned the court in April 2006 to order FDA to classify EAADM, and to remove the medical device from the market until the Agency has made a classification decision. 

The FDC Act, as amended by the 1976 Medical Device Amendments, authorizes FDA to regulate medical devices.  FDA regulates devices by placing them into one of three classes on the basis of the controls necessary to reasonably assure their safety and effectiveness. Class I or II devices require the manufacturer to submit a premarket notification (i.e., a 510(k)) requesting permission for commercial distribution. Class III devices, which are deemed by FDA to pose greater risk than Class I and II devices, require FDA approval of a Premarket Approval (“PMA”) application. Pre-amendment devices refer to devices legally marketed in the United States before the enactment of the 1976 Medical Device Amendments (i.e., May 28, 1976) that have not been significantly changed or modified since then, and for which a regulation requiring a PMA application has not been published by FDA.  Pre-amendment devices are considered to be “grandfathered” devices and do not require a 510(k).

In dismissing the Petitioners’ petition, the court stated:

As to subject matter jurisdiction, FDA’s failure to classify a device does not directly give rise to judicial review in this Court under the FDCA. Under section 360g, persons who are adversely affected by specified FDA regulations or orders may file, in the courts of appeals, a petition for judicial review within thirty days of the relevant FDA action. 21 U.S.C. § 360g(a). Specifically, petitioners invoke provisions authorizing this Court’s review of three FDA decisions: (1) subjecting a device to pre-market approval under subsection (a)(4); (2) determining that a post-amendment device is substantially equivalent to a pre-amendment device under subsection (a)(8); and (3) reclassifying a device from one class to another under subsection (a)(9). As petitioners concede, however, the FDA has engaged in none of these actions with regard to EAADM.  These provisions thus cannot support jurisdiction in this Court.

Shortly after the court issued its ruling, Petitioners’ counsel sent a letter to FDA stating that “FDA’s policy on mercury amalgam is legally unsustainable, intellectually indefensible, and morally unconscionable,” and that FDA “needs to choose between (1) compliance with the law vs. covering for errant colleagues, (2) children’s health vs. dentist economics, and (3) the integrity of an agency committed to ending mercury vs. special privileges accorded a mercury-using special interest group by the Center for Devices.” 

It has been reported that a second lawsuit against FDA is in the works, this time calling for EAADM to be permanently removed from the market.  Congress might also hold hearings on the health risks associated with EAADM, and Representatives Dan Burton (R-IN) and Diane Watson (D-CA) reportedly plan to reintroduce legislation that would phase-out dental amalgams.

RELATED READING:

• Consumers For Dental Choice – Information on Moms Against Mercury v. FDA.

On April 16, 2007, Cell Therapeutics, Inc. (“CTI”) agreed to pay $10.5 million to resolve allegations of the company’s illegal marketing of TRISENOX (arsenic trioxide), a prescription drug indicated for treatment of refractory or relapsed acute promyelocytic leukemia.  The case arose out of a complaint filed by a whistleblower (relator) under the Federal False Claims Act in which the Government intervened.  The Complaint in Intervention alleged that CTI promoted TRISENOX for off-label uses, which caused doctors to prescribe TRISENOX and submit claims to Medicare for uses not approved or medically accepted.  The complaint also alleged that CTI used illegal kickbacks to induce physicians to prescribe TRISENOX in violation of the Federal healthcare program antikickback statute.

According to the Complaint in Intervention, CTI allegedly implemented a plan to convince physicians and Medicare carriers that various off-label uses of TRISENOX were medically accepted and eligible for Medicare reimbursement.  Many oncologists rely on the Compendia Based Drug Bulletin to determine whether a drug is listed as medically accepted in the major medical compendia.  CTI allegedly gave the publisher of the Bulletin an educational grant of $10,000 per year in exchange for listing TRISENOX’s off-label indications in the Bulletin in a manner indicating that they were approved by the compendia, when they were not.  The publishers of the Bulletin also agreed to ship 3,000 copies of the next 3 issues of the Bulletin to CTI.  CTI then distributed copies of Bulletin to physicians and sent letters to Medicare carriers referring to the Bulletin, claiming that the off-label uses were medically accepted.  Many carriers paid claims for TRISENOX based on these false representations.

According to the Settlement Agreement, CTI has contended that to the extent it provided any false or misleading statements regarding the availability of Medicare reimbursement for TRISENOX, such statements were due to negligent advice provided by a third party, The Lash Group.  This subject of the advice provided by the Lash Group is the subject of a lawsuit between CTI and The Lash Group, Cell Therapeutics, Inc. v. The Lash Group et al., No. 07-310-JLR (W.D. Wash.).

The Complaint in Intervention also alleged that CTI provided kickbacks to physicians to induce prescribing of TRISENOX, including:

•         Sham consulting agreements in which physicians were paid $500-$1,000 to attend conferences in order to listen to presentations on off-label uses of TRISENOX;

•         Consultant dinners at lavish restaurants with honoraria;

•         Advisory boards held at resort locations where all expenses, including entertainment, were paid for by CTI and attendees received $1,000 honoraria

•         Monetary incentives to high prescribers in the form of speaker agreements in which physicians were paid $1,500 per lecture to discuss TRISENOX, especially off-label uses;

•         Grants to reward physicians who demonstrated that they were advocates and active prescribers of TRISENOX (the grants ostensibly were for clinical studies but required little of the physicians and were paid out of the marketing budget);

•         Purported independent CME programs that were not independent; and

•         Routine monitoring of return on investment from “consultant” meetings, advisory boards, and CME programs

CTI is not currently manufacturing, marketing, selling, or distributing any products reimbursed by Federal health care programs.  For the next five years, CTI has agreed to notify the Office of Inspector General (“OIG”) of the Department of Health and Human Services and negotiate and enter into a Corporate Integrity Agreement prior to commencing the manufacture, marketing, sales, or distribution of such products.  According to the Settlement Agreement, the OIG has agreed to refrain from seeking permissive exclusion from the Federal health care programs, but it has reserved its right to comply with its statutory obligation to pursue mandatory exclusion for CTI.

By Michelle L. Butler

On April 18, 2007, Analysis Group, Inc. announced the release of a report assessing the effects of the market entry of authorized generics on paragraph IV patent certifications.  FDA has described an authorized generic as “[a]ny marketing by an NDA holder or authorized by an NDA holder, including through a third-party distributor, of the drug product approved under the NDA in a manner equivalent to the marketing practices of holders of an approved ANDA for that drug.”  The introduction of an authorized generic may be timed to coincide with either the end of the NDA holder’s period of marketing exclusivity for the brand name drug before there is generic competition, or with a generic applicant’s 180-day exclusivity.

The Analysis Group report, titled “Do Authorized Generic Drugs Deter Paragraph IV Certifications,” was authored by Ernst R. Berndt of MIT’s Sloan School of Management and the National Bureau of Economic Research and Richard Mortimer  and Andrew Parece from the Analysis Group.  According the authors, who analyzed three datasets on paragraph IV certifications:

[D]espite increasing and relatively high rates of authorized generic entry, the rate of paragraph IV certifications is higher than it has ever been. . . .  [E]ven when authorized generic entry reduces the expected gains from filing paragraph IV challenges, the recent evidence is clear that sufficient incentives remain so that in spite of recent increased authorized generic entry, the intensity of filing Paragraph IV challenges remains high.  There is no evidence to suggest that authorized generic entry causes delayed generic entry.

The Analysis Group report is one of several reports released over the past year on authorized generics, including reports by the Congressional Research Service, GPhA, and IMS Consulting for PhRMA.  GPhA’s report concludes that authorized generics “significantly reduce incentives for independent generic firms to challenge invalid brand name patents and to develop non-infringing processes.”  The report prepared for PhRMA concludes that authorized generics lead to lower drug prices for consumers.

Congress has also taken an interest in authorized generics.  In January 2007, Sen. Jay Rockefeller (D-WV) introduced S. 438, the Fair Prescription Drug Competition Act.  If enacted, S. 438 would prohibit the marketing of authorized generics during a generic applicant’s 180-day exclusivity period.  The House version of S. 438, H.R. 806, was introduced by Rep. Jo Ann Emerson (R-MO) in February 2007.  The bills have been referred to committee.  Also, as discussed in the RAPS Focus article below, Congress has changed the Medicaid rebate calculation to include sales to authorized generic distributors in the brand manufacturer’s price calculation.

RELATED READING:

• RAPS Focus Article on Authorized Generics

Hyman, Phelps & McNamara, P.C. is pleased to announce that Carrie S. Martin has joined the firm as an associate.  Ms. Martin earned a law degree with honors from The George Washington University Law School in 2004. She served as an Articles Editor for the American Intellectual Property Law Association Quarterly Journal, in which her student note was published.  Ms. Martin graduated magna cum laude from the University of Arizona with a Bachelor of Science degree in Molecular and Cellular Biology and a Bachelor of Arts degree in Art History, and was inducted into Phi Beta Kappa.

Earlier today, FDA issued its decision with respect to amlodipine generics and the applicability of Mylan’s 180-day exclusivity and Pfizer’s pediatric exclusivity.  The U.S. District Court for the District of Columbia in Mylan v. Leavitt had ordered FDA to respond to Mylan’s TRO motion by April 18, 2007.  According to FDA’s notice to the court, “FDA has decided not to approve ANDAs other than Mylan’s at this time.”  FDA’s 14-page decision letter accompanying the notice concludes that:

·        All of the unapproved ANDAs are currently blocked by Pfizer’s pediatric exclusivity.

·        If and when the mandate effectuating the panel’s March 22 decision issues in the Apotex case, Apotex’s ANDA will not be blocked by Pfizer’s pediatric exclusivity.

·        FDA cannot determine on the current record whether other ANDAs will continue to be blocked by pediatric exclusivity at this time.

·        Mylan’s 180-day marketing exclusivity terminated when the patent expired.

It is unclear at this time what action generic applicants other than Mylan might take to challenge FDA’s decision.  We will continue to update you on this developing story.

RELATED READING:

·        April 10, 2007 FDA Law Blog Post

On April 12, 2007, the Association of American Physicians & Surgeons (“AAPS”), Concerned Women for America, Family Research Council, and Safe Drugs For Women filed a complaint in the U.S. District Court for the District of Columbia against FDA seeking declaratory and injunctive relief concerning the Agency’s August 24, 2006 approval of a supplemental NDA for PLAN B (levonorgestrel) Tablets, 0.75mg.  FDA’s PLAN B approval permitted Over-the-Counter (“OTC”) use of the drug in women 18 years and older and maintained prescription status for women 17 years old and younger, and was made after the Agency solicited comment on the novel issues presented by the PLAN B switch.

The AAPS complaint asks the court to:

• Vacate FDA’s approval of PLAN B for OTC distribution;
• Declare that FDA lacks authority to approve the same drug product for simultaneous OTC-prescription distribution;
• Declare that FDA lacks authority to bifurcate a drug product’s OTC versus prescription status based on the patient’s age;
• Declare that FDA lacks authority to create a hybrid “third class” of behind-the-counter drug beyond the FDC Act’s OTC and prescription classes;
• Declare that FDA failed to conduct the required rulemakings necessary to authorize OTC distribution of PLAN B; and
• Declare that FDA unlawfully approved PLAN B for OTC distribution under improper pressure from Senators Clinton and Murray.

AAPS contends that “the methodologies used and the workproduct prepared by the staff at Defendant FDA’s Reproductive Health Division diverge from accepted scientific and regulatory methods.”  For example, AAPS alleges that FDA did not consider safety data in overweight women, smokers, and adolescents, and only considered acute safety data without assessing the chronic impacts of the drug.

The complaint also alleges that FDA’s PLAN B approval violates the Administrative Procedure Act (“APA”) and the Pediatric Research Equity Act of 2003 (“PREA”).

Under FDA’s “meaningful difference” policy, the Agency has interpreted the FDC Act to allow marketing of the same active ingredient in products that are both prescription and OTC, assuming some meaningful difference exists between the two that makes the prescription product safe only under the supervision of a licensed practitioner.  Historically, these “meaningful differences” have been active ingredient, indication, strength, route of administration, or dosage form.  The PLAN B approval added age as a sixth parameter.  AAPS contends that “[b]y failing to convene a rulemaking to add its new, patient-based ‘age’ parameter to the its prior, drug-based, five-parameter interpretation of the meaningful-difference test, FDA amended a rule without the required notice-and-comment rulemaking” in violation of the APA.

PREA requires sponsors of marketing applications to include in their application (unless the requirement is waived or deferred) an assessment and relevant data for each relevant pediatric age group to enable FDA to assess the drug’s safety and efficacy for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective.  AAPS contends that:

[FDA] premised [its] authority to approve OTC status only for women 18 and over, without requiring PREA data, on the SNDA’s changing the Plan B labeling only for non-PREA subpopulations (i.e., “adults” aged 18 and older).  Contrary to Defendants’ premise, PREA does not include such rigid age ranges, and puberty extends beyond the eighteenth birthday for a significant pediatric subpopulation of young women. . . .   Because PREA applies past the eighteenth birthday for systemically absorbed hormonal drugs like Plan B, the Plan B SNDA required not only dosage and administration data to support all indications for all pediatric subpopulations (i.e., regardless of Rx versus OTC distribution), but also safety and efficacy data to support the OTC indication for pediatric subpopulations past their eighteenth birthday but still within puberty and/or adolescence.  [The] data submitted to support Plan B’s age-bifurcated Rx-to-OTC switch did not satisfy PREA’s (and thus FFDCA’s) requirements.

FDA’s PLAN B approval has been controversial.  It seems unlikely, however, that the AAPS complaint -despite some novel arguments- will result in FDA withdrawing approval.

On April 4, 2007, FDA published proposed regulations for the labeling of irradiated foods and dietary supplements.  The proposed revisions are in response to the Farm Security and Rural Investment Act of 2002, which directed FDA to propose changes to the current regulations at 21 C.F.R. Part 179, and to amend the definition of “pasteurization” in section 403(h)(3) of the Federal Food, Drug, and Cosmetic Act (“FDC Act”).  The proposed regulations address three issues: 1) when an irradiated food or dietary supplement does not need to be labeled “irradiated”; 2) when an irradiated food may be labeled “pasteurized” rather than “irradiated;” and (3) when a manufacturer may use an alternative term for “irradiated.”   

The most significant revision is FDA’s proposal that an irradiated food need not be labeled with the radura symbol and a radiation disclosure statement unless the irradiation causes a material change.  FDA explains in the preamble that a material change is “a change in the organoleptic, nutritional, or functional properties of a food . . . that the consumer could not identify at the point of purchase,” e.g., irradiation of bananas to slow the ripening process.  The effect of irradiation is not material if the change is “within the range of characteristics normally found.”  FDA asks for comments with respect to the Agency’s position that the extension of shelf life by inactivating micro organisms and other pests does not constitute a material change.  FDA is also soliciting comments regarding material and non-material irradiation-induced changes.

An irradiated product that is materially changed must be labeled with the radura symbol and a radiation disclosure statement.  The proposed regulations provide two alternatives to labeling the product as “irradiated.”  These proposals are essentially restatements of statutory provisions.  The option for use of “pasteurized” rather than “irradiated” incorporates the definition of pasteurization in FDC Act § 403(h)(3) allowing an irradiated food to be labeled “pasteurized” provided that certain conditions are met.  The manufacturer must notify FDA and submit data showing the effectiveness of the irradiation process 120 days before a manufacturer plans to label an irradiated product as “pasteurized.”  If during those 120 days FDA has not objected to the proposed use, the manufacturer may label the irradiated product as “pasteurized.”  In addition to the term “pasteurized,” alternative terms are permitted.  For use of an alternative term, the manufacturer must submit a petition to FDA rather than a notification.  A petition must contain data that “show consumer understanding of the purpose and intent of the proposed alternative labeling.”  This option has been available since 2002 under an FDA guidance document.  To date, FDA has not received a petition requesting the use of an alternative for irradiated foods.  Because the proposed regulations will reduce the number of foods that must be labeled with a radiation disclosure, future use of this provision seems unlikely.

Written comments to the proposed regulations should be submitted to Docket No. 2005N-0272 by July 3, 2007. 

By Riëtte van Laack

On April 10, 2007, CMS issued a draft of its revised Clinical Trial Policy, renamed Clinical Research Policy.  The draft policy was issued after CMS’s consideration of public comments on the agency’s July 10, 2006 coverage tracking sheet announcing the reconsideration of the September 19, 2000 Clinical Trial Policy.  CMS also considered recommendations from the December 13, 2006 Medicare Evidence Development and Coverage Advisory Committee (MedCAC) after further consideration by a panel of federal agencies.  There will be a 30 day public comment period on the draft Clinical Research Policy followed by issuance of a final policy 60 days later.

Among other changes, the draft Clinical Research Policy:

·         Renames the seven highly desirable characteristics of a clinical research study as "General Standards for a Scientifically Sound and Technically Sound Clinical Research Study;"

·         "Deems" FDA required and approved post-approval studies as meeting the general standards of a scientifically and technically sound clinical research study;

·         "Deems" studies conducted under a National Coverage Determination requiring Coverage with Evidence Development (CED) as meeting the general standards of a scientifically and technically sound clinical research study;

·         Expands "deemed" studies to those approved by any HHS agency, the Department of Veterans Affairs and the Department of Defense;

·         Requires a written protocol for research studies;

·         Revises the Medicare coverage requirements for a clinical study and renames the requirements as "Medicare -Specific Standards," which include, among other requirements:

·         an explanation in the research protocol of how the results are generalizable to the Medicare population;

·         a discussion in the research protocol of inclusion criteria and consideration of relevant subpopulations (as defined by age, gender, race/ethnicity, socioeconomic or other factors);

·         study results, negative or positive, must be published;

·         Clarifies and renames "routine clinical services" that will be covered under the policy;

·         Clarifies and defines administrative services that Medicare will not cover;

·       Defines investigational clinical services that may be covered for clinical research studies or through CED.

Manufacturers conducting clinical trials on drugs, biologics or medical devices that treat Medicare covered diseases or injuries should review the draft policy carefully and consider commenting on the draft policy.   

By Kirk L. Dobbins

The Government Accountability Office (“GAO”) recently released a report detailing the revenue information from certain companies that participate in the Medical Device User Fee Program (“MDUFMA”).  MDUFMA authorizes FDA to charge user fees to review applications for the clearance or approval of medical devices.  MDUFMA was passed in 2002 out of concern that FDA lacked the resources necessary to review such applications in a timely manner.  FDA’s authority to collect fees under MDUFMA will sunset on October 1, 2007, unless Congress reauthorizes the law.

The GAO report was issued in response to a 2006 letter from Representative Joe Barton (R-TX), the Ranking Minority Member on the House Committee on Energy and Commerce, which requested the revenue information to assist Congress in determining whether changes to MDUFMA’s small business qualification are necessary.  The fees charged under MDUFMA vary, depending on details such as the type of application and the size of the company submitting the application.  For example, in Fiscal Year 2006, fees for Premarket Notifications (for clearance of a device through the 510(k) process) were $3,833, while fees for Premarket Approval (“PMA”) applications were $259,600.  These fees can be reduced or waived if companies filing the applications qualify as small businesses.  When MDUFMA was enacted in 2002, a company could qualify as a small business if its annual revenues (including those of any affiliate, partner, or parent) were $30 million dollars or less.  In 2005, this threshold was increased to $100 million.

Based on GAO’s review of FDA application data and companies’ revenue information, 697 companies qualified as small businesses under MDUFMA in Fiscal Year 2006.  These companies’ applications constituted about 20% of the approximately 4,500 device applications subject to user fees that were submitted to FDA that year.  Ninety-five percent of the small businesses –656– had revenues below the original $30 million small business threshold.  Forty-one companies had revenues above $30 million but below the current $100 million small business threshold; of these, thirty-five companies’ revenues were below $70 million. 

The GAO report also revealed that there were 258 publicly traded companies that submitted device applications subject to user fees in Fiscal Year 2006 that did not qualify as small businesses.  These companies were responsible for about 37% of the approximately 4,500 device applications subject to user fees that were submitted to FDA that year.  Sixty percent of these companies –155– had revenues that exceeded $500 million.  Another forty-seven companies had revenues between $100 million and $500 million; fifty-six companies had revenues below the $100 million small business qualification threshold, but for reasons that were not determined, did not qualify as small businesses. 

By Christine P. Bump

Last week, we reported on several citizen petitions submitted to FDA by Mylan and Pfizer concerning the availability and applicability of 180-day exclusivity and pediatric exclusivity to amlodipine drug products.  FDA has also established a separate docket to solicit the views of interested parties on these issues as part of the Agency’s efforts to respond to the U.S. District Court for the District of Columbia’s order in Mylan Laboratories, Inc. v. Leavitt that FDA decide by Wednesday, April 11th whether it will approve any Abbreviated New Drug Applications (“ANDAs”) for generic amlodipine besylate besides Mylan’s ANDA.  In a new development, Zydus Pharmaceuticals (USA) Inc. has submitted a fourth citizen petition to FDA concerning amlodipine. 

The Zydus petition requests that FDA “file papers in opposition to plaintiff Mylan’s application for a [Temporary Restraining Order (‘TRO’)] in [Mylan Laboratories, Inc. v. Leavitt] and to seek a dissolution of the TRO . . . that lasts until April 13, 2007 at 5:00 pm.”  Zydus also requests that FDA “approve all complete amlodipine besylate ANDA[s] that are currently pending.”  In support of its requests, Zydus contends that:

Mylan through its petitions and TRO intends solely to prevent any other generic from entering the market during a period in which approved ANDA holders are rightfully permitted to enter the market. . . .  [Additionally,] by obtaining such an order, Mylan intends to extend the 180-day exclusivity period beyond that permitted statutorily . . . .  Zydus believes that Mylan has forfeited any 180-day exclusivity period that may have been awardable to it . . . .

Stay tuned for more updates on this evolving case.   

RELATED READING:

• April 5, 2007 Orange Book Blog Post

UPDATE:

Earlier today, the U.S. District Court for the District of Columbia issued an order extending from April 11, 2007 to April 18, 2007 the date on which FDA must notify the court of the Agency’s decision with respect to the issues involved in Mylan Laboratories, Inc. v. Leavitt.  Further, the court changed the date until which FDA is enjoined from taking final agency action from April 13, 2007 to April 20, 2007.

During the past several years, government enforcement authorities have focused an increasing amount of attention on the marketing activities of medical device companies.  This increased scrutiny has taken the form of investigations through subpoenas and intervention in qui tam lawsuits (lawsuits initiated by a third party on behalf of the government).  Often, these actions are brought by whistleblowers under the Federal False Claims Act (FCA).

Michelle L. Butler and Jeffrey N. Wasserstein recently published an article in Medical Device & Diagnostic Industry addressing kickback issues in the medical device industry. 

“Orphan drugs” are products recognized by FDA that are intended for use in a “rare disease or condition” ─generally a disease or condition with a United States prevalence less than 200,000 persons.  Because the market for orphan drugs is often limited, Congress and FDA have traditionally accorded orphan drugs special consideration.  For example, sponsors of applications for designated orphan drugs are statutorily exempt from paying the one-time application user fee.  This is significant.  The full application user fee for Fiscal Year 2007 is $896,200 (a figure that is certain to rise under the next iteration of the Prescription Drug User Fee Act (“PDUFA”)). 

Orphan drug sponsors are not exempt under the FDC Act from paying annual product and establishment fees (which for Fiscal Year 2007 are $49,750 and $313,100, respectively ─also certain to rise under PDUFA IV).  Instead, such sponsors may request that FDA waive or reduce the annual product and establishment fees on the basis that a waiver/reduction “is necessary to protect the public health,” or because “the assessment of the fee would present a significant barrier to innovation because of limited resources available to such person or other circumstances.”  FDC Act § 736(d)(1)(A)-(B).  Indeed, when Congress enacted PDUFA in 1992, it specifically contemplated that although user fee waivers and reductions would be available to all NDA sponsors, the so-called “public health” and “barrier to innovation” waivers “will give the FDA sufficient authority to waive fees for orphan drugs.”  H.R. Rep. No. 102-895, at 17 (1992). 

According to recent testimony from the National Organization for Rare Disorders (“NORD”), however, Congress’ intent has been impeded by an FDA policy developed in 1993 under which the Agency interprets both the “public health” and the “barrier to innovation” waiver/reduction mechanisms to involve a specific financial test (i.e., $10 million in annual gross revenues and no corporate parent or funding source with annual gross revenues of $100 million or more).  According to NORD:

The current waiver program administered by FDA for product and facility fees has chosen to interpret gross revenues of $10 million or greater as evidence that an entity and its affiliates are fully capable of developing and marketing orphan drugs without regard to the cost of users fees.  We know that FDA believes that a higher threshold than $10 million in corporate gross sales will result in a significant expansion of waived products and a noticeable increase in the fees that would be charged to remaining companies.  Nonetheless, this does not conform with any common sense view of what constitutes a small company in the bio-pharmaceutical industry and seems unrealistically low, especially with the higher fees that will be required under PDUFA IV.

NORD is requesting that Congress resolve the issue “in a way that assures the continued success of the Orphan Drug Act without undercutting the user fee program.”  Specifically, NORD believes that FDA should waive product and establishment user fees for drug products with annual United States revenues less than $25 million.  One recent PDUFA IV proposal does not include any user fee relief for orphan drug sponsors specifically.  There is still plenty of opportunity, however, for Congress to address the issue in new draft legislation.

FDA was previously asked to address this issue in a January 2003 citizen petition submitted by Orphan Medical, Inc.  The petition (supported by NORD) requested, in part, “that FDA establish a clear and fair waiver policy from the establishment and product fees for orphan drugs that have modest sales.”  The petition was withdrawn in August 2006 without a substantive response by FDA.