By Alan Kirschenbaum —

In an effort to salvage health care reform, the Obama Administration will hold a bipartisan health care reform meeting this Thursday, February 25.  Invited are the Congressional leadership of both parties and the Chairmen and ranking membership of committees involved in health care reform.  Today the White House released a health care reform outline described as a “proposal to work off of at the meeting.”  The outline can be found here and additional detail is posted on the White House web site.  The drug and device-related points of the outline draw on many of the provisions that appear in the House and Senate bills, which we’ve described in previous posts.  (You’ll find our report on the House bill here and the Senate bill here.)  Among the familiar provisions appearing in the President’s outline are the following:

•  Medicare Part D Donut Hole:  Like the House bill, the proposal would phase out the Part D coverage gap over the next ten years.  In 2010, a $250 rebate would be provided to Part D beneficiaries who enter the donut hole.  Though the outline provides no detail, this rebate would presumably be funded by pharmaceutical manufacturers.

•  Medicaid rebates:  Like both the House and Senate bills, the proposal would increase the minimum Medicaid rebate for innovator drugs to 23.1 percent of AMP, impose an additional rebate for new formulations of an innovator drug, and require new rebates on drugs dispensed to Medicaid managed care enrollees.  The proposal does not mention an increase in the minimum rebate for generics, which was included in the Senate bill.

•  Industry fees and excise taxes:  The annual fee on the drug industry, which is $23 billion over 10 years in the Senate bill, is increased to $33 billion but delayed until 2011.  Instead of a fee on the device industry as contained in the Senate bill, the President has opted for the House bill’s excise tax on device sales beginning in 2013.  The outline doesn’t indicate whether the excise tax is 2.5 percent of the wholesale price, as under the House bill.

•  Physician payment sunshine:  Like both the House and Senate bills, the President’s proposal includes physician payment reporting requirements.
 
•  Ending pay-for-delay arrangements:  The President’s proposal adopts House provisions prohibiting brand name drug manufacturers from paying generic manufacturers to forego manufacturing or marketing of generic drugs.

•  Biosimilar approval:  The President’s proposal adopts from both bills a new approval pathway for biosimilars.
 
•  340B program expansion:  A cryptic reference to extending drug discounts to “hospitals and communities that serve low-income patients” indicates that the President’s proposal includes the 340B drug discount program expansion provisions included in both the House and Senate bills, though the extent of the expansion (which differs between the two bills) is uncertain. 

It is far from certain whether Thursday’s meeting will break the partisan logjam on health care reform.  However, if it does, the drug and device provisions outlined in the President’s proposal are likely to be included in any surviving bill.

By David B. Clissold and Nisha P. Shah

On February 19, 2010, FDA issued a proposed rule that would require sponsors to report any person that has or may have engaged in the falsification of data in studies that involve human or animal subjects.  FDA believes the proposed rule is “intended to help ensure the validity of data that the agency receives in support of applications and petitions for FDA product approvals and authorization of certain labeling claims and to protect research subjects.”

Key definitions under the proposed rule are: 
•  “Sponsor” would broadly include sponsors of studies conducted on humans and animals; petitioners submitting food additive, color additive, nutrient content claim, and health claim petitions; and manufacturers or distributors submitting new dietary ingredient notifications.
•  “Falsification of data” would be defined as “creating, altering, recording, or omitting data in such a way that the data do not represent what actually occurred.” The proposed rule would not be intended to address “unintentional errors in recording or reporting information”, such as typographical errors or transposed numbers or characters.
•  “Data” would include, though not limited to, “individual facts, tests, specimens, samples, results, statistics, items of information, or statements made by individuals.”

The rule would require a sponsor to report information indicating that a “person has, or may have, engaged in the falsification of data in the course of reporting study results, or in the course of proposing, designing, performing, recording, supervising, or reviewing studies that involve human subjects or animal subjects conducted by or on behalf of a sponsor.”  A sponsor would not be required to determine definitively that data have been falsified, nor the intent of the person who has, or may have, falsified data.  Rather, a sponsor would be required to report information of which it is aware suggesting that a person has, or may have, engaged in the falsification of data. The reporting obligation would exist regardless of the amount of evidence, if any, the sponsor has with regard to the intent of the person who has, or may have, falsified data.  The agency emphasized that the sponsors should not wait to determine conclusively whether falsification actually occurred, or seek to determine the circumstances that led to the falsification before reporting the information with FDA. Therefore, a sponsor must report any confirmed or possible falsification of data.

The sponsor would be required to report the information to the appropriate FDA center “promptly”, but no later than 45 calendar days after the sponsor becomes aware of the information.  The reporting requirement would be ongoing and cover the periods before and after study completion.  Information in the report to FDA must include the following: 
•  The name of the person who has, or may have, falsified data, 
•  The last know address(es) and phone number(s) of that person, 
•  The specific identify of the potentially affected study, including, when applicable, application information such as the application number, investigational protocol number, study title, study site(s), and study dates, and 
•  Information suggesting that falsification occurred and describing the falsification. 

FDA commented that the agency is considering also whether additional information should be included in the report, such as the National Clinical Trial (“NCT”) number assigned to a study when the study is registered with ClinicalTrials.gov. 

FDA intends to use the reported information to determine whether further agency investigation is warranted in conjunction with other information available to the agency.  According to FDA, these investigations might form the basis of administrative or enforcement actions, such as excluding clinical trials from consideration by FDA, placing a clinical trial on hold, or initiating disqualification of investigators or criminal proceedings.  Failure to report possible falsification of data might constitute a violation of section 301(e) of the Food, Drug, and Cosmetic Act (21 U.S.C. § 331(e)) (concerning failure to make a required report) or 18 U.S.C. § 1001 (concerning the submission of a false statement to the federal government).

This proposed rule is a dramatic shift in regulatory obligations with serious implications for study sponsors and investigators alike.  Currently, if the sponsor of a clinical study under an IND determines that an investigator “is not complying” with the protocol or with FDA regulations (conduct that would include data falsification), they must discontinue the investigator’s participation in the trial and notify FDA.  Note that a mere “suspicion” of non-compliance is not enough to trigger this obligation.  In contrast, the proposed rule requires sponsors to report “possible” falsification.  FDA claims they are not interested in “errors” but as any experienced clinical trial auditor will tell you, there is a lot of gray area between an “error” and “falsification.”  As FDA noted, “falsification is more difficult for FDA to detect than errors . . . because persons who engage in the falsification process are more likely to attempt to conceal their actions.”  That is undoubtedly true, but such people are no more likely to reveal those actions to a sponsor’s representative than they are to an FDA investigator.  Moreover, data falsification is not always obvious right away, even to an auditor or monitor.  FDA generally gets to review these allegations on their own timeline with the benefit of 20:20 hindsight, yet the sponsor is expected to report suspicious activity, or apparently even unusual activity that is not resolved within 45 days, under penalty of civil penalty.  Not addressed in the proposed rule is whether FDA will expect the sponsor to continue to develop evidence for the Agency after it has reported suspected falsification.
 
Comments on the proposed rule must be submitted by May 20, 2010.

By William T. Koustas —

 The FDA has announced that it will require all drugs known as Erythropoiesis-Stimulating Agents (“ESAs”) to have a Risk Evaluation and Mitigation Strategy (“REMS”).  At the present time, this class of drugs is limited to three Amgen products: Procrit, Epogen (both epoetin alfa) and Aranesp (darbepoetin alfa).  FDA required Amgen to create a “risk management program,” or REMS, in April of 2008 for ESAs based on new safety information received from studies that showed ESAs caused tumors to grow faster, leading to premature death in some cancer patients.

 The REMS consists of a medication guide, communication plan, and elements to assure safe use (“ETASU”).  The medication guide is to be provided at retail/hospital outpatient pharmacies as well as in physician offices, clinics, hospital inpatient and in-clinic services and upon request.  The communication plan will consist of letters to Nephrology and Oncology related professional societies, “Dear Healthcare Provider” letters to hospital Directors of Pharmacy/Administrators and to those healthcare providers who directly purchase/prescribe ESAs and ensure access to communication materials online. 

 The most onerous part of this REMS is the required ETASU that includes certification for healthcare providers who both prescribe and dispense ESAs as well as the hospitals themselves.  Amgen has established Assisting Providers and cancer Patients with Risk Information for the Safe use of ESAs (“APPRISE”) which provides each eligible healthcare provider and/or hospital with an APPRISE enrollment number and ensures that they re-enroll in the APPRISE program every three years.  Failure to do so will result in that provider/hospital no longer having access to ESAs.  Further, the ETASU require that Amgen ensure that certified hospitals and healthcare providers only dispense ESAs after they have discussed the risks with the patient and the patient has signed an “Acknowledgment Form.” 

 We have previously discussed on this blog how FDA may expand its use of class-wide REMS as it continues to become more comfortable with its new powers under FDAAA, and this appears to further confirm that FDA is moving in that direction. 
  

By Ricardo Carvajal and A. Wes Siegner –

According to a press release issued by FTC, the agency “has sent letters to 11 companies that promote various Omega-3 fatty acid supplements, telling them they should review their product packaging and labeling to make sure they do not violate federal law by making baseless claims about how the supplements benefit children’s brain and vision function and development.”  The companies have been given two weeks to respond.  As an example of the level of substantiation that FTC would find acceptable, the letters point to “well-conducted, clinical cause-and-effect studies demonstrating that the use of the combination of Omega-3 fatty acids provided in Product X, in the same dosage as provided by one serving of that product, improves or promotes brain function, cognitive function, attention span, intelligence, memory, learning ability, and visual acuity in normal children ages 2 years and older.”

This latest action is consistent with remarks delivered by an FTC staff attorney at the Food and Drug Law Institute’s recent conference on hot topics in food and dietary supplement law.  In her remarks, the staff attorney indicated that FTC intends to closely scrutinize claims relating to omega-3 fatty acids, probiotics, fiber products, antioxidants, and products marketed for use by children.  The products targeted in FTC’s latest action span two of these categories, suggesting that they may have been at especially high risk.  Notably, FTC’s press release encourages the filing of consumer complaints against companies that “may be deceptively advertising dietary supplements for children.”

By Douglas B. Farquhar –

A recent of a New Jersey federal court is bound to encourage some manufacturers of an FDA-approved version of a long-marketed drug to sue competitors that continue to market unapproved versions of the same drug.
 
Mutual Pharmaceutical Company, Inc. and two other companies brought a lawsuit after receiving FDA approval of their applications to market colchicine in July 2009.  Colchicine has been used for centuries to treat gout.  Mutual sought a preliminary injunction to block competitors marketing unapproved versions of the drug.  The motion for preliminary injunction was denied by the California federal court, where the case was filed, as discussed in our .  The California court then transferred the case to the court in New Jersey. 

In a decision issued February 8th, Judge Garrett E. Brown, Jr., of the U.S. District Court for the District of New Jersey, held that, although Mutual cannot sue competitors for marketing the drug in violation of the Federal Food, Drug, and Cosmetic Act (inasmuch as the FDC Act does not permit a private right of action), the Court could not determine, at this preliminary stage of the case, whether the unapproved marketers of the drug had engaged in marketing activities that effectively misrepresented the unapproved status of their drugs in violation of the federal Lanham Act.

The decision is unpublished (meaning that it will not be published in the Federal Reporter, where district court judges can decide to place decisions on matters they think should have precedential impact).  However, inasmuch as the judge issued a decision allowing the case to continue, it will likely boost the optimism of similarly situated marketers of approved drugs that lawsuits will at least harass competitors which have not yet received FDA approvals.

The Court's decision is at odds with numerous court rulings in Lanham Act cases which have ruled that plaintiffs have improperly used the Lanham Act as a vehicle to enforce the FDC Act.  For instance, in Schering-Plough Healthcare Products, Inc., v. Schwarz Pharma, Inc., 586 F.3d 500 (7th Cir., 2009), the Seventh Circuit affirmed the dismissal of a Lanham Act case, ruling that the lawsuit sought to usurp FDA's primary jurisdiction concerning the legality of labels that FDA had earlier approved.   Hyman, Phelps & McNamara, P.C. represented Schwarz Pharma, Inc. and Kremers Urban, LLC in that case.  Our firm is writing an article in the next edition of FDLI Update magazine about the interplay between the Lanham Act and the FDC Act.

By Ricardo Carvajal –

In an effort to grant FDA additional authority over dietary supplements, Senators John McCain and Byron Dorgan have introduced the Dietary Supplement Safety Act of 2010.  The bill would require dietary supplement facilities to provide FDA with information on supplements and their ingredients on an ongoing basis, would substantially alter the requirements applicable to new dietary ingredients ("NDI’s"), would give FDA mandatory recall authority, and would expand adverse event reporting requirements, among other changes. 
 
Particularly noteworthy are the changes in the requirements applicable to NDI’s that would take effect if the bill were to become law.  Currently, FDCA § 413(c) defines an NDI as “a dietary ingredient that was not marketed in the United States before October 15, 1994 and does not include any dietary ingredient which was marketed in the United States before October 15, 1994.”  If a dietary ingredient meets the definition of an NDI, then a manufacturer or distributor must submit a 75-day premarket notification to FDA that provides the basis on which the manufacturer or distributor has concluded that a dietary supplement containing the NDI will reasonably be expected to be safe, with one exception.  A premarket notification need not be submitted if “the dietary supplement contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.”

In conjunction with the passage of the Dietary Supplement Health and Education Act of 1994, dietary supplement trade associations developed “grandfather” lists of dietary ingredients that were marketed in the U.S. before October 15, 1994, and therefore were not subject to regulation as NDI’s.  Although FDA does not regard these lists as dispositive of a dietary ingredient’s status as a grandfathered dietary ingredient, manufacturers and distributors continue to rely on the lists.  The proposed legislation would amend the existing definition of an NDI to eliminate the references to October 15, 1994, and instead authorize FDA to establish a list of “accepted dietary ingredients.”  Dietary ingredients not on that list would be regulated as NDI’s.  Further, all such ingredients would have to be the subject of a 75-day premarket notification to FDA because the proposed legislation would abolish the exception to the premarket notification requirement described above. 

In proposing the legislation, Sen. McCain referenced a previous GAO report that made numerous recommendations with regard to FDA’s regulation of dietary supplements, including a recommendation that FDA issue guidance to clarify when a dietary ingredient is a new dietary ingredient (that guidance has yet to issue).  Notably, GAO just sent out letters to a number of supplement manufacturers seeking information on specific dietary ingredients, including substantiation of any company determinations that submission of an NDI notification is not required.  Just as the previous GAO report is being cited in support of calls for reform, the results of the current GAO inquiry could well be seized upon by advocates of reform if that inquiry reveals any apparent shortcomings in FDA’s oversight of NDI’s.

By Alan M. Kirschenbaum –      

Late last year, we reported on a decision of the D.C. District Court upholding the Department of Defense’s ("DOD’s") authority to apply Federal Ceiling Price ("FCP") limitations to all prescriptions filled on or after January 28, 2008 under the TRICARE Retail Pharmacy Program.  While that decision represented a victory for DoD, the court also criticized DoD’s interpretation that the authorizing statute requires the discount pricing to be implemented through a refund system to the exclusion of other approaches, and the court remanded the implementing regulation back to DoD without vacatur to consider other approaches to implementing FCP pricing.

Although not required under the court order, DoD published a notice in the Federal Register yesterday soliciting additional public comments on its final rule establishing the current refund program (which we summarized when it was promulgated in March 2009), as well as comments on other possible approaches to implementing FCP pricing.  DoD will consider alternatives that are consistent with the Congressional intent and with best business practices, and that are practical to administer.  Comments are due by March 11, 2010.  In the interim, because DoD’s final rule was remanded without vacatur, the current refund program and Pricing Agreements will remain in effect.  It will take unusually persuasive comments to overcome the inertia of a refund program that has now been in effect since May 2009.

By Kurt R. Karst –      

Two recent rulings out of the U.S. District Court for the Eastern District of Pennsylvania stemming from allegations about antitrust violations from the submission of citizen petitions have once again raised the issue of so-called “sham” citizen petitions and, insofar as there are allegations of violation of Section 2 of the Sherman Act, Noerr-Pennington immunity.  In each case – In Re: Flonase Antitrust Litigation and Roxane Laboratories v. Smithkline Beecham – the plaintiffs allege that GlaxoSmithKline, Inc. (“GSK”) submitted a series of “sham” citizen petitions several years ago that delayed and restrained competition for generic versions of GSK’s FLONASE (fluticasone propionate) in violation of competition laws.  And in each case the court denied (here and here) motions from GSK to dismiss the actions.  The underlying competition issues have yet to be decided.  Based on the recent track record of challenging “sham” citizen petitions, however, the plaintiffs in each case have a difficult road ahead. 

Under the Noerr-Pennington doctrine, private entities are immune from antitrust liability in petitioning the government to influence the passage or enforcement of laws, even if the laws they advocate for would have anticompetitive effects.  See Eastern Railroad Presidents Conference v. Noerr Motor Freight, Inc., 365 U.S. 127 (1961); United Mine Workers v. Pennington, 381 U.S. 657 (1965).  Immunity extends to citizen petitions submitted to FDA.  The Noerr-Pennington doctrine is grounded in the First Amendment protection of political speech, and “upon a recognition that the antitrust laws, ‘tailored as they are for the business world, are not at all appropriate for application in the political arena.’” City of Columbia v. Omni Outdoor Advertising, Inc., 499 U.S. 365, 380 (1991) (quoting Noerr, 365 U.S. 127, 141 (1961)).

Noerr-Pennington immunity is not absolute, however.  When petitioning activity “ostensibly directed toward influencing governmental action[] is a . . . sham to cover what is . . . nothing more than an attempt to interfere directly with the business relationships of a competitor[, then] the application of the Sherman Act would be justified.”  Noerr, 365 U.S. at 144.  The sham exception requires that a petition be “(i) ‘objectively baseless,’ and (ii) ‘an attempt to interfere directly with the business relationships of a competitor through the use of the governmental process – as opposed to the outcome of that process – as an anticompetitive weapon.’”  Primetime 24 Joint Venture v. Nat’l Broad. Co., 219 F.3d 92, 100-01 (quoting Prof’l Real Estate Investors, Inc. v. Columbia Pictures Indus., Inc., 508 U.S. 49, 60 (1993)).

In 2009, the U.S. District Court for the Southern District of New York declined to find that a March 2005 citizen petition submitted on behalf of Sanofi-aventis concerning generic versions of ARAVA (leflunomide) was “objectively baseless” and denied the plaintiff’s – Louisiana Wholesale Drug Co., Inc. (“LWD’s”) – Motion for Judgment as a Matter of Law.  The ruling followed a jury verdict concluding that the petition was not “objectively baseless.”  

LWD argued that the ARAVA petition is a prime example of a sham citizen petition.  In the petition, Sanofi-aventis requested that:

(1) if an ANDA applicant is not seeking approval of a 100-mg leflunomide tablet that is bioequivalent to Arava 100-mg tablets, [FDA] require the applicant to perform in viva bioequivalence testing to confirm that five of its 20-mg tablets are bioequivalent to one Arava 100-mg tablet, and (2) the Agency withhold final approval of any leflunomide ANDA that either (a) does not seek approval of a 100-mg leflunomide tablet that is bioequivalent tom Arava 100-mg tablets or (b) does not establish in vivo bioequivalence between five 20-mg lleflunomide tablets and one Arava 100-mg tablet.

FDA uncharacteristically (at least at that time) denied the petition less than six months after it was submitted to the Agency and simulteneously approved ANDAs for generic ARAVA.  FDA ruled that it “will require the labeling for generic leflunomide products to include the labeling approved for the RLD, Arava, conceming the use of a 100-mg loading dose,” and that Sanofi’s concern about certain generic labeling omissions or changes “is unfounded.”

In ruling for Sanofi, the court commented that “[i]n short, there was ample evidence introduced at trial that tended to show that the issue raised by the Citizen Petition was sufficiently novel and unsettled to permit an objectively reasonable drug company to ‘perceive[] some likelihood’ that the FDA would grant the relief requested.”  A pretty high sham citizen petition standard to meet indeed!

Hyman, Phelps & McNamara's Jeffrey N. Wasserstein (co-chief blogger at fdalawblog.net and self-described social media guru) will be speaking on the regulation of social media at the American Conference Institute’s 8th Expert Regulatory Guide to Advertising, eMarketing and Promotions for the Pharmaceutical Industry, taking place in the City of Brotherly Love, (that's Philadelphia, PA) from April 14-April 15, 2010.   Registration materials for the conference can be found here.  Loyal readers of the blog may obtain a $200 discount by using discount code 876L10.S.

By Kurt R. Karst –      

FDA’s ability to force a prescription-to-over-the-counter switch (“Rx-to-OTC switch”) has been hotly contested over the past decade.  The crux of the debate concerning forced Rx-to-OTC switches is whether FDA, absent a New Drug Application (“NDA”) sponsor’s consent, has the authority to force an Rx-to-OTC switch; and if so, on what legal basis.  (Although FDA attempted a forced switch once – almost 30 years ago – when the Agency proposed to switch metaproterenol sulfate metered-dose inhaler drugs from Rx to OTC status under the OTC Drug Review, FDA did not carry through with the switch after extensive adverse comment.)  A little-known FDA response to a citizen petition, however, appears to have settled what FDA believes is its legal basis to effect a forced switch.  But first, some background . . . .

The 1951 Durham-Humphrey Amendments to the FDC Act gave FDA the authority to require that drugs be limited to Rx status when they cannot be used safely for OTC use.  Thus, the underlying presumption (then and now) is that Rx restrictions are the exception, and that if a drug can be used safely and effectively OTC it should be.  The Durham-Humphrey Amendments also amended the FDC Act (§ 503(b)(3)) to state that FDA “may by regulation remove drugs subject to [FDC Act § 505 [(i.e., new drugs)] from the requirements of [FDC Act § 503(b)(1)] when such requirements are not necessary for the protection of the public health.”  FDA’s regulation implementing § 503(b)(3) is codified at 21 C.F.R. § 310.200(b), and states that FDA may approve an Rx-to-OTC switch when Rx dispensing is:

not necessary for the protection of the public health by reason of the drug’s toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, and . . . [t]he drug is safe and effective for use in self-medication as directed in proposed labeling. 

There are two different mechanisms under the FDC Act for FDA to make an Rx-to-OTC switch: (1) FDC Act § 503(b)(3) explicitly provides FDA with the authority to issue a regulation changing the status of an Rx drug to an OTC drug; and (2) the FDC Act grants FDA the authority to approve and reject NDAs. 

FDA’s regulation at 21 C.F.R. § 310.200(b), which implements FDC Act § 503(b)(3), identifies processes for initiating consideration of an Rx-to-OTC switch.  Specifically, a proposal to exempt a drug from Rx-only requirements may be initiated by the FDA Commissioner or by “any interested person” in the form of a sponsor submitting an NDA or by a third party petitioning FDA.  Regardless of who initiates a request for an Rx-to-OTC switch, however, the evidence must demonstrate that the statutory Rx-only dispensing requirements are no longer necessary to protect the public health, and that the drug is safe and effective for use in self-medication as directed in proposed labeling. 

Those opposed to forced switches have argued that FDA can only authorize a switch over the NDA sponsor’s objections following a formal, trial-like administrative process known as an adjudication, and that FDA lacks the authority to force an Rx-to-OTC switch through rulemaking.  (The distinction between rulemaking and adjudication is based on the nature of the decision facing an agency.  Actions pursuant to generalized facts do not require an individual hearing and can be taken according to procedures applicable to rulemaking – either formal rulemaking, informal notice-and-comment rulemaking, or the rarely used negotiated rulemaking.  Actions pursuant to individualized facts require some level of hearing and are classified as an adjudication.)  Moreover, forced switch opponents have argued, among other things, that even if rulemaking is appropriate, FDA cannot use informal notice-and-comment rulemaking, but instead must use formal, hearing-based rulemaking.  

Forced switch proponents have argued, among other things, that the FDC Act expressly authorizes FDA to force a switch following rulemaking – not adjudication – and that FDA is free to undertake any type of rulemaking the Agency deems appropriate, such as informal notice-and-comment rulemaking. 

Over the past decade, FDA has been asked on at least three separate occasions to make a forced switch.  First, in July 1998, WellPoint (Blue Cross of California) submitted a citizen petition to FDA (Docket No. FDA-1998-P-0254) requesting that the Agency convert from Rx to OTC status several antihistamine drugs.  (The WellPoint petition was the subject of a joint meeting of the Nonprescription Drugs Advisory Committee & the Pulmonary – Allergy Drugs Advisory Committee in May 2001.)  Second, in March 2007, FDA was petitioned (Docket No. FDA-2007-P-0056) to force a switch of fexofenadine HCl and cetirizine HCl.  FDA has not substantively responded to either petition.   

Finally, in February 2001, the Center for Reproductive Rights petitioned FDA (Docket No. FDA-2001-P-0123) to force a switch of PLAN B (levonorgestrel) Tablets.  FDA denied the petition in June 2006 “because it did not contain sufficient data to satisfy the statutory and regulatory requirements for an Rx-only to OTC switch for Plan B.”  Moreover,  given the then-pending NDA supplement for OTC PLAN B, FDA refused to allow the petition to “circumvent the [NDA supplement] process to which the sponsor of the drug is entitled.”  Importantly, however, FDA noted in its response that:

Although your petition does not explicitly state that you are requesting FDA initiate notice-and-comment rulemaking, the Act . . . authorizes only two mechanisms for FDA to make an Rx to OTC switch: [informal] notice-and-comment rulemaking and approval of a drug application . . . . You are not yourselves applicants for drug approval, and you are not permitted to submit a supplement to another company’s application.  21 CFR 314.71(a).  Accordingly, your petition can only be construed as a request that we initiate notice-and-comment rulemaking proceedings pursuant to which a rule would be promulgated allowing Plan B and other emergency contraceptives to be made available OTC. [(emphasis added)]

In other words, FDA in its petition decision appears to have determined that informal notice-and-comment rulemaking is the appropriate route to effect a forced switch over an NDA sponsor’s objections, and that administrative adjudication is not necessary. 

By Michelle L. Butler –

This week, the parties in the Winston Laboratories case filed a Stipulation of Dismissal with Prejudice Pursuant to Fed. R. Civ. P. 41(a).  This case involved FDA’s interpretation of the term “affiliate” in its decision to deny Winston a small business waiver of the PDUFA fee for a new drug application.  Given the Court’s prior decision denying the Government’s Motion to Dismiss, it is likely that the parties settled the case on terms favorable to Winston.  We do not yet know how FDA will deal with similar small business waiver determinations going forward, but we will provide updates as information becomes available.

By Kurt R. Karst –      

Late last month, FDA denied a citizen petition submitted by Graceway Pharmaceuticals, LLC (“Graceway”) requesting that the Agency refuse to approve Abbreviated New Drug Applications (“ANDAs”) for generic versions of Graceway’s ALDARA (imiquimod) Cream, 5%, unless such applications contain, among other things, data from bioequivalence studies conducted in patients with each of ALDARA’s approved conditions – actinic keratoses (“AK”), primary superficial basal cell carcinoma (“sBCC”), and external genital and perianal warts/condyloma acuminata (“EWG”) – and pharmacokinetic studies under “maximal use” conditions in patients with EGW and AK.  ALDARA is approved under NDA No. 20-723.

The primary issue raised in the Graceway petition – whether an generic applicant can demonstrate bioequivalence for a multi-indication Reference Listed Drug with a comparative clinical trial in just one indication – was the topic of another citizen petition FDA denied in 2008.  In that case, FDA ruled, in the context of approving ANDAs for generic versions of EFUDEX (fluorouracil) Topical Cream, 5%, which is approved for AK and sBCC, that “even when clinical trials are needed, it has not been the Agency’s policy to require that bioequivalence be shown in every indication if drug release from the dosage form and appearance at the or sites of activity has been demonstrated.”  FDA’s decision was challenged in court, and in September 2009, the U.S. District Court for the Central District of California ruled in FDA’s favor. 

Graceway states in its petition that “[t]he straightforward application of FDA’s reasoning in the Efudex matter mandates that an ANDA for a generic version of Aldara contain data from a bioequivalence study in patients with EGW and a separate study in patients with sBCC.”  FDA disagreed, and concluded that a well-designed study in AK will suffice to show bioequivalence of a generic version of ALDARA:

[T]here is a reasonable scientific basis for concluding, and the Agency has in fact concluded, that the successful demonstration of equivalent drug delivery in AK is sufficient to show bioequivalence.  This conclusion is based on considerations including the following: (a) the site of topical imiquimod action is the same for all three conditions, (b) all three conditions are “related” in that they are responsive to topical treatments, such as imiquimod, that enhance local and cell-mediated immunity, (c) treatment success is dependent upon the induction of an effective host immune response in immunocompetent individuals, and (d) the stratum corneum is the primary barrier to topical drug delivery.

More generally, FDA commented that:

For a drug product with multiple indications, one aspect of appropriate study design is the choice of which indication or indications to study.  It is the Agency’s policy to require only those studies necessary to assess bioequivalence – if bioequivalence can be shown for a multiindication drug with a comparative clinical trial in just one indication, the other indications need not be studied. . . .

[W]hen the site of action is the same for all indications of a multi-indication drug, there is generally no need to conduct a comparative clinical study in more than one of those indications to show bioequivalence.  That is, clinical endpoint data from one indication showing equivalent drug delivery at the site of action are suffcient when all indications share the same site of action.  The question then becomes which indication or indications should be studied.  The answer will depend on the specific product.  For some products there may be a scientific basis for concluding that a study in one indication would be significantly more sensitive or discriminating than a study in any of the other indications, whereas for other products this may not be the case.

Whether Graceway will challenge FDA’s decision in court is unclear.  Regardless, we note that courts have uniformly held that FDA’s bioequivalence determinations fall squarely within the broad discretion of the Agency.

FDA is expected to rule on a second Graceway petition later this month.  In that petition, Graceway requests that FDA not approve any ANDA or 505(b)(2) application for a generic version of ALDARA Cream that substitutes another ingredient(s) for isostearic acid, unless the applicant has demonstrated that any substituted inactive ingredient does not affect the safety of the drug product by providing certain data, and that if such data are from animal or clinical investigations (other than bioavailability and bioequivalence studies), FDA should refuse to approve an ANDA and require the submission of a 505(b)(2) application. 

By Kurt R. Karst & Frank J. Sasinowski –      

We recently reported on the banner year FDA’s Office of Orphan Products Development (“OOPD”) had in 2009, surpassing the 2,000 orphan drug designation mark and designating a near-record 160 products for orphan (i.e., rare) diseases and conditions.  That followed a record 165 designations in 2008, which we reported on here.  As additional information has been made available, however, the 2009 designation figure is tempered by what appears to be a low success rate. 

According to our data (shown in the tables below), OOPD received 250 orphan drug designation requests in 2009, but only granted 160 designations, for a designation rate of 64%.  That is below the historical (cumulative) success rate of 70%, and far below the 2008 success rate of 89%.  To be fair, not all designations submitted in a particular calendar year are acted on in that year.  For example, a designation request submitted in December might not be acted on until February or March of the next calendar year.  And in some cases, it takes a couple of years for OOPD to grant designation because the data and information submitted with an orphan drug designation request are insufficient to support designation at that time, but later-acquired information adequately addresses OOPD concerns.  Nevertheless, the 2009 figure seems to validate a comment we made about the 2008 designation figure: 

It is unclear whether the recent increase in orphan drug designations reflects a shift in OOPD policy, or whether the Office is receiving more designation requests.  Our experience is that the depth and thoroughness of OOPD review has certainly not decreased.  In fact, OOPD seems to be placing a greater emphasis on the scientific rationale and medical plausibility components of an orphan drug designation request than it has in the past.  Thus, we believe the increase in orphan drug designations is largely a function of the quantity of requests OOPD is receiving.    

As orphan drug designation requests continue to stream into OOPD, companies need to be reminded that quality counts, and that OOPD appears to be scrutinizing designation requests more so today than it has in the past.  We’ll see how the 2010 designation figures pan out when we present them next year.

By Kurt R. Karst –      

As we predicted, Massachusetts-based The Medicines Company (“TMC”) has sued the U.S. Patent and Trademark Office (“PTO”) and FDA in connection with the company’s efforts to obtain a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering ANGIOMAX (bivalirudin).  FDA approved ANGIOMAX at 5:18 PM on Friday, December 15, 2000 under New Drug Application (“NDA”) 20-873, and TMC submitted its PTE application to the PTO on February 14, 2001 – 62 days after NDA approval (including the December 15, 2000 date of approval).

The Complaint and Motion for Summary Judgment, filed last week in the U.S. District Court for the Eastern District of Virginia (Alexandria Division), follows the PTO’s January 8, 2010 denial of TMC’s December 2009 Request for Reconsideration (see our previous post here) asking the PTO to employ a “rule of construction” under which the Office would consider the 60-day PTE application submission period at 35 U.S.C. § 156(d)(1) to commence on the first business day after the day the FDA transmits notice of NDA approval of the drug product if that transmittal occurs after normal business hours.  In the case of the PTE application for the ‘404 patent covering ANGIOMAX, that would mean the 60-day period would have begun on December 18, 2000 and the PTE application would have been timely filed within 35 U.S.C. § 156(d)(1).  The lawsuit also follows TMC’s failed attempts (see our previous post here) to get legislation enacted that would permit the PTO to accept late-filed PTE applications.  The ‘404 patent expires on March 23, 2010, but is subject to a 6-month period of pediatric exclusivity that will expire on September 23, 2010.  TMC claims that if a PTE were applicable to the ‘404 patent, it would extend the patent expiration date until December 2014. 

TMC’s Complaint alleges that the PTO’s denial of the company’s PTE application for the ‘404 patent and FDA’s decision regarding PTE application timeliness violated the Administrative Procedure Act (5 U.S.C. § 706(2)(A)).  Specifically, TMC alleges that:

The PTO’s denial of [TMC’s] application for a patent term extension, the PTO’s refusal to reconsider that determination, and the PTO’s and the FDA’s determinations that MDCO’s application for an extension of the term of [the ‘404 patent] was not timely filed under 35 U.S.C. § 156(d)(1) misinterpreted § 156, failed to provide adequate explanations for their conclusions, failed to respond to significant arguments raised by [TMC], reflected a misapprehension of agency authority under § 156, and misinterpreted agency regulations and, relevant case law.

Among other things, TMC argues that there is a discrepancy in how FDA (and the PTO) treats the dates of NDA receipt and approval:

[U]nder the government’s approach to [the PTE] statute, an application for approval of a new drug received by the FDA after business hours is deemed to be filed on the following business day.  By contrast, when a [NDA] is approved after business hours, the government deems the approval to have occurred on the same business day and takes the position that this day starts the 60-day period for filing a patent term extension application.  Despite this inconsistency, the PTO somehow concluded that its interpretation was mandated by statute and regulation.

As a result, TMC alleges that “[t]he PTO’s decision is not merely arbitrary and capricious; it is profoundly unfair and undermines the remedial design of the patent term restoration system.” 

TMC requests the court to vacate and set aside various PTO and FDA deicisions made in connection with the ‘404 patent PTE application, to declare that ANGIOMAX “received permission . . . for commercial marketing or use” within the meaning of 35 U.S.C. § 156(d)(1) no earlier than December 18, 2000 and that the company’s PTE application was timely filed, and to order the PTO to extend the ‘404 patent until December 2014.  TMC also requests the court to grant expedited consideration of the case and to “grant any preliminary injunctive relief necessary to maintain the status quo pending resolution of this case.” 

For heavily-regulated companies, such as those regulated by the Food and Drug Administration, it is common for companies to seek advice from in-house and outside counsel regarding whether proposed conduct would violate the law. It has become increasingly popular for federal prosecutors to target the company's actions that related to the legal advice that counsel previously rendered to a company or individual who is under criminal investigation or has actually been indicted.  A recently published article in the January/February 2010 issue of FDLI Update discusses the benefits and risks of a defendant presenting the testimony of a lawyer who previously provided legal advice.