By Kurt R. Karst –      

On December 7, 2011, FDA will publish a Federal Register notice – a prepublication version of which is available here – announcing a December 16th public meeting and comment period (Docket No. FDA-2011-N-0326) to discuss the Agency’s proposed recommendations for a user fee program for biosimilar biological products for Fiscal Years (“FYs”) 2013 through 2017.  The meeting and comment period is required by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which was enacted on March 23, 2010 as part of the Affordable Care Act, and which created, under new section 351(k) of the Public Health Service Act (“PHS Act”), a route to obtain approval of biosimilar and interchangeable versions of a reference product licensed under PHS Act § 351(a).  The December announcement follows a May 2011 notice (see our previous post here) FDA held with public and industry stakeholders regarding the development of a § 351(k) application user fee program for FYs 2013-2017. 

FDA’s notice includes both a discussion of the proposed user fees, and the Agency’s proposed performance goals and procedures for the next five FYs.  Each topic is discussed below.

Proposed User Fees.  FDA proposes the establishment of four types of biosimilars user fees.  Three of the fees – the one-time application fee, and the annual product and establishment fees – are well known to industry and would be set equal to the rates established under the Prescription Drug User Fee Act (“PDUFA”) for a particular FY.  For FY 2012, the PDUFA fees are $1,841,500 (application), $520,100 (establishment), and $98,970 (product) – see our previous post here.  

The big difference for biosimilars is the proposed fourth fee type – the Biosimilar Product Development (“BPD”) fee for products in development.  It is a fee that would initially be due either upon the date of submission of an Investigational New Drug Application (“IND”) pursuant to FDC Act § 505(i) “describing an investigation that FDA determines is intended to support a biosimilar biological application for a product,” or within five days after FDA grants a request for a so-called “BPD Meeting” (discussed below) for a product.  According to the proposal, the initial BDP fee would be equal to 10% of the PDUFA application fee established for a particular FY.  After paying the initial BDP fee, sponsors would pay an annual BPD fee (due on or before October 1st each year) until the sponsor submits a § 351(k) application that is accepted for filing, or until the sponsor discontinues participation in the BPD program for the product.  The cumulative BPD fees paid by a sponsor for a product would be subtracted from the application fee.  Front-loading the fees in this manner, says FDA, will allow the Agency “to generate fee revenue in the near-term and to enable sponsors to have meetings with FDA early in the development of biosimilar biological product candidates.”      

Some other highlights concerning the proposed BPD fees include:

• Only one BPD fee per product will be assessed regardless of the number of proposed indications for the biosimilar product;
• Each person that has submitted an IND before the date of enactment of legislation authorizing the biosimilars user fee program, and that FDA determines is intended to support a § 351(k) application for a product, will be subject to the initial BPD fee;
• An IND sponsor may discontinue participation in the BDP program only after withdrawing the affected IND, and must do so by August 1 of the year of discontinuation to avoid incurring a fee for the next FY;
• A sponsor that has discontinued participation in the BPD program for a product must pay  a reactivation fee equal to twice the initial BPD fee for that fiscal year in order to resume participation in the BPD program for that product;
• Failure to pay the any of the BPD fees (i.e., initial, annual, or reactivation) would result in FDA refusing to grant a BPD Meeting relating to the biosimilar biological product for which the fees are owed.  In addition, “if a sponsor that owes BPD fees submits an IND that FDA determines is intended to support a biosimilar biological product application, FDA would not consider the sponsor’s IND to have been received under [FDC Act § 505(i)(2)].”  For a sponsor with an existing IND, FDA would impose a “financial hold” prohibiting the sponsor from continuing the investigation.  Finally, if a sponsor has failed to pay required BPD fees, then any § 351(k) or supplement submitted by that sponsor “would be considered incomplete and would not be accepted for filing until all fees owed by the sponsor have been paid.”

Proposed Performance Goals and Procedures.  FDA’s notice includes a summary of the proposed performance goals for a number of items, including proprietary name review, major dispute resolution, clinical holds, special protocol assessments, first cycle performance goals, and, as discussed below, review performance goals and meeting management goals.  The full description of FDA’s proposed performance goals and procedures for the biosimilars user fee program are in the draft biosimilars user fee commitment letter that is hot off the presses.

FDA’s proposed review performance goals include goals for biosimilar biological product application submissions and resubmissions, supplements with clinical data, and original manufacturing supplements.  As with the initial iteration of PDUFA, FDA takes a step-wise approach over the first few FYs to reach a goal of 90% for original and resubmitted § 351(k) applications.  This is depicted in the tables below.

Performance Goals for Original and Resubmitted Applications and Supplements

Performance Goals for Original and Resubmitted Supplements

Proposed additions to FDA’s meeting lexicon are five types of meetings related to a sponsor’s biosimilar biological product development program:

• Biosimilar Initial Advisory Meeting – This is an initial assessment meeting limited to a general discussion regarding the feasibility of licensure under PHS Act § 351(k), and general advice on the expected content of the development program if the § 351(k) route is feasible. 
• BPD Type 1 Meeting – Similar to a Type A meeting under PDUFA, this is “a meeting which is necessary for an otherwise stalled drug development program to proceed (e.g. meeting to discuss clinical holds, dispute resolution meeting), a special protocol assessment meeting, or a meeting to address an important safety issue.”
• BPD Type 2 Meeting – This is a meeting for the sponsor and FDA to discuss a specific issue, such as a proposed study design or endpoints, or to discuss questions seeking targeted advice from FDA regarding an ongoing development program.
• BPD Type 3 Meeting – This is an in-depth data review and advice meeting that may include “substantive review of full study reports, FDA advice regarding the similarity between the proposed biosimilar biological product and the reference product, and FDA advice regarding additional studies, including design and analysis.”
• BPD Type 4 Meeting – This is a meeting to discuss the format and content of a § 351(k) application or supplement. 

FDA’s target timeframes for the various meeting types are shown below.  FDA’s performance goals for the meetings begin with 70% in FY2013 and progress to 90% by FY2017.

After the December 16th public meeting, will finalize its user fee and performance goal proposals, revising them as necessary in response to comments or concerns raised at the public meeting and in docket comments.  Under § 7001(f)(1) of the Affordable Care Act, FDA must transmit its recommendations to Congress by January 15, 2012.

Additional Reading:

• PhRMA Statement on Biosimilar User Fees

By Ricardo Carvajal - 

Recent FDA actions suggest that dietary supplement firms who fail to correct deficiencies in their GMP’s do so at their peril.  For example, FDA recently filed a complaint for permanent injunction against ATF Fitness Products, Inc. et al. ("ATF"), a manufacturer and distributor of dietary supplements.  The complaint alleges that a recent inspection found numerous deviations from the GMP requirements at 21 C.F.R. Part 111.  The complaint further alleges that ATF engaged in substitution of dietary ingredients and dietary supplements so as to render misbranded certain of its products, and that ATF failed to reports serious adverse events.  The complaint contends that ATF “did not respond to the Form FDA-483 or promise to correct all of the deficiencies,” and that a prior audit by a consultant had identified numerous significant GMP deviations that were the same as those identified by FDA.

As another example, FDA filed a seizure complaint against dietary supplements manufactured and distributed by Syntec Nutraceuticals that are alleged to have been prepared, packed or held under conditions that do not meet GMP requirements.  According to the complaint, FDA’s most recent inspection identified a number of significant violations that were similar to those identified in two previous inspections.  Some of the supplements are also alleged to have been marketed as unapproved new drugs.

When coupled to DOJ’s announcement of prison terms in another case arising in part from GMP violations (see our prior blog posting here), the ATF and Syntec cases suggest that significant and continuing alleged GMP violations can be expected to weigh heavily into FDA’s decision to pursue court action.

By Riëtte van Laack –

Representative Louise Slaughter (D-NY) recently sent a 4-page letter to FDA expressing her discontent with the Agency’s action (or lack thereof) related to antibiotic use in animal agriculture.  Specifically, Rep. Slaughter criticizes:

1. FDA’s delay in finalizing the industry guidance #209, titled the Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals;

2. The lack of transparency in the annual report regarding antibiotic use in animals required by the Animal Drug User Fee Amendments (“ADUFA”); and

3. FDA’s rejection of two citizen petitions – see here – requesting that FDA withdraw approvals for the nontherapeutic use of certain antimicrobials in food producing animals.  (As we previously reported, both petitions are the subject of an ongoing lawsuit.) 

Rep. Slaughter urges FDA to follow the proactive precautionary principle allegedly used in European and Asian countries.  

Citing a recent report by Tufts University School of Medicine concerning the correlation between antibiotic use in food animals and antibiotic ineffectiveness in humans and the recent outbreak related to antibiotic-resistant Salmonella causing 136 people to be infected Slaughter urges FDA to take action.  She requests that FDA provides additional details concerning the use of certain antibiotics above and beyond what ADUFA requires, and provide additional details concerning the use of antibiotics in food producing animals and the type and amount of antibiotics used in human medicine.  Rep. Slaughter also questions FDA’s explanation for the publication of a revised report on the 2010 ADUFA sales data. 

Reminding FDA of its public mandate to protect pubic health rather than protect agriculture industry, Rep. Slaughter requests the Agency take action.

Rep. Slaughter has a long history of interest in antibiotic use in food producing animals.  She is the sponsor of the Preservation of Antibiotics for Medical Treatment Act, which would, among other things, phase out the non-therapeutic use in livestock of medically important antibiotics. 

By Ricardo Carvajal –

FDA issued a warning letter to a food manufacturer for labeling as “all natural” a product that contains disodium dihydrogen pyrophosphate, purportedly a synthetic chemical preservative.  The letter cites an alleged violation of FDC Act § 403(a)(1), under which a food is deemed misbranded if its labeling is false or misleading in any particular.  As noted in the letter, “FDA considers use of the term ‘natural’ on a food label to be truthful and non-misleading when ‘nothing artificial or synthetic…has been included in, or has been added to, a food that would not normally be expected to be in the food.’”

The letter is notable for the fact that the “all natural” claim is the only violation cited.  Evidently, FDA considers the misuse of a “natural” claim significant enough to warrant the issuance of a warning letter, even in the absence of other violations.  The letter closes with good generic advice: “We recommend that you review all of your product labels to be consistent with our policy to avoid additional misbranding of your food products.”

FDA Law Blog is pleased to announce that we’ve been selected as one of the LexisNexis Top 25 Torts Law Blogs of 2011!  Here’s what the folks at LexisNexis had to say:

The Top 25 group includes some of the best talent in the blogosphere and creates an invaluable content aggregate for all segments of the Torts Law practice.  Most good blogs provide frequent posts on timely topics, but the authors in this year’s collective take their blogs to a different level by providing insightful commentary that demonstrates how blogs can—and do—impact and influence the world of business and corporate law.

We’re blushing.

Obviously, our focus is on FDA law, not tort law; however, some of the topics we touch on – such as preemption – do bleed over into the tort world.  We’re honored to be among such a stellar group of honorees – you can see the full list here.  

And while we have your attention, we’ll take this opportunity to remind you that you can follow us on Twitter.  We tweet thoughout the day on new FDA decisions, petitions, legislation . . . . the whole gamut. 

By Kurt R. Karst –      

In what appears to be the second guidance of its kind, FDA proposed in a draft bioequivalence guidance document issued earlier this week that companies seeking approval to market generic versions of RITALIN LA (methylphenidate HCl) Extended-Release Capsules must, in addition to demonstrating bioequivalence using the traditional metrics of area under the plasma concentration versus time curve (“AUC”) and maximum (i.e., “peak”) drug concentration (“Cmax”), demonstrate bioequivalence using certain partial AUC (“pAUC”) metrics.  FDA’s proposal follows an April 2010 meeting of FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee at which FDA discussed, among other things, the use of pAUC for the evaluation of ANDAs for products with complex pharmacokinetic profiles. 

RITALIN LA, which is approved under NDA No. 021284, is a multiphasic modified-release formulation designed to release a bolus of methylphenidate followed by slower delivery later in the day.  Other multiphasic methylphenidate drug products include METADATE CD (methylphenidate HCl) Extended-Release Capsules (NDA No. 021259) and CONCERTA (methylphenidate HCl) Extended-Release Tablets (NDA No. 021121).  FDA’s proposal for generic RITALIN LA is to require three studies – one study under fed conditions and two studies under fasting conditions (in one of which the contents of the drug are sprinkled over a spoonful of applesauce).  For the fed study, FDA says that “[t]he partial AUCs, AUC0-4 and AUC4-t, have been determined to be the most appropriate parameters for evaluation of the drug bioavailability responsible for the quick onset and sustained maintenance of the clinical response throughout the 24 hr dosing period,” and, along with other bioequivalence measures, “will ensure that the pharmacokinetic profiles and clinical effects of test and reference products are sufficiently similar.”  With respect to both of the fasting studies, FDA says that the pAUCs of AUC0-3 and AUC3-t are most appropriate, and, along with other bioequivalence measures, “will ensure that the pharmacokinetic profiles and clinical effects of test and reference products are sufficiently similar.”  The proposed 3- and 4-hour pAUCs are consistent with FDA’s proposals at the April 2010 advisory committee meeting.

FDA’s proposal to require pAUC measurements for purposes of approving ANDAs for generic versions of RITALIN LA appears to be the second instance in which FDA has issued drug product-specific bioequivalence guidance seeking such information.  In a guidance finalized in October 2011 for generic versions of AMBIEN CR (zolpidem tartrate) Extended Release Tablets (NDA No. 021774), FDA established the pAUCs of AUC0-1.5, AUC1.5-t in the required fasting study.  The finalization of the zolpidem bioequivalence guidance was preceded by an October 2010 response to a June 2007 citizen petition (Docket No. FDA-2007-P-0182).  In its response, FDA agreed that AUC and Cmax are not adequate to demonstrate bioequivalence and discussed what were at that time the proposed pAUCs for generic AMBIEN CR.

Notably absent from FDA’s announcement earlier this week of the availability of new draft bioequivalence guidances, including RITALIN LA, were draft bioequivalence guidances for generic METADATE CD and CONCERTA.  After all, all three of the multiphasic methylphenidate drug products – RITALIN LA, METADATE CD and CONCERTA – were up for discussion at the April 2010 advisory committee meeting.  Their absence, however, may be explained by the existence of long-pending citizen petitions submitted in March 2004 for CONCERTA (Docket No. FDA-2004-P-0151) and in May 2004 for METADATE CD (Docket No. FDA-2004-P-0290).  Both of the citizen petitions request that FDA require certain pAUC measures in connection with ANDA approvals.  FDA may have delayed issuing product-specific guidances for these two drugs until the Agency has wrapped up responses to the citizen petitions and is poised to make ANDA approval decisions. 

By Jeffrey K. Shapiro –

In our continuing quest to enlighten, we are launching today an occasional series that will examine significant or interesting warning letters involving medical device companies.

As you probably know, FDA issues warning letters to allege violations of the Federal Food, Drug, and Cosmetic Act and/or implementing regulations.  A warning letter is a statement of FDA’s enforcement position and a threat to pursue legal remedies if the target does not comply.  Usually, the alleged violation does not break new ground.  But, on occasion, FDA issues a warning letter that reveals a new or little known enforcement position.  This type of warning letter will be our critical focus.

Case in point:  A recent warning letter issued by the Philadephia District to a ventilator company appears to create a new standard for reporting malfunctions in life sustaining or life supporting devices or implantable devices.

As background, a malfunction complaint is reportable to FDA if a recurrence would be likely to cause or contribute to a death or serious injury.  See 21 C.F.R. § 803.50(a)(2).  In this case, there were complaints of ventilator malfunction that were not reported that FDA apparently believes should have been reported.  This led FDA to issue a Form 483 observation.  The warning letter followed.

The warning letter does not describe the malfunction events at issue.  The story gets interesting, however, when FDA assesses the firm’s response to the Form 483 observation.  Apparently, the firm had revised its reportability criteria to limit reportability to “ventilator failure modes that result in a loss of therapy.”  This limitation seems perfectly reasonable.  If a malfunction is not capable of causing a loss of therapy, almost by definition it is unlikely to cause or contribute to a serious injury or death.  Therefore, such malfunctions do not trigger the regulatory requirement for reportability.

Yet, FDA rejected the proposed limitation.  The agency relies upon the preamble to the medical device adverse event reporting (“MDR”) regulation.  See 60 Fed. Reg. 63,578, 63,585 (Dec. 11, 1995) (comment 12).  This comment expresses FDA’s interpretive view that a malfunction involving a life sustaining or life supporting device is reportable.

This citation is not adequate to support FDA’s position.  In context, the preamble statement seems merely intended to establish an enforcement presumption that loss of therapy in a life sustaining or life supporting device is likely to cause a serious injury or death.  The preamble does not appear to intend that literally every possible malfunction in such a device will be reportable even if the basic regulatory requirements for reportability are absent.  (Even if that were FDA’s intent, the agency legally cannot alter the basic terms of a regulation via a preamble statement.)

For example, if a red light bulb in an “on” switch indicator in a ventilator is off because internal wiring has gone bad, but a white bulb next to it still works and the user can tell that the device is “on,” there would be no interruption in treatment due to this malfunction and no death or serious injury could occur.  Therefore, this malfunction is not reportable under the MDR regulation.  Under the approach taken in FDA’s warning letter, however, it would appear that this malfunction would need to be reported.

FDA’s final statement in the letter (on this topic) states:  “[Y]our firm should submit an MDR for complaints referencing ventilator failures.”  This statement introduces a new ambiguity by using the term “failures” rather than “malfunctions.”  it appears that FDA is using these terms interchangeably, even though they really are not synonymous.  In any event, in light of the warning letter’s earlier rejection of a policy limiting reportability to malfunctions resulting in a loss of therapy, FDA’s position appears to be that all ventilator malfunctions are reportable without further analysis as to whether they meet the reporting criteria in the MDR regulation.  If so, FDA’s position extends well beyond the plain language of the MDR regulation.

It is hard to know whether this warning letter is simply a “one off” or a harbinger.  Under the previous administration, Chief Counsel’s office was required to review the legal sufficiency and consistency with agency policy of all warning letters.  Now that this review is restricted to warning letters that present significant or novel legal issues, it is not clear whether this warning letter received legal review. 

What is clear is that the reasoning of this warning letter is not limited to ventilators.  It would appear to be applicable to any device deemed life sustaining or life supporting, e.g., insulin infusion pumps, dialysis machines, cardio pulmonary bypass pumps, critical care diagnostic monitors, automated external defibrillators, insulin infusion pumps, and the like.  In light of this warning letter, manufacturers of all such devices will need to keep a wary eye on FDA’s enforcement of the MDR regulation. 

The International Conference on Drug Development (“ICD2”), formerly known as the International Industrial Pharmacy Conference, continues its annual tradition of offering an informal forum for the exchange of ideas concerning the drug discovery and development process.  The 2012 conference, which is presented by The University of Texas at Austin College of Pharmacy, is scheduled for February 27-29, 2012 at the Barton Creek Conference Center in Austin, Texas.  The 2012 conference theme is “Fostering Innovation and Translational Research in Support of Public Health and Economic Growth.”  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will present at the conference during a session titled “Legal Considerations to Establish Biosimilarity and Therapeutic Interchangeability.”

The ICD2 conference is known for bringing together national and international scientists from academia, the pharmaceutical industry, the biotechnology industry, and regulatory agencies for the opportunity to learn about and discuss new initiatives for finding a better way to develop new drugs and improve the quality of existing drug products.   Information about the 2012 conference, including registration information, is available here.  A copy of the conference agenda is available here.

By Kurt R. Karst –      

Last week, the Government Accountability Office (“GAO”) released a report, titled “Food and Drug Administration: Better Coordination Could Enhance Efforts to Address Economic Adulteration and Protect the Public Health,” in which the GAO examines FDA’s approaches to detecting and preventing so-called “economic adulteration” of food and medical products, and the challenges FDA faces in detecting and preventing such adulteration.  The report responds to requests from Representatives Henry Waxman (D-CA), Frank Pallone (D-NJ), and John Dingell (D-MI) that the GAO review how FDA oversees the safety of products to prevent and respond to economic adulteration.  The requests followed two high-profile cases of economic adulteration involving melamine and melamine-related compounds in pet foods and oversulfated chondroitin sulfate in the blood thinner heparin – in both cases, the products were imported from China.

Economic adulteration (also known as “economically motivated adulteration”) is defined in the report to mean “the fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production, i.e., for economic gain.”  Economic adulteration includes, for example, “dilution of products with increased quantities of an already-present substance (e.g., increasing inactive ingredients of a drug with a resulting reduction in strength of the finished product, or watering down of juice) to the extent that such dilution poses a known or possible health risk to consumers, as well as the addition or substitution of substances in order to mask dilution.”  (The definition of “economic adulteration” used in the GAO report is the same definition FDA proposed in April 2009 as a working definition for “economically motivated adulteration” – see 74 Fed. Reg. 15,498 (Apr. 6, 2009).)  Economic adulteration, a form of “intentional adulteration” whose primary purpose is financial gain, differs from other types of adulteration – both intentional adulteration, whose primary purpose is to cause harm (e.g., bioterrorism or sabotage), and “unintentional adulteration” (e.g., adulteration for failure to follow good manufacturing practices) – says GAO in the report.  The FDC Act does not make a distinction between intentional and unintentional adulteration, but rather prohibits the introduction of adulterated food, drugs, and medical devices into interstate commerce.  Similarly, “FDA primarily approaches economic adulteration as part of its broader efforts to combat adulteration in general, such as efforts to ensure the safety of imported products.”

FDA officials and stakeholders GAO interviewed in preparing the report noted several key challenges to detecting and preventing economic adulteration, including increased globalization, an increase in supply chain complexity, and difficulties with gathering information from industry (due to concerns about sharing proprietary information).  To enhance FDA’s efforts to combat economic adulteration, GAO recommends that Commissioner Hamburg take three actions: (1) officially adopt a working definition of “economic adulteration,” because “[w]ithout such a definition, when FDA detects adulteration, it is more difficult for the agency to make a distinction between economic adulteration and other forms of adulteration to guide the agency’s thinking about how to be more proactive about this issue;” (2) “provide written guidance to agency centers and offices on the means of addressing economic adulteration;” and (3) “enhance communication and coordination of agency efforts on economic adulteration,” because “[w]ithout such communication and coordination, in these times of economic uncertainty, FDA may not be making the best use of its scarce resources.”

FDA notes in the Agency’s response to the GAO report that FDA recently established the Working Group on Economically Motivated Adulteration (“WEMA”), which is comprised of staff from all FDA centers, the Office of Regulatory Affairs, and Office of the Commissioner.  WEMA, which held its first meeting on September 23, 2011, and will use the Agency’s proposed working definition of economically motivated adulteration to identify topics of broad Agency interest, “seeks to encourage information sharing across FDA on issues relevant to economically motivated adulteration.”

In his recent article appearing in FDLI Update, Hyman, Phelps & McNamara, P.C. Of Counsel, and former diversion investigator for the Drug Enforcement Administration (“DEA”), Larry K. Houck, explains the scope of DEA pre-registration and cyclic inspections as a step-by-step guide to actions and procedures registrants should take to prepare for and manage such inspections.  Citing, among other things, a recent notice (see our previous post here) stating that DEA is conducting more frequent scheduled investigations, as well as increasing the depth of review, Mr. Houck says that “there are certain actions and procedures that registrants can and should follow to prepare for and manage the inspection – before, during and afterwards.”

By Kurt R. Karst –      

Almost a year after having notified Genentech of a proposal to withdraw the approval of Avastin® (bevacizumab) for use with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer, and almost five months after holding a hearing (Docket No. FDA-2010-N-06211) on the topic, FDA, on November 18th, announced FDA Commissioner Margaret Hamburg’s decision to withdraw the approval.  FDA approved Avastin® under BLA No. 125085 on February 22, 2008 for the breast cancer use under the Agency’s “accelerated approval” regulations.  Avastin® was initially approved on February 26, 2004 as a first-line treatment in combination with intravenous 5-fluorocil-based chemotherapy in patients with metastatic carcinoma of the colon and rectum, and has since been approved for other uses.  None of those uses are affected by FDA’s November 18th decision. 

In December 1992, FDA promulgated final regulations under which the Agency will accelerate the approval of certain new drugs and biologics for serious or life-threatening illnesses, and when such products provide a meaningful therapeutic benefit to patients over existing treatments.  These accelerated approval regulations are located in Subpart H (21 C.F.R. Part 314) of FDA’s drug regulations, and in Subpart E (21 C.F.R. Part 601) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based on a demonstrated effect on a surrogate endpoint reasonably likely to predict clinical benefit and a sponsor’s commitment to complete with due diligence the required postmarketing studies to confirm the product’s clinical benefits.  A surrogate endpoint is an alternative measurement of the symptoms of a disease or condition that is substituted for measurements of observable clinical symptoms. 

Importantly, FDA may withdraw the approval of an application approved under the accelerated approval regulations if, for example, “[a] postmarketing clinical study fails to verify clinical benefit,” “[o]ther evidence demonstrates that [a] product is not shown to be safe or effective under its conditions of use,” or if a sponsor “fails to perform the required postmarketing study with due diligence.”  FDC Act § 506 – Fast Track Products – was enacted in 1997 as part of the FDA Modernization Act and is generally considered to have codified FDA’s accelerated approval regulations.  Like FDA’s accelerated approval regulations, FDC Act § 506 provides that FDA “may withdraw approval of a fast track product using expedited procedures,” if, for example, “a post-approval study of the fast track product fails to verify clinical benefit of the product,” or “other evidence demonstrates that the fast track product is not safe or effective under the conditions of use.” 

FDA’s February 2008 approval of Avastin® was based on a single study – the E2100 study – in which metastatic breast cancer patients showed an improvement of 5.5 months of median Progression Free Survival (“PFS”), the surrogate endpoint, but that did not demonstrate an overall survival benefit or improvement in quality of life.  The required postmarketing studies to confirm the benefit of Avastin® for the breast cancer indication – named AVADO and RIBBON1 – had already begun at the time of approval.  In both studies, PFS was the primary endpoint.  The results of the AVADO and RIBBON1 studies were submitted to FDA in November 2009.  FDA determined that the results of the studies did not confirm that the increase in PFS was as substantial as the E2100 study supporting the accelerated approval of Avastin® had suggested – i.e., the studies did not, according to FDA, verify clinical benefit – and the Agency proposed to withdraw the breast cancer indication. 

Genentech promptly requested a hearing on the proposed withdrawal.  FDA and Genentech disputed the effectiveness information for the Avastin® breast cancer indication and the appropriate risk-benefit analysis to be applied in this case.  At the conclusion of the hearing, the advisory committee unanimously voted that the AVADO and RIBBON1 studies failed to verify clinical benefit, that the available evidence on Avastin® demonstrates that the drug has not been shown to be effective for the breast cancer indication, that the available evidence on Avastin® do not demonstrate that it is safe for the breast cancer indication and that Avastin® has not been shown to present a clinical benefit that justifies the risks associated with the drug for the breast cancer indication, and that the FDA Commissioner should not continue the approval of Avastin® for the breast cancer indication while Genentech designs and conducts additional studies intended to verify the product’s clinical benefit if the Commissioner agrees with certain grounds for withdrawal.

FDA Commissioner Hamburg states in her 69-page decision that after having carefully reviewed the record, the conditions for withdrawal have been met, and that “the currently available data do not support continued accelerated approval of this drug for this indication.”  The results of the AVADO and RIBBON1 studies, says Commissioner Hamburg, “substantially changed the profile of [Avastin®],” and “have not verified the clinical benefit shown in E2100.            

The Avastin® withdrawal is not the first instance in which a product granted accelerated approval has been withdrawn from the market – either because a postmarketing study failed to verify clinical benefit, or because of a sponsor’s failure to complete a required postmarketing study with due diligence – although it is the first instance in which the hearing procedures have been completed and FDA has made a withdrawal decision.  As we previously reported, Pfizer voluntarily withdrew (at least insofar as a voluntary withdrawal is truly voluntary when FDA requests it) MYLOTARG (gemtuzumab ozogamicin for Injection) from the market after a required postmarketing study failed to demonstrate clinical benefit.  In addition, in August 2010, FDA issued a hearing notice and proposal withdraw approval of all marketing applications for the accelerated approval drug Midodrine HCl, which FDA first approved in September 1996 under the brand name PROAMATINE to treat orthostatic hypotension (see our previous post here).  Since that time, a hearing has been requested, but FDA appears to have delayed scheduling a hearing.  Instead, FDA opened a public docket (FDA-2010-N-0637) “to provide a forum to facilitate communication regarding the conduct of clinical trials needed to verify and describe the clinical benefit of midodrine hydrochloride.” 

Additional Reading:

• Genentech Press Release
• Genentech Avastin® Website
• Senator David Vitter (R-LA) Comments on FDA Avastin Decision
• National Breast Cancer Coalition Statement
• Mississippi Lawmakers Knock FDA Decision

By Kurt R. Karst –      

Less than a month before the U.S. Supreme Court is scheduled to hear Oral Argument in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, Docket No. No. 10-844 (see here and here), concerning whether the patent delisting counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I), as added by the Medicare Modernization Act, may be used to correct or delete an Orange Book-listed Patent Use Code (“PUC”), the U.S. District Court for the District of New Jersey granted a Motion to Dismiss a similar counterclaim in Hoffmann-La Roche Inc. v. Orchid Chemicals & Pharmaceuticals Ltd., a patent infringement lawsuit concerning generic BONIVA (ibandronate sodium) Tablets, 150 mg (“BONIVA Once-Monthly”).

BONIVA Once-Monthly, approved under NDA No. 021455, is a bisphosphonate indicated for the treatment and prevention of postmenopausal osteoporosis.  The drug is currently listed in the Orange Book with five patents, including U.S. Patent Nos. 7,718,634 (“the ‘634 patent”) and 7,410,957 (“the ‘957 patent”).  Both the ‘634 and ‘957 patents are listed in the Orange Book as method-of-use patents and expire on May 6, 2023.  The ‘634 patent, which issued on May 18, 2010, is listed with a “U-642” PUC, defined as “TREATMENT AND PREVENTION OF OSTEOPOROSIS,” and the ‘957 patent, which issued on August 12, 2008, is listed with a “U-887” PUC, defined as “TREATMENT AND PREVENTION OF OSTEOPOROSIS.” 

Orchid Healthcare, an unincorporated division of Orchid Chemicals and & Pharmaceuticals Ltd. (“Orchid”), submitted ANDA No. 078998 to FDA on or about May 16, 2007 seeking approval to market a generic version of BONIVA Once-Monthly, and containing a certification to the then-listed Orange Book patents for NDA No. 021455.  After having amended ANDA No. 078998 with Paragraph IV certifications to the ‘634 and ‘957 patents, Hoffmann-La Roche, Inc. (“Roche”) sued Orchid for patent infringement.  In response to Roche’s First Amended Complaint, Orchid included in its Answer, among other things, a counterclaim pursuant to FDC Act § 505(j)(5)(C)(ii)(I) requesting that the court issue an order requiring Roche to correct the PUCs for the ‘634 and ‘957 patents.  According to Orchid, “Roche’s use codes do not accurately describe the patented methods of use found in the claims of the 634 and 957 patents, in that they state that the 634 and 957 patent claims cover prevention of osteoporosis,” and “Roche must correct the use code for the 634 patent . . .  from ‘U-642: treatment and prevention of osteoporosis’ to ‘treatment of osteoporosis,’ and correct the use code for the 957 patent . . . from ‘U-887: treatment and prevention of osteoporosis’ to ‘treatment of osteoporosis.’”

Of course, hanging over Orchid’s counterclaim was the Federal Circuit’s 2010 decision in Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd., 601 F.3d 1359 (Fed. Cir. 2010), in which the Court reversed and vacated a 2009 decision from the U.S. District Court for the Eastern District of Michigan (Southern Division).  The district court ruled and issued an Order and Injunction requiring Novo Nordisk to change an Orange Book-listed PUC for a patent concerning PRANDIN (repaglinide) Tablets as a result of Caraco’s FDC Act §505(j)(5)(C)(ii)(I) counterclaim.  The Federal Circuit ruled that Caraco “does not have a statutory basis to assert a counterclaim requesting” a court to enter an order to change a PUC.  First, the Federal Circuit ruled that “the Hatch-Waxman Act authorizes a counterclaim only if the listed patent does not claim any approved methods of using the listed drug.”  Second, “the terms of the counterclaim provision do not authorize an order compelling the patent holder to change its use code narrative,” just the patent number and expiration date of an Orange Book-listed patent.  As noted above, the Federal Circuit’s decision is before the Supreme Court. 

Orchid says in its counterclaim that it believes the Federal Circuit’s “ruling is incorrect and that a cause of action for equitable relief exists . . . .”  Roche, however, says otherwise it its Motion to Dismiss: “[U]nder Caraco, the specific patent-listing issue for which the counterclaim was created does not apply here.  Since, there is no statutory basis for the new counterclaim as the Federal Circuit has stated in Caraco, Orchid’s Third Counterclaim should be dismissed pursuant to Fed. R. Civ. P. 12(b)(6), for failure to state a claim upon which relief can be granted.”  Orchid attempted to bolster its case in the company’s opposition to Roche’s Motion to Dismiss, stating that “[g]iven the substantial possibility that the law in this area will change before the present case is concluded, Roche’s motion to dismiss should be denied, without prejudice to renewal after the Supreme Court decision in Caraco.”   But Roche fired back that Orchid’s counterclaim is “dead in the water.”  “The highly speculative possibility that the Supreme Court might overturn years of established precedent in implied private right of action cases in a way that would give Orchid some grounds for relief does not justify burdening this Court or Plaintiffs with additional discovery and delay as the case is prepared for trial early next year,” argued Roche. 

Judge Stanley R. Chesler quickly dispensed with Orchid’s PUC counterclaim, saying that it “may be decided easily.”  Orchid’s sole argument in opposition to Roche’s Motion to Dismiss, writes Judge Chesler “is that a case is pending before the Supreme Court which might change existing law, and so this Court should abstain from deciding this motion now.  This Court construes this position as a concession that the third counterclaim is not valid under existing law.”  Accordingly, Judge Chesler granted Roche’s Motion to Dismiss Orchid’s third counterclaim.

By Ricardo Carvajal –

Late last month, a district court issued a ruling of interest in a Lanham Act case brought by sugar producers and trade associations against corn refiners and the Corn Refiners Association ("CRA") over their marketing of high fructose corn syrup ("HFCS").  The suit alleges that CRA’s claims that “HFCS is corn sugar,” “HFCS is natural,” and “sugar is sugar” constitute false advertising because HFCS is not naturally occurring and has effects on the body that differ from those of table sugar. 

In denying Defendants’ motion to dismiss as to Defendant CRA, the court rejected CRA’s contention that the challenged claims are not advertising, but are instead part of an “education campaign.”  The court noted that statements are not insulated from action under the Lanham Act by virtue of relating to a public health issue, and concluded that the challenged statements were promotional in nature:

As a trade organization made up of corn refiners, an economic motive exists, and the statements refer specifically to [HFCS].  The statements themselves also clearly are promoting corn syrup to food and beverage purchasers. 

However, the court granted Defendants’ motion to dismiss as to the individual corn refiners.  The court rejected Plaintiffs argument that CRA’s conduct should be imputed to the refiners because CRA is an agent of the refiners, all of whom are CRA members and financed CRA’s campaign:

Plaintiffs’ allegations as to the relationship between CRA and its members are conclusory and do not establish the authority to control that is required to show an agency relationship.  Hence, the Court cannot impute CRA’s actions to the remaining defendants.  Furthermore, Plaintiff’s allegations do not establish a false advertising claim against the individual member companies, as the First Amended Complaint lacks any allegations of the Member Defendants engaging in any advertising.

Although CRA has submitted a citizen petition to FDA seeking to rename HFCS as “corn sugar,” the court refused to apply the doctrine of primary jurisdiction.  That doctrine “allows a court to stay or dismiss an action without prejudice pending resolution by a government agency of an issue within its special competence.”  The court noted that the suit raises issues that would not be resolved by a decision on the citizen petition, and that there is no precedent for applying the doctrine in a case involving a challenge to an advertising campaign. 

By Jennifer D. Newberger –

On Tuesday, November 15th, Senator Al Franken (D-MN) announced the introduction of S. 1865, the “Patient Access to Medical Innovation Act.”  The bill is intended to accomplish two goals:  first, to allow manufacturers of products granted a humanitarian device exemption ("HDE") to profit from development of devices used in both adult and pediatric populations and, second, to ease conflict of interest restrictions on FDA advisory committee members.

Manufacturers may obtain an exemption from the effectiveness requirements for a device if (1) the device is “designed to treat or diagnose a disease or conditions that affects fewer than 4,000 individuals in the United States,” (2) the device would not be available to a person with the disease or condition unless FDA granted the exemption, and there is no comparable device available to treat or diagnose the condition, and (3) “the device will not expose patients to an unreasonable or significant risk of illness or injury and the probable benefit to health from the use of the device outweighs the risk of injury or illness from its use.”  FDC Act § 520(m)(2). 

Senator Franken’s bill retains these requirements for obtaining an HDE.  What it changes is the manufacturer’s ability to profit from sale of an HDE device.  Currently, the law prohibits a manufacturer from selling the device “for an amount that exceeds the costs of research and development, fabrication, and distribution of the device,” unless the device “is intended for the treatment or diagnosis of a disease or condition that occurs in pediatric patients or in a pediatric subpopulation, and such device is labeled for use in pediatric patients or in a pediatric subpopulation in which the disease or condition occurs.”  FDC Act §§ 520(m)(3), 520(m)(6)(A)(i)(I).  Senator Franken’s proposal would allow manufacturers to profit from the sale of any device granted an HDE, regardless of the intended patient population. 

Senator Franken’s bill also includes language that would make the legislation retroactive.  This means that manufacturers who currently market a product under an HDE, and who are unable to profit from the sale of such device, will be able to profit after the legislation is enacted, even if they obtained the HDE prior to its enactment.

In addition to changes to the HDE legislation, Senator Franken’s bill proposes changes to FDC Act Section 712, Conflicts of Interest.  Currently, section 712 limits the number of conflict-of-interest waivers that FDA may provide to experts that it would like to serve on its advisory committee.  The result of this restriction has been that FDA is often unable to obtain industry’s most qualified experts to serve.  The language in Senator Franken’s bill would require FDA to “ensure that each [waiver] considers the scope and magnitude of the financial interest at issue with the public health need for the expertise of the member on the advisory committee.”  This is intended to allow FDA to access a broader range of experts who would be unable to serve under the current legislation, and balance the potential conflict-of-interest against the need for participation by experts in a particular field.  Such expert consultation can play a critical role in bringing products to market.  If Congress enacts Senator Franken’s legislation, hopefully FDA will take advantage of the newly available expertise.

By Kurt R. Karst –      

On November 16th, Senators Jeff Bingaman (D-NM), David Vitter (R-LA), Sherrod Brown (D-OH), and Jeff Merkley (D-OR) announced the introduction of the Fair And Immediate Release of Generic Drugs Act, or the “FAIR GENERxICS Act,” a draft version of which is available here. 

The bill would make significant changes to the Hatch-Waxman Amendments, as amended by the Medicare Modernization Act, with respect to 180-day exclusivity under FDC Act § 505(j), as well as to the patent laws at 35 U.S.C. § 271(e), and is aimed at addressing the perceived ill-effects on generic competition of patent settlement agreements between drug companies (or what opponents refer to as “pay-for-delay” or “reverse payment” agreements).  According to the bill’s sponsors, the bill is intended to address “the root cause of anti-competitive pay-for-delay settlements between brand and generic pharmaceutical manufacturers: the unintended, structural flaw in the Hatch-Waxman Act that allows ‘parked’ exclusivities to block generic competition.”

As with most things Hatch-Waxman, the bill is complex.  In a future post we may dissect the various provisions of the bill, which include broadening the FDC Act’s definition of “first applicant” and the interplay with patent settlement agreements.  According to a summary of the FAIR GENERxICS Act:

The legislation would prevent “parked exclusivities” from delaying full, fair, and early generic competition by:

• Granting the right to share exclusivity to any generic filer who wins a patent challenge in the district court or is not sued for patent infringement by the brand company.
• Maximizing the incentive for all generic challengers to fight to bring products to market at the earliest possible time by holding generic settlers to the deferred entry date agreed to in their settlements.
• Creating more clarity regarding litigation risk for pioneer drug companies and generic companies by requiring pioneer companies to make a litigation decision within the 45 day window provided for in the Hatch-Waxman Act.

As a result, say the bill’s sponsors, “companies who prevail in their patent challenges and immediately come to market may be the sole beneficiary of the 180 day exclusivity period.  In addition, companies will understand litigation risk before launching generic products.” (Italics in original.)

It is worth noting that the FAIR GENERxICS Act bears some resemblance to the Drug Price Competition Act of 2009, which was introduced in the U.S. Senate by Sen. Bill Nelson (D-FL) as S. 1315, and in the House of Representatives by Rep. Alcee Hastings (D-FL) as H.R. 3777.  We previously reported on the bill here.  The Drug Price Competition Act of 2009 died with the adjournment of the last Congress, but not before  Rep. Hastings, in December 2009, proposed and then withdrew from consideration his bill as an amendment to the House Health Care Reform Bill.