By Jeffrey K. Shapiro –

The de novo classification procedure was added to the FD&C Act in 1997 to create a middle pathway between the 510(k) process and full blown premarket application ("PMA") approval.  It is intended for devices that utilize novel technologies that are not risky enough to justify regulation under the burdensome PMA process, but which lack a predicate device that would allow 510(k) clearance.  Under the procedure, a 510(k) submission must first be denied with a “not substantially equivalent” letter.  Then, the submitter may request de novo classification.

With FDA cracking down on the creative use of predicates, particularly split predicates, the threat to device innovation is that novel technologies will inappropriately be subject to the PMA approval process.  This process is so onerous and expensive that some of these novel technologies will simply be abandoned.

One solution would be a timely and efficient de novo classification.  Unfortunately, the device center’s 510(k) Working Group looked at de novo and found that it is not efficiently implemented at present.  Their report showed that average review times for therapeutic devices sky rocketed from 254 days in 2005 to 904 days in 2008, to 752 days in 2009.  The review times for diagnostic devices were somewhat better, increasing from 261 days in 2005 to 308 days in 2008 and 448 days in 2009.

We call your attention to a study published in June 2010 by Boston Medtech Advisors.  The study report can be found here.  It confirms the general tenor of the 510(k) Working Group’s data, but provides greater detail and more sophisticated analysis.  It is also more comprehensive:  Boston Medtech Advisors reviewed FDA’s entire de novo database from 1998 to 2009.   The report is worth reading in its entirety.

We learn from the report that there have been a mere 54 successful de novo classifications in 11 years, 38 diagnostic devices and 16 therapeutic devices.  This figure alone suggests that FDA has used de novo infrequently.  To some extent, that is appropriate if the 510(k) process is sufficiently elastic in the use of predicate devices.  But with FDA tightening up the use of predicate devices, there needs to be a greater use of de novo classification.

FDA committed at the outset to complete review of de novo applications in 60 days.  Until the end of 2006, all but two reviews were completed within 100 days, with an average review time of 62 days (median 51).  Since 2007, however, only 4 of 13 applications were reviewed in less than 100 days, and the average review time has been 241 days (median 217).  When the 510(k) review time is added in, the overall de novo review times are almost twice as long as target review times for panel-track PMAs!  Obviously, this delay lessens the attractiveness of de novo review for a device that has been denied 510(k) clearance because it lacks a predicate device.

The larger point is that FDA has a serious timing problem with its reforms.  If FDA is going to restrict the use of predicate devices, there needs to be a safety valve short of full PMA approval that allows novel technologies to reach patients.  Otherwise, device innovation is simply going to be stifled.  Not every innovation is worth the time and expense of the PMA approval process.  At present, however, the de novo process takes too long and is not used often enough, especially for therapeutic devices. 

Our own experience is that FDA is already tightening up the use of predicate devices, even prior to implementation of the 510(k) Working Group's recommendations.  If FDA wishes to further restrict the use of predicate devices, it should reform the de novo process first, so that there is a viable alternative when 510(k) clearance is denied for lack of a predicate device.  If FDA does not do so, many useful new technologies will simply be abandoned, with patients being the losers.

REMINDER: Register for HPM's free webinar "The Evolution of the Park Doctrine" on October 8th. (link to registration: http://hpmwebinar.eventbrite.com/)

By Kurt R. Karst –   

Just two days after Novartis Pharmaceuticals Corporation (“Novartis”) filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s September 14th approval of Watson Laboratories, Inc.’s ANDA No. 78-278 for a generic version of the herpes drug FAMVIR (famciclovir) Tablets, FDA, on September 24th, updated the Agency’s drug approval database (Drugs@FDA) to show that ANDA No. 78-278 is tentatively approved.  FDA’s move could signal an end to the litigation. 

As we reported last Thurdsay, Novartis’s Complaint alleges that FDA failed to require a split certification (Paragraph IV certification and “section viii” statement) with respect to  U.S. Patent No. 5,246,937 (“the ‘937 patent”), one of five patents listed in the Orange Book for FAMVIR, and requests that the court enter an order requiring FDA to withdraw approval of ANDA No. 78-278 until March 21, 2011.  The ‘937 patent expired on September 21, 2010, but is subject to a period of pediatric exclusivity that expires on March 21, 2011.  The ‘937 patent was listed in the Orange Book in 1994 and has since been flagged with only a method-of-use; however, Novartis alleges that the ‘937 patent also includes compound claims that cannot be carved out with a “section viii” statement. 

Prior to August 2003, technological limitations prevented FDA’s Orange Book listings from reflecting the fact that an NDA sponder submitted a patent as claiming both a drug product or drug substance claim and a method-of-use claim.  ANDA No. 78-278 contained a “section viii” statement to the ‘937 patent (and to the other four Orange Book-listed patents, which are flagged with the same patent use code as the ‘937 patent), but not a certification to the patent.

Novartis followed up its Complaint with a Motion for a Temporary Restraining Order and Preliminary Injunction (“TRO/PI”).  As with the company’s Complaint, Novartis argues in its TRO/PI motion that FDA’s decision to approve ANDA No. 78-278 is inconsistent with a March 15, 2010 FDA citizen petition decision.  In that case, FDA said that the Agency would not consider ANDAs eligible for final approval unless such application contained an appropriate certification (i.e., a split certification) to patents listed in the Orange Book for ACTOS (pioglitazone HCI) Tablets and ACTOPLUS MET (pioglitazone HCl; metformin HCI) Tablets.

Last Friday, Judge John D. Bates issued a Minute Order in the FAMVIR case for a September 30, 2010 scheduling conference.  Provided FDA maintains the tentative approval for ANDA No. 78-278 there might not be much to discuss at that conference.

REMINDER: Register for HPM's free webinar "The Evolution of the Park Doctrine" on October 8th. (link to registration: http://hpmwebinar.eventbrite.com/)

By Kurt R. Karst –   

On September 22, 2010, Novartis Pharmaceuticals Corporation (“Novartis”) filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s September 14th approval of Watson Laboratories, Inc.’s ANDA No. 78-278 for a generic version of the herpes drug FAMVIR (famciclovir) Tablets.  Unlike many recent lawsuits against FDA challenging ANDA approval based on bioequivalence issues and that involve the first marketing of a generic, the Novartis lawsuit takes issue with patent certification/“section viii” labeling carve-out statement issues and involves a subsequent approval.  (Back in August 2007, FDA approved the first generic version of FAMVIR under ANDA No. 77-487 and granted 180-day exclusivity.)

FDA first approved FAMVIR under NDA No. 20-363 in June 1994.  FAMVIR is listed in the Orange Book with five patents, including U.S. Patent No. 5,246,937 (“the ‘937 patent”).   The ‘937 patent expired on September 21, 2010, but is subject to a period of pediatric exclusivity that expires on March 21, 2011.  The ‘937 patent was listed in the  Orange Book shortly after the approval of NDA No. 20-363, and has since been flagged with only a U-96 patent use code, which is defined in an Orange Book addendum as  “METHOD OF TREATING VARICELLA ZOSTER (SHINGLES) INFECTIONS.”

FDA’s approval letter for ANDA No. 78-278 states that the application contains a “section viii” statement with respect to each of the five Orange Book-listed patents (all five patents are flagged with the same U-96 patent use code).  According to Novartis, however:

The FDA approved Watson’s ANDA improperly in violation of the [FDC Act] and the Administrative Procedure Act ("APA"), 5 U.S.C. § 551, et seq., because (i) Watson's ANDA No. 78-278 did not satisfy a statutory precondition to FDA approval in that it failed to include a certification, pursuant to 21 U.S.C. Section 355(j)(2)(A)(vii), with respect to the compound claims in the '937 patent directed to famciclovir; and (ii) as reflected in the FDA's Orange Book, Novartis is entitled to marketing exclusivity with respect to those tablets until March 21, 2011.

That is, Novartis alleges that the ‘937 patent covered more than a method-of-use claim and required a patent certification in addition to a “section viii” statement – i.e., a split certification.  According to the Complaint:

Watson’s section viii statement was potentially sufficient only with respect to method of use claims in the ‘937 patent, but was insufficient with respect to the drug product claims in the '937 patent.  Where a patent has been submitted for Orange Book listing that claims both the drug product and a method of using the drug, FDA has repeatedly ruled that the ANDA applicant must address all claims for which the patent was submitted. (internal quotation omitted). 

Novartis relies on FDA’s March 15, 2010 citizen petition response to a Sandoz petition involving ACTOS (pioglitazone HCI) Tablets and ACTOPLUS MET (pioglitazone HCl; metformin HCI) Tablets to support its position.  As we previously reported, the Sandoz petition requested that FDA refuse to approve any ANDA for a generic version of ACTOS and/or ACTOPLUS MET if the ANDA includes a “section viii statement” with regard to certain Orange Book-listed patents, but does not also include a Paragraph IV certification to the respective patent (i.e., a split certification). 

As with the ‘937 patent, the patents at issue in the Sandoz petition were submitted to FDA for Orange Book listed prior to August 18, 2003 and were flagged with method-of-use claims.  August 18, 2003 is the date on which FDA’s June 2003 regulations implementing the FDC Act’s patent listing provisions went into effect, and when the Agency made a technological leap in identifying Orange Book-listed patents.  As FDA explained in its March 2010 petition response, prior to 2003, the “Orange Book database lacked the technological capacity to display a single patent as claiming more than one aspect of the drug.”  Patents submitted to FDA after August 18, 2003 may be identified in the Orange Book as covering the drug product, drug substance, and/or an approved method of use. 

FDA granted the Sandoz petition and stated that the Agency would consider ANDAs that do not address the relevant drug product claims in the patents at issue to be ineligible for final approval.  Why? Because according to FDA:

Under the plain language of the statute, the patent certification requirement is not triggered by the publication in the Orange Book of patent information submitted to FDA.  Rather, . . . the statute requires certification where the patent (or patent claim) claims a listed drug, and where the NDA holder is required to submit and has submitted that patent information to FDA.  This obligation to certify attaches regardless of whether that submission is accurately reflected in the Orange Book.  Thus, the pre-2003 technological limitations that prevented our Orange Book listings from reflecting the fact that [the NDA holder] submitted the patents as claiming both a drug product and a method of using that drug product do not limit [the NDA holder’s] rights to receive patent certifications for the drug product claims in the [patents at issue.]

It is unclear whether Novartis notified FDA when the company first submitted the ‘937 patent for Orange Book listing that the patent contains both method-of-use and drug product/drug substance claims.  It will certainly be an interesting case for Hatch-Waxman folks to watch!

UPDATE:

• Novartis also filed a Motion for a Temporary Restraining Order and Preliminary Injunction later on September 23rd.  

REMINDER: Register for HPM's free webinar "The Evolution of the Park Doctrine" on October 8th. (link to registration: http://hpmwebinar.eventbrite.com/)

By Jennifer B. Davis –

On September 20, 2010, the Health Resources and Services Administration (“HRSA”) issued two Advanced Notices of Proposed Rulemaking and Requests for Comment (here and here) announcing its preliminary plans, and requesting stakeholder input, on how best to implement new authorities over the 340B Drug Pricing Program conferred by section 7102(a) of the Patient Protection and Affordable Care Act (“PPACA”).  We previously blogged about this and other drug- and device-related provisions of PPACA.

Among other mandates relating to the 340B Program, PPACA § 7102 requires HHS to adopt regulations establishing the standards and procedures for imposing civil monetary penalties on manufacturers that “knowingly and intentionally” overcharge covered entities for 340B Program drugs, as well as regulations prescribing the procedures for resolution of claims by covered entities that they have been overcharged, and claims by manufacturers that covered entities have violated the prohibition on duplicate discounts or rebates, and resale of 340B Program drugs.  The two recent Notices focus on these mandates. 

In the Notice concerning “Manufacturer Civil Monetary Penalties,” HRSA says it is reviewing the civil monetary (“CMP”) authorities currently used by other federal agencies such as the Office of Inspector General (“OIG”) of the Department of Health and Human Services, the Federal Aviation Administration, Treasury, the Food and Drug Administration and the Centers for Medicare & Medicaid Services to determine which parts of those procedures could be adapted for the 340B Program.  It is also considering the use and adaptation of the OIG’s CMP procedures codified at 42 CFR Part 1003.  HRSA requests comment on which portions of these existing models should be incorporated into the 340B Program CMP regulations, and on anticipated elements of the regulations – for example, the threshold criteria for deciding when to impose CMPs; the type of notice that should be issued to manufacturers and given to third parties and the public regarding proposed CMPs; the hearing and administrative appeals processes; and the method and criteria for computing the penalty.  Worth particular note is HRSA’s request for comment on its view of the “knowing and intentional” requirement.  HRSA contemplates a definition that allows “knowledge and intention” to be inferred from the circumstances and imputed to the manufacturer, even in cases where no single employee may have had knowledge of all the facts or an intention to overcharge.  HRSA also envisions that repeated violations could be considered “knowing and intentional” if, for example, a manufacturer repeatedly miscalculates a ceiling price or creates a system where overcharging is a highly likely consequence.

In the Notice regarding “Administrative Dispute Resolution Process,” HRSA seeks comment on what aspects of existing dispute resolution models – such as the current 340B Program voluntary dispute resolution guidelines – can be adapted to the new 340B dispute resolution regulations.  It also requests input on the standards and threshold requirements for bringing and requesting review of a claim; the role of and appropriate format and scope of a hearing requirement; the appropriate kind of decision-making official or body; the process for discovery of information from participating manufacturers and covered entities; the guidelines for the audit a manufacturer must conduct of a covered entity before bringing a claim; and when third party organizations can bring claims on behalf of member covered entities. 

Comments on both Notices are due by November 19.  HRSA says it will consider the comments in formulating its proposed regulations.  There will be another opportunity to comment on the proposals. 

Register for HPM's free webinar "The Evolution of the Park Doctrine" on October 8th. (link to registration: http://hpmwebinar.eventbrite.com/)

By Riëtte van Laack & Wes Siegner –

In recent consent decrees against Nestle, discussed here, and Iovate, discussed here, the Federal Trade Commission (“FTC”) appeared to be tightening its substantiation standard, prohibiting future claims for defendants’ food and dietary supplements unless they are supported by two well-controlled clinical studies.  A Complaint by POM Wonderful LLC (“POM”) against FTC filed on September 13, 2010, alleges that the FTC intends to apply this requirement to all claims for food and dietary supplements.  If POM’s allegations accurately reflect current FTC policy, the agency has embarked on a radical shift in direction on the core issue of advertising, substantiation of claims.

According to the Complaint, in its communications with POM, the FTC asserted that the standard described in these recent consent orders is the FTC’s “new standard.”  POM alleges that the standard is no longer “competent and reliable evidence,” which may vary case by case depending on the claim.  POM maintains that the FTC now asserts that “competent and reliable evidence” equates two well-controlled clinical studies.  Although the FTC Act authorizes the FTC to define the standard for substantiation, POM points out that the FTC must follow the proper process of notice and comment rulemaking, which the FTC has not done.  According to POM, FTC’s actions violate the FTC Act and the Administrative Procedures Act.

POM also alleges that the FTC now requires that FDA approve “certain health-related claims” for a food or dietary supplement, even if the claims are supported by two well-controlled clinical studies.  The requirement for approval by FDA was apparently first included in the recent consent decree against Nestle.  However, it was not clear from the decree that the FTC intended that this requirement would apply to parties not subject to the consent decree.  POM alleges that wholesale application of this requirement constitutes a violation of an advertiser’s First Amendment rights and is beyond FTC’s authority.  The FTC Act prohibits deceptive advertising; it does not authorize FTC to require that FDA approve claims in order for the claims to be non-deceptive.  Further, were the FTC to attempt to impose such a requirement, besides raising legal and constitutional issues, an approval requirement would be difficult if not impossible to implement in the many cases where the Federal Food, Drug, and Cosmetic Act requires approval but FDA exercises enforcement discretion or otherwise chooses not to require approval.

POM asks the Court to declare FTC’s new standard invalid.

By Jeffrey N. Wasserstein & David B. Clissold –

In a move that signals the future of medical product development, the Food and Drug Administration ("FDA") and the Centers for Medicare and Medicaid  Services ("CMS") announced that they are considering establishing a parallel review process for reviewing and evaluating premarket, FDA-regulated medical products when the product sponsor and both agencies agree to such parallel review. The stated goal is to reduce the time between FDA marketing approval or clearance decisions and CMS national coverage determinations ("NCDs").  Currently, medical products undergo two reviews: the first by FDA to determine if the product may be approved or cleared and a second review by CMS to determine whether it will be covered by Medicare. 

Implicit in the proposed parallel review function, however, is the potential that use of comparative efficacy data in making NCD decisions may have a spillover effect on FDA approval issues.  The initial focus of the program appears to be on medical devices, but the process will have implications for drugs and biologics as well.

The two agencies have opened a docket to receive comments from the public on what products would be appropriate for parallel review by the two agencies, what procedures should be developed, how the considered parallel review process should be implemented, and other related issues related to the effective operation of the process.  The Federal Register notice asks 17 specific questions, including, most critically:

• Should anyone other than the product sponsor be able to initiate a request for parallel review (for example, the FDA, CMS, an interested third party)?

• For which classes of products would consumers, payers, or sponsors benefit most from parallel review?

• Should CMS be permitted to review indications for which the sponsor is not seeking FDA clearance or approval under parallel review (that is, off label indications)?

• Are there any barriers (for example, regulatory, legal, scientific) to parallel review and if so, how might they be overcome?

• Should a voluntary process be put in place to encourage the conduct of clinical trials that are appropriately designed to support both FDA approval/clearance and CMS national coverage decisions? If so, what process should be established?

• What criteria should the FDA and CMS use to decide whether to grant a request for parallel review?

• Should the agencies offer joint meetings to sponsors?  Joint advisory committees?

• Should FDA and CMS have access to the same data and information about the product during parallel review?

• Once FDA and CMS have opened a parallel review should a sponsor be able to terminate or withdraw the request for parallel review? If this happens, should that information be made public?

The agencies also announced their intent to create a pilot program for parallel review of medical devices once they’ve received and reviewed public comments.  Comments to the docket are due by December 16, 2010.

By Kurt R. Karst –   

Last Friday, a group of Republican Senators (Sens. Jeff Sessions (R-AL), Tom Coburn, (R-OK), John Cornyn (R-TX), and John Thune (R-SD)) sent a letter to Senate Republican leaders expressing their “vigorous objection” to the inclusion of the “Preserve Access to Affordable Generics Act” (S. 369) in the Fiscal Year 2011 Financial Services and General Government Appropriations Bill (S. 3677).  As we previously reported, in late July, the U.S. Senate Committee on Appropriations approved the inclusion of the “Preserve Access to Affordable Generics Act” in the report (Senate Report No. 111-238; pages 144-148 & 150-151) accompanying S. 3677.  The legislation would make patent settlements (or what opponents call “pay-for-delay” or “reverse payment” agreements) presumptively anticompetitive and unlawful if challenged by the Federal Trade Commission (“FTC”), unless it can be demonstrated “by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.” 

According to the September 17th GOP lawmaker letter:

S. 369 is a complex bill that addresses the intersection between antitrust and patent law, the economics and anticipated outcomes of patent infringement lawsuits, and the factors that are legitimately considered when settling such suits. We believe that the reported bill gives excessive power over such settlements to the FTC – a power that the FTC has shown itself in the past to be unable to exercise in a responsible or economically rational manner – and that the bill would do serious violence to the Hatch-Waxman process for the market entry of generic drugs.

The inclusion of this bill in an appropriations bill, despite the objection of the ranking member of the Judiciary Committee and other committee members, is a gross breach of Senate custom and of jurisdictional boundaries.

The September 17th letter echoes a similar sentiment expressed by Senators Orrin Hatch (R-UT), Jon Kyl (R-AZ), John Cornyn (R-TX), and Tom Coburn (R-OK) in a February 2010 report accompanying on S. 369.  According to that report:

the bill would amount to a de facto per se ban on covered settlements – and would entail all of the evils attendant to a per se ban . . . . For a legal-presumption rule to work, however, the parties must be afforded a forum in which they can quickly and fairly test whether they have overcome the presumption and whether the agreement is valid.  Unfortunately, under the reported bill, settlements would be made presumptively unlawful, but the bill does not create a process for quickly resolving whether the agreement is unlawful.  The issue would not be resolved until the FTC brings an action to challenge the settlement, which could be years after the settlement was entered into.  Moreover, the current bill requires the brand and generic companies to rebut the presumption that the agreement is unlawful by clear and convincing evidence.  This is a heavy burden that is not appropriate for commercial litigation and that tilts the scales in a lawsuit sharply in the government’s favor. . . . By effectively preventing the parties from settling, it is likely that this bill will discourage generic drug companies from bringing challenges to brand companies’ patents in the first place—and as a result, the bill will ultimately reduce competition and raise prices for drugs that are currently subject to invalid or low-quality patents.

Inclusion of the “Preserve Access to Affordable Generics Act” legislation in S. 3677 was followed by a Congressional Budget Office cost estimate criticizing  the estimated savings from the measure as “significantly overstated,” and a U.S. Court of Appeals for the Second Circuit decision that denied without comment a Petition for Rehearing and Rehearing En Banc concerning an an antitrust challenge to certain patent settlement agreements involving Ciprofloxacin HCl (CIPRO).  Patent settlement opponents had thought the full Court might take up the issue of the legality of patent settlements after a 3-judge panel invited the submission of the petition for rehearing en banc.

Join Hyman, Phelps & McNamara, P.C. attorneys on October 8, 12:00 p.m. – 1:30 p.m. for a free webinar on a very important, timely topic.  You can register for the free webinar here.  (Please register by September 29th.)

In criminal prosecutions of corporate executives, ignorance of the law and the facts is often no defense.  FDA’s application of the Park Doctrine has taken different forms in the decades since its inception.  In the 1960’s through 1980’s, FDA frequently prosecuted company officials without any allegation that the defendant intended to violate the law. However, FDA has rarely brought these cases since that time.  Recently, FDA announced it will resuscitate the so-called Park Doctrine under which FDA, through the U.S. Department of Justice (“DOJ”), can criminally prosecute food, drug, medical device, and cosmetic company executives and other employees when their company has allegedly violated the Federal Food, Drug, and Cosmetic Act, even though the government can’t prove the employee knew about or approved the alleged conduct.
 
The webinar will feature attorneys from Hyman, Phelps & McNamara, P.C. with decades of experience in FDA’s application of the Park Doctrine. You will hear from FDA’s Chief Counsel from the 1980’s when many of these cases were initiated and from DOJ officials who pursued such prosecutions. They will:

• Share their insights of the doctrine from their government days;
• Make predictions as to the type of cases they believe are most likely to lead to a prosecution under the doctrine;
• Provide tips on how companies and their executives can minimize their risk of being subject to one of these criminal prosecutions;
• Discuss potential career-ending consequences of misdemeanor convictions; and
• Answer participants' questions submitted during or before the webinar.

Your presenters:

John Fleder specializes in litigation and internal investigations in criminal, civil, and regulatory matters relating to FDA, the FTC, and the CPSC. Mr. Fleder served as the Director of the Department of Justice's Office of Consumer Litigation between 1985 and 1992, after serving in various other capacities in that office since 1973. He also served as a Special Assistant United States Attorney in Baltimore. As Director of the Office of Consumer Litigation, he directed enforcement cases in federal court for FDA, FTC and CPSC.  See Mr. Fleder’s recent article on the Park Doctrine here.

Doug Farquhar works primarily on civil and criminal litigation, arbitration, and enforcement issues. He has handled a variety of consent decrees, criminal investigations, civil seizures, injunction actions (both those brought by FDA and those brought against FDA), difficult FDA inspections, lawsuits against competitors of clients, and criminal prosecutions and appeals. From 1990 to 1997, Mr. Farquhar served as an Assistant U.S. Attorney in the District of Maryland.

Tom Scarlett has practiced food and drug law for more than 40 years.  In 1971, he joined the Office of the General Counsel of the Department of Health and Human Services (then HEW) as a staff attorney in the Social and Rehabilitation Services Division. Two years later, he became a trial attorney in the FDA Chief Counsel's Office in HHS, where he served until 1979, concluding as Deputy Chief Counsel for Regulations and Hearings.  After practicing with Morgan, Lewis & Bockius from 1979 to 1981, he was appointed Chief Counsel of FDA, a position he held until 1989, when he became a Director at Hyman, Phelps & McNamara, P.C.  He now serves as Senior Counsel to the firm.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is proud to announce that the inaugural “Best Law Firms” survey by U.S. News & World Report has ranked HP&M as a “Tier 1” law firm in the area of FDA Law.  Only six firms made it to the top of the heap in the FDA Law practice section.  U.S. News released the rankings following a survey that involved soliciting comments from “thousands of law firm clients; leading lawyers and law firm managers; partners and associates; and marketing officers and recruiting officers.”  

By Kurt R. Karst –   

FDA will soon announce in the Federal Register a two-day public hearing (November 2 and 3, 2010) to obtain input on specific issues and challenges associated with the implementation of the Biologics Price Competition and Innovation Act of 2009 (“BPCI Act”).  According to an advance version of the Federal Register notice, FDA is soliciting input on a broad range of BPCI Act topics, including biosimilarity, interchangeability, patient safety and pharmacovigilance, exclusivity, and user fees.  FDA’s notice follows an announcement from earlier this year after the enactment of the BPCI Act as part of the Patient Protection and Affordable Care Act (Public Law No. 111-148) that the Agency created the position of Acting Associate Director for Biosimilars (filled by Dr. Leah Christl) in Office of New Drugs and established a Biosimilars Review Committee. 

Information presented and submitted to FDA for the public hearing, which will be held at FDA’s White Oak Campus in Silver Spring, Maryland and that will also be webcast live, will be used as the Agency develops guidance and regulations to implement the BPCI Act.  Specific questions posed by FDA in the draft Federal Register notice include:

Biosimilarity

1. What scientific and technical factors should the agency consider in determining whether the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components?

2. What scientific and technical factors should the agency consider in determining the appropriate analytical, animal, and clinical study or studies to assess the nature and impact of actual or potential structural differences between the proposed biosimilar product and the reference product?

3. What range of structural differences between a proposed biosimilar product and the reference product is consistent with the standard “highly similar” and may be acceptable in a 351(k) application if the applicant can demonstrate the absence of any clinically meaningful differences between the proposed biosimilar product and the reference product?

4. Under what circumstances should the agency consider finding that animal studies or a clinical study or studies are “unnecessary” for submission of a 351(k) application?

Interchangeability

1. What factors should the agency consider in determining whether a proposed interchangeable biological product can be “expected to produce the same clinical result as the reference product in any given patient?”

2. What factors should the agency consider in evaluating the potential risk related to alternating or switching between use of the proposed interchangeable biological product and the reference product or among interchangeable biological products?

Patient Safety and Pharmacovigilance

1. What factors unique to proposed biosimilar or interchangeable biological products and their use should the agency consider in developing its pharmacovigilance program for such products?

2. What approaches can be undertaken by the agency, industry, or health care community to ensure appropriate pharmacovigilance for biosimilar and interchangeable products?

3. Assuming each product is given a unique nonproprietary name, should a distinguishing prefix or suffix be added to the nonproprietary name for a related biological product that has not been demonstrated to be biosimilar, a biosimilar product, or an interchangeable product to facilitate pharmacovigilance? What factors should be considered to reduce any negative impact on the healthcare delivery system related to unique nonproprietary names for highly similar biological products?

4. What safeguards should the agency consider to assist the healthcare community when prescribing, administering, and dispensing biological products to prevent inadvertent substitution of products not identified as interchangeable without the intervention of the prescribing health care provider?

5. What are some mechanisms that FDA may consider to communicate findings that a particular product is or is not biosimilar to or interchangeable with a given reference product?

The Use of Supportive Data and Information

1.  From a scientific perspective, to what extent, if any, should animal or clinical data comparing a proposed biosimilar product with a non-U.S.-licensed comparator product be used to support a demonstration of biosimilarity to a U.S.-licensed reference product?

2.  What type of bridging data or information would be needed to scientifically justify the relevance of the comparative data?

Definition of a Biological Product

1. What scientific and technical factors should FDA consider in developing a regulatory definition for the category of “protein” (as distinguished from peptide or polypeptide)?

2. What scientific and technical factors should FDA consider in developing a regulatory definition for the category of “any chemically synthesized polypeptide”?

Guidances

1. What types of guidance documents for industry should be a priority for the agency during the early period of implementation?

2. Section 351(k)(8)(E) of the PHS Act permits the agency to indicate in a guidance document that the science and experience, as of the date of the guidance document, with respect to a product or product class (not including any recombinant protein) does not allow approval of a 351(k) application for such a product or product class. What scientific and technical factors should the agency consider in determining if the existing science and experience are sufficient to allow approval for a product or product class under section 351(k) of the PHS Act?

Exclusivity

1. In light of the potential transfer of BLAs from one corporate entity to another and the complexities of corporate and business relationships, what factors should the agency consider in determining the types of related entities that may be ineligible for a period of 12-year exclusivity for a subsequent BLA?

2. What factors should the agency consider in determining whether a modification to the structure of the licensed reference biological product results in a change in safety, purity, or potency, such that a subsequent BLA may be eligible for a second 12-year period of marketing exclusivity?

Transition Provisions

1. What scientific factors should FDA consider in defining and applying “product class” for purposes of determining which applications for biological products may be submitted under the FD&C Act during the 10-year transition period?

2. What scientific factors should FDA consider in determining whether another biological product approved under section 351(a) of the PHS Act could serve as the reference product for an application submitted under section 351(k) of the PHS Act?

User Fees

1. If the existing fee structure under the Prescription Drug User Fee Act (PDUFA) were to be considered as a model in establishing a user fee structure for applications and supplements for proposed biosimilar and interchangeable biological products, what factors and changes should FDA take into consideration, and why?

2. What factors should FDA take into account when considering whether to recommend that user fees for biosimilar and interchangeable biological products should also be used to monitor safety after approval?

By Kurt R. Karst –   

Do you have an ANDA prior approval supplement pending at FDA?  How long has it been pending – 6 months?  One year?  18 months?  Well it might still some time until there is any action on it.  Over the past few weeks we have received sporadic reports that FDA’s Office of Generic Drugs (“OGD”) has quietly placed a hold on ANDA prior approval supplement reviews and approval actions until further notice to focus instead on original ANDA submissions (and minor amendments). 

Although the details of the directive are still a bit sketchy, from what we understand, it is not a per se suspension.  OGD will review ANDA supplements if there is a compelling reason, such as supplements that might ordinarily qualify for expedited review – i.e., “supplements which would accomplish a public health need, eliminate an extraordinary hardship on the applicant, or accomplish a bona fide Agency goal” (MaPP 5240.1).  But that is the exception to the directive.  We also understand that although OGD hopes the directive will be short-lived it could remain in effect until OGD has made some headway in addressing the original ANDA backlog.  As we previously reported, and according to FDA-Track, there is a backlog of more than 2,000 original applications – 2,136 as of June 2010 (approximately 1,600 of which have been pending for more than 180 days).  And the backlog continues to grow.  So OGD has apparently decided to let the ANDA prior approval supplement queue grow (which may account for 50% of the total supplement backlog of about 3,900) in an effort to shorten the original ANDA queue.

Word of the ANDA supplement review directive has come out just as the debate over generic drug user fees has been heating up.  On Friday (September 17th), FDA will hold a public meeting to discuss and solicit from industry what a generic drug user fee system might look like.  There are several significant issues to be discussed, including how to handle the ANDA backlog and what the review goals should be.  And, of course, legislation needs to be enacted.   Industry will certainly not be happy to learn that supplement reviews have been stalled for the time being, even though there is a renewed effort to use “scarce agency resources” to tackle the original ANDA queue, for which OGD has been criticized.  The supplement directive could help drive FDA and stakeholders to come to a quicker consensus on generic drug user fees.  

By Ricardo Carvajal –

A district court dismissed a complaint alleging consumer fraud in food labeling that highlights the presence of fiber.  Plaintiff alleged that defendants violated state consumer fraud laws by failing to disclose that their products contain alleged “non-natural” fibers that “have not been shown by current scientific evidence to possess all of the health benefits of natural fibers.”  The court dismissed the case on the ground that the consumer’s state law claim is preempted by the Federal Food, Drug, and Cosmetic Act ("the Act").  The Act preempts any state requirement for nutrition labeling, nutrient content claims, or health claims that is not identical to the requirements of the Act.  With respect to fiber, the Act and its implementing regulations require food labels to bear nutrition information on the amount of dietary fiber present in a food, specify how dietary fiber must be disclosed, authorize nutrient content claims for fiber, and specify how health claims for fiber can be made.  In light of these requirements, the court concluded that the Act preempts plaintiff's demand under state law that certain fiber ingredients be labeled as “non-natural” and that the labeling disclose the purported differences in health benefits of “non-natural” fibers.

It’s that time of year again when the Blawggeratti (legal bloggers) are all atwitter about the American Bar Association’s (“ABA’s”) Blawg 100 – the top 100 legal blogs in the blogosphere.  With your help we made the top 100 list last year, and we are hoping for a repeat in 2010 – with your help once again!   The ABA announced that it is now accepting nominations for 2010.  We ask that FDA Law Blog readers visit the ABA’s “Blawg 100 Amici” website and nominate FDA Law Blog!  Thank you!  (It will only take a couple of minutes. Remember, when you complete the nomination form, our URL is www.fdalawblog.net.)

By Kurt R. Karst –   

How much is the potential for four month being lopped off your NDA review period (i.e., the difference between FDA’s standard and priority review goals under PDUFA)?  FDA set the baseline earlier this week when the Agency issued a Federal Register notice setting the Priority Review Voucher (“PRV”) User Fee for Fiscal Year 2011 at (drumroll please) . . . $4,582,000.  And that is in addition to the Fiscal Year 2011 application fee of $1,542,000 that must accompany the submission of an NDA.  We won’t bother you with all of the numbers that went into the calculation, but they are detailed in FDA’s notice if you are interested. 

PRVs were established by § 1102 of the 2007 FDA Amendments Act, which created  FDC Act § 524.  Under the statute, applicants for certain new drugs and biologics for “tropical diseases” that have received priority review may receive a PRV entitling the holder to a 6-month priority FDA review of another application that would otherwise be reviewed under FDA’s standard 10-month review clock.  To our knowledge, FDA has granted only a single PRV – in connection with the April 2009 approval of NDA No. 22-268 for COARTEM (artemether; lumefantrine) for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least five kilograms. 

PRVs are transferable – indeed, FDC Act § 524 allows for a single actual transfer of a PRV from the original recipient to another sponsor, and FDA has clarified in draft guidance that “contractual arrangements such as the use of an option or transfer of the right to designate the voucher’s recipient could comply with the terms of the statute” – so there has been speculation that a market could be created for them.  In fact, one non-profit organization has created a website to track the PRV program and to help build a market for the vouchers.  As we previously commented, ultimately, the value of a PRV must be based on two considerations: (1) the prospect of saved approval time; and (2) the anticipated sales of a new drug.  And it is difficult  to predict either with any certainty.  A redemption fee of $4,582,000, however, could hurt PRV marketability in light of these uncertainties. 

Moreover, a redemption fee of $4,582,000 could hurt the prospects for the passage of the Creating Hope Act of 2010 (S. 3697).  As we previously reported, S. 3697 was introduced earlier this year and would, among other things, amend the PRV program to extend it to applications for a “rare pediatric disease” – that is, a disease “recognized in the medical community as affecting a pediatric population” and that is “a rare disease or condition, within the meaning of section 526” (i.e., the Orphan Drug Act).  With such a high redemption fee, the marketability of a PRV (i.e., sale for profit) is questionable, and support for the bill could wane.  Of course, Congress could amend the PRV statute to require a different redemption fee calculation or set a flat fee, either for a rare pediatric PRV or for a tropical PRV, or both. 

By Kurt R. Karst –   

Earlier this week, Senator Patrick Leahy (D-VT) introduced the Food Safety Accountability Act of 2010 (S. 3767).  The bill, which follows Sen. Leahy’s Food Safety Enforcement Act of 2010 (S. 3669) introduced earlier this year and the recent egg recall, is intended to strengthen criminal penalties for food safety violators. 

S. 3767 would amend Title 18 of the U.S. Code (Chapter 47 – Fraud and False Statements) to add a new section – § 1041 Misbranded and adulterated food – making it unlawful for any person to knowingly: “(1) introduce or deliver for introduction into interstate commerce any food that is adulterated or misbranded; or (2) adulterate or misbrand any food in interstate commerce.”  A violation of proposed § 1041 would carry with it a fine and/or imprisonment for not more than 10 years.  S. 3669 would have amended the FDC Act to impose criminal penalties for persons who knowingly contaminate the food supply.

According to a press release, Sen. Leahy, who chairs the Senate Judiciary Committee, has scheduled a Committee business meeting for Thursday, September 16th that will include a discussion of the bill.  Continuing concern about the safety of the food supply could increase pressure on Congress to pass food safety legislation that might include at least some version of the Food Safety Accountability Act.