By Jennifer D. Newberger –

As part of the Medical Device User Fee Act of 2012 (MDUFA III) Commitment Letter, FDA and the medical device industry agreed to participate in a comprehensive assessment of the medical device review process.  MDUFA III Commitment Letter (April 18, 2012), at 12.  FDA contracted with Booz Allen Hamilton to conduct the two-phase assessment.  The results of the first phase are to be issued within one year of the contract award, with findings on a set of priority recommendations within six months. 

On December 11, 2013, Booz Allen released its report detailing the following priority recommendations: 

• Develop criteria and establish mechanisms to improve consistency in decision making throughout the review process
• Provide mandatory full staff training for the three primary IT systems that support MDUFA III reviews
• Identify metrics and incorporate methods to better assess review process training satisfaction, learning, and staff behavior changes
• Adopt a holistic, multi-pronged approach to address five quality component areas to standardize process lifecycle management activities and improve consistency of reviews

For anyone who follows FDA’s medical device review processes, none of these recommendations should come as a surprise.  Industry has, for years, been encouraging CDRH to improve consistency in decision making, and has been very vocal in its criticism of CDRH’s failure to do so.  Time and again, we learn of situations, for example, in which CDRH requests data in a 510(k) submission that were not required of a recently cleared predicate, or where CDRH relies upon a draft guidance or a policy that has not been communicated to industry. 

The second and third points relate to CDRH’s lack of sufficient and/or efficient training of its reviewers.  Once training is complete, there is little to no follow-up to determine whether the training achieved its goals, and if additional training is necessary.  With respect to the IT systems, Booz Allen found that only 53% of reviewers who received training on the new IT systems found that the training eased review.  As for training programs intended to “increase knowledge on submission review for both new and experienced staff,” Booz Allen found “gaps in FDA’s ability to objectively assess the impact of learning and the extent to which participants’ review behaviors changed as a result of training.”  It is not clear from the report whether FDA has in place processes to assess the impact of training—if it does, this would come as a surprise—or whether the lack of training assessment itself is the gap.  Either way, FDA should find a way to determine whether its training programs are beneficial.

Finally, the last bullet encompasses many of the issues identified in the prior bullets.  The five quality component areas include Senior Management Responsibility, Resource Management, Document Control, Process Improvement, and System Evaluation.  Booz Allen’s recommendations with respect to these five areas relate primarily to ensuring accountability and follow-up with respect to both review issues and training, establishing consistency in document control, formalizing a means of making improvements to the review process, and better monitoring the quality and effectiveness of the review process. 

All areas identified by Booz Allen are ones in which industry has long been encouraging CDRH to make improvements to its system.  Perhaps because these recommendations stem from the MDUFA Commitment Letter, rather than simply frustrated industry representatives, CDRH will pay more attention this time.  However, for many in the industry, the report will likely just be seen as more recommendations to CDRH of areas that need improvement that will go unheeded.

By Kurt R. Karst –    

Last week, FDA announced the issuance of a long-anticipated draft guidance document, titled “Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules,” providing details on acceptable physical attribute differences between generic drugs and their NDA Reference Listed Drug (“RLD) counterparts.  Issuance of a draft guidance on this topic is contemplated as a Regulatory Science Plan goal the Agency agreed to under the 2012 Generic Drug User Fee Amendments, and as reflected in the Generic Drug User Fee Act Program Performance Goals and Procedures for Fiscal Year 2013:

Topic 10: Evaluation of drug product physical attributes on patient acceptability
Impact: Laboratory and human studies on physical attributes such as tablet size, shape, coating, odor perception (residual solvents), score configuration, taste masking or color on the ability of patient to use (for example swallow) or perceive quality (for example smell) will allow OGD to provide better guidance to applicants on how these physical attributes should be controlled and compared to the RLD.

The issue of generic drug physical attributes and how they compare to their RLD counterparts is not new; however, there seems to be increasing focus on the issue by FDA.  As we reported nearly two years ago, FDA has refused to approve various ANDAs because of size issues, and has issued various documents on topics such as bead size and tablet scoring.  (Size issues have even found their way into ANDA 180-day exclusivity decisions – see here and here.)  And although not the topic of FDA’s draft guidance, we note that physical attribute issues are not just cropping up where tablets and capsules are concerned.  They come up in other contexts as well.  For example, in drug-device combination products.  We’ve seen instances in which FDA has advised potential applicants that their device component should be “interchangeable in patient hands” vis-à-vis the RLD device component.  FDA has even gone so far as to recommend that “the color scheme be similar to the RLD . . . . because patients associate color schemes with the product and strength.”

The problem, of course, is that the more FDA requires a generic drug product to look and feel the same as the RLD product, the greater the likelihood that a generic will run smack dab into intellectual property protections on the brand-name drug, such as patents and trademarks.  Indeed, with tight restrictions on physical attribute differences, some companies may now more than ever be incentivized to seek the issuance of patents with claims broad enough to cature the physical attribute variations identified by FDA as permissible.  What physical attribute variations you ask?  Well, before we go there, let’s start with the “why”? 

The gist of FDA’s draft guidance is that generic drug manufacturers should consider physical attributes when they develop Quality Target Product Profiles (“QTPPs”) for their generic product candidates because it is in the interest of patient safety.  As FDA states:

[A] variety of factors may affect the ability of a patient to swallow a tablet or capsule.  Although not all patient factors can be addressed through pharmaceutical design and manufacture, the physical characteristics of a product can be.  These characteristics influence the ability of certain patients to swallow the product, particularly in vulnerable populations.  We believe that tablets and capsules can be effectively developed and manufactured to minimize swallowing difficulties, which can encourage and improve patient compliance with medication regimens. 

With that in mind, and after a whole lot of citation to published literature, FDA states its draft recommendations.  Insofar as tablet size is concerned, FDA recommends limiting size differences between therapeutically equivalent tablets as follows:

• If the RLD is less than or equal to 17 mm in its largest dimension, the generic product should be no more than 20 percent larger than the RLD in any single dimension (the resulting dimension not to exceed 17 mm) and no more than 40 percent larger than the RLD in volume.
• If the RLD is greater than 17 mm in its largest dimension, the generic product should be no larger than the RLD in any single dimension or in volume.
• We recommend that the largest dimension of a tablet or capsule should not exceed 22 mm and that capsules should not exceed a standard 00 size.

For products that are 8 mm or smaller in their largest dimension, FDA comments that “[a]dditional flexibility may be given,” but also reemphasizes that “efforts should be made to develop tablets and capsules that are of a similar size and shape to the RLD.”

Insofar as capsule size is concerned, FDA references the standard capsule size convention (provided below) and says that it will:

generally allow an increase of one capsule size, when the RLD capsule is of size 3 or smaller.  When the RLD capsule is of size 2 or larger, an increase of one capsule size should only be considered when adequate justification can be provided for the size increase.  These recommendations would allow an increase of one capsule size when the capsule size is less than capsule size 00. . . .  

Moving on to shape, FDA recommends “manufacturing tablets and capsules that have a similar shape or have a shape that has been found to be easier to swallow compared with the shape of the RLD.”  Earlier in the guidance, FDA notes that “[i]n vitro studies suggest that flat tablets have greater adherence to the esophagus than capsule-shaped tablets,” and that “[s]tudies in humans have also suggested that oval tablets may be easier to swallow and have faster esophageal transit times than round tablets of the same weight.”

Finally, in a catch-all “other physical attributes” bucket, FDA merely notes that “[o]ther physical attributes of tablets and capsules should be considered in the context of their effect on ease of swallowing.  For example, tablet coating, weight, surface area, disintegration time, and propensity for swelling should be considered when developing a QTPP for generic tablets.” 

Generic drug manufacturers clearly have a lot to consider these days as FDA tightens the screws on them – whether in product pysical attributes or labeling changes for that matter (see our previous post here).    

By Kurt R. Karst –    

On December 12th, a group of bipartisan lawmakers led by Representatives Phil Gingrey (R-GA) and Gene Green (D-TX) introduced H.R. 3742, the Antibiotic Development to Advance Patient Treatment Act of 2013 (“ADAPT Act”).  If enacted, the ADAPT Act would, among other things, amend the law to create a pathway for the prompt approval of antibacterial and antifungal drugs intended to treat serious or life-threatening diseases or conditions.  Introduction of the ADAPT Act came on the same day that FDA’s Dr. Janet Woodcock testified during a House hearing concerning drug development and manufacturing challenges that legislation is needed for FDA to create a program to develop products designed to attack drug-resistant “superbugs” (see here).  In addition, earlier this week, FDA issued a proposed rule and guidance document concerning the use of antimicrobial new animal drugs to assure their appropriate and judicious use.  There has been growing concern about the risk of antimicrobial resistance from the use of drugs in food-producing animals, and at least one bill is pending in Congress: S.1256, the Preventing Antibiotic Resistance Act of 2013.

The ADAPT Act has been in the works for some time now.  The approval mechanism it would create has been informally known as the Limited Population Antibacterial Drug (“LPAD”) pathway, and has drawn strong support from the Pew Charitable Trusts and the Infectious Diseases Society of America (see here and here).  Earlier this year, FDA held a public hearing on “Creating an Alternative Approval Pathway for Certain Drugs Intended to Address Unmet Medical Need” (Docket No. FDA-2012-N-1248) at which both organizations called for the creation of the LPAD pathway. 

The ADAPT Act is viewed as successor legislation to the Generating Antibiotics Incentives Now Act (‘GAIN Act”), which was enacted in July 2012 as part of the FDA Safety and Innovation Act.  The GAIN Act, which itself builds on provisions included in 2007 FDA Amendments Act (“FDAAA”), is intended to improve antibiotic access and innovation by providing incentives for the development of qualified infectious disease products (see our summary here; pages 47-50). 

So what exactly does the ADAPT Act do to advance drug development?  According to a press release from Rep. Gingrey, the ADAPT Act advances drug development in three ways:

1.)    Develops a new, accelerated pathway for antibiotics and antifungals

This pathway provides for FDA-approval of drugs in order to treat emerging threats in limited and specific patient populations.

2.)    Strengthen resistance monitoring by the CDC

The CDC will also monitor use of antibiotics to treat serious and life-threatening infections and make this data publically available to providers, hospitals, and academics.

3.)    Update Susceptibility Test Interpretive Criteria for Microbial Organisms or “breakpoints”

The ADAPT Act streamlines the antibiotics labeling process at the FDA to ensure up-to-date and cutting-edge data is available to healthcare professionals.

Specifically, the ADAPT Act would amend the FDC Act to add Section 505(x), allowing the sponsor of an antibacterial or antifungal drug intended to treat a serious or life-threatening disease or condition (or a biological products intended to treat a bacterial or fungal infection associated with a serious or life-threatening disease) to request that FDA approve the drug “to treat a limited population of patients for which there is an unmet medical need.”  In determining whether to grant such approval for a limited population of patients, FDA “may rely on traditional endpoints, alternative endpoints, or a combination of traditional and alternative endpoints; datasets of limited size; pharmacologic or pathophysiologic data; data from phase 2 clinical studies; and such other confirmatory evidence as the [Agency] deems necessary.”  The labeling of products approved under the limited population pathway must include the statement: “This drug is indicated for use in a limited and specific population of patients.”

The bill would also ament the Public Health Service Act (“PHS Act”) to require FDA to use the National Healthcare Safety Network (or another appropriate monitoring system) to monitor the use of antibacterial and antifungal drugs (including limited population drugs under proposed FDC Act § 505(x)), and to monitor changes in bacterial and fungal resistance to drugs.  Data collected by FDA under such monitoring would be made public for the purposes of “improving the monitoring of important trends in antibacterial and antifungal resistance,” and “ensuring appropriate stewardship of antibacterial and antifungal drugs.”  This portion of the ADAPT Act somewhat resembles provisions in H.R. 2285, the Strategies to Address Antimicrobial Resistance Act, which was introduced earlier thie year.

Finally, the ADAPT Act would amend FDC Act § 511, which was added to the statute by the 2007 FDAAA, to require FDA to “identify upon approval and subsequently update susceptibility test interpretive criteria for antibacterial drugs (including biological products intended to treat a bacterial infection and other types of antimicrobial drugs, as deemed appropriate by [FDA]), including qualified infectious disease products.”  Susceptibility test interpretive criteria, which are more commonly known as “breakpoints,” are used to select an appropriate antibacterial drug to treat a patient with a bacterial infection.  A “breakpoint” reflects the concentrations at which bacteria are categorized as susceptible to treatment with a given antibiotic drug and can change over time.  An outdated breakpoint can result in the unknowing selection of ineffective treatments, which can also contribute to antibiotic resistance.  As we previously reported, the Government Accountability Office issued a report in January 2012 saying that FDA has not taken sufficient steps to ensure that antibiotic labels contain up-to-date information.  In October 2013, FDA held an advisory committee meeting to discuss breakpoints.

Immediately after introduction of the ADAPT Act, the Pew Charitable Trusts applauded the action in a letter to Representatives Gingrey and Green.  “Your legislation would help streamline the regulatory pathway for antibiotics that could address [carbapenem-resistant Enterobacteriaceae] and other dangerous pathogens,” wrote the organization.  “Drugs approved under this pathway would be studied for use in smaller populations than other antibiotics.  This will help lower development costs and make clinical trials more feasible.”

By Kurt R. Karst –      

Congress has been silent on new legislation addressing drug patent settlement agreements (aka “reverse payment agreements” or “pay-for-delay agreements”) since the U.S. Supreme Court issued its June 2013 opinion in Federal Trade Commission v. Actavis, Inc., 570 U.S. ___ (2013).  As we previously reported, the Court declined to hold that reverse payment settlement agreements are presumptively unlawful, and that “Courts reviewing such agreements should proceed by applying the ‘rule of reason,’ rather than under a ‘quick look’ approach.”  Notwithstanding the Court’s holding on the appropriate test to apply to drug patent settlement agreements, however, the Court also held that the FTC should have been given the opportunity to prove its antitrust claims and that the exclusionary potential of a patent does not immunize a drug patent settlement agreement from antitrust attack.  (That case in now progressing as reported yesterday by Law360.)  The silence from Capitol Hill was broken earlier this week when Representative Bobby Rush (D-IL) introduced “new” legislation: H.R. 3709, the Protecting Consumer Access to Generic Drugs Act of 2013.

H.R. 3709, which has apparently been ready for introduction since July 2013 (according to the date stamp on the version obtained by the FDA Law Blog), is the same bill Rep. Rush introduced in February 2012: H.R. 3995, the Protecting Consumer Access to Generic Drugs Act of 2012.  In fact, other than a change from 2012 to 2013, H.R. 3709 appears to be identical to H.R. 3995.  The same thing happened in the U.S. Senate with that chamber’s drug patent settlement bills: S. 214, the Preserve Access to Affordable Generics Act, which was introduced in February 2013 (see our previous post here), and S. 504, the Fair And Immediate Release of Generic Drugs Act (“FAIR Generics Act”), which was introduced in March 2013 (see our previous post on an earlier version of the bill).

As we previously reported, the Protecting Consumer Access to Generic Drugs Act is different than the current versions of the Preserve Access to Affordable Generics Act and the FAIR Generics Act, although the House bill does harken back to a February 2009 version of the Preserve Access to Affordable Generics Act.  Specifically, the Protecting Consumer Access to Generic Drugs Act does not include the controversial presumption that an agreement, if challenged by the FTC, is anticompetitive and unlawful unless it can be demonstrated by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.  Instead, the Protecting Consumer Access to Generic Drugs Act of 2013 simply says:

It shall be unlawful for any person to directly or indirectly be a party to any agreement resolving or settling a patent infringement claim in which – (1) an ANDA filer receives anything of value; and (2) the ANDA filer agrees not to research, develop, manufacture, market, or sell, for any period of time, the drug that is to be manufactured under the ANDA involved and is the subject of the patent infringement claim.

There are exceptions to this blanket rule.  H.R. 3709 would not prohibit agreements in which the value received by the ANDA sponsor includes no more than the right to market the drug product before the expiration of certain patents and non-patent marketing exclusivities.  A violation of the blanket rule (unless otherwise excepted) would be treated as an unfair and deceptive act or practice and an unfair method of competition in or affecting interstate commerce prohibited under the FTC Act.  The bill would also permit the FTC to promulgate regulations to further implement the exceptions included in the bill.

It’s been quite a month for Hyman, Phelps & McNamara, P.C. (“HP&M”)!  First, the American Bar Association named the FDA Law Blog to the 2013 ABA Journal Blawg 100 (see here).  Now there are three more honors to report! 

Earlier this week at the Food and Drug Law Institute’s (“FDLI”) Annual Holiday and Leadership Awards Reception, HP&M Director Jeffrey N. Gibbs was honored when the organization awarded him with the 2013 Distinguished Service and Leadership Award.  The award is given each year to as many as four individuals from various areas of the food and drug law community for their notable service and leadership.  Joining Mr. Gibbs in the 2013 award are Jane A. Axelrad, the Associate Director for Policy in FDA’s Center for Drug Evaluation and Research; Kay Holcombe, Vice President of Government Relations and Senior Health Policy Advisor at Genzyme; and Richard Kingham, a partner at Covington & Burling LLP.  (For more on the award recipients, see here).  Mr. Gibbs joins a distinguished list of past award recipients, including HP&M’s Paul M. Hyman (2003) and Stephen H. McNamara (2004).

Moving on . . . .  HP&M has once again been ranked as a “Tier 1” law firm in the area of “FDA Law” (both nationally and in Washington, D.C.) by the folks over at U.S. News & World Report, who  teamed up with Best Lawyers for the “America’s Best Law Firms 2014” rankings.  More than 11,000 law firms are ranked in 120 practice areas in 170 metropolitan areas and 8 states.  “[R]ankings are based on a rigorous evaluation process that includes the collection of client and lawyer evaluations, peer review from leading attorneys in their field, and review of additional information provided by law firms as part of the formal submission process,” according to U.S. News.  The 2014 list of America’s Best Law Firms can be searched here, or viewed here (we’re noted on page 51).

Finally, HP&M has been busy on the publication front.  A new book published by Thomson Reuters, titled “Commercialisation of Health Care: Jurisdictional Comparisons,” delves into how health care products, including drugs, medical devices, biologics, and dietary supplements, are regulated across 21 major jurisdictions throughout the world.  The new book, for which HP&M’s Jeff Gibbs is one of the general editors, includes contributions from expert regulatory lawyers in each jurisdiction.  The chapter on United States regulation was co-authored by HP&M’s Jennifer D. Newberger, Alexander J. Varond, and Jeff Gibbs.

By Riëtte van Laack –

In addition to the many (more than 20,000) comments to FDA on the draft rules regarding Produce and Preventive Controls implementing the Food Safety Modernization Act (“FSMA”) (Docket Nos. FDA-2011-N-0920 and FDA-2011-N-0921), FDA has received a flurry of letters from Congress – see here, here, here, and here – expressing concerns about the unintended effect of FDA’s draft rules on agriculture and small businesses and reminding FDA of the intent of FSMA.

Although the letters highlight different aspects, the common thread appears to be a concern that, if implemented as proposed, the rules will result in unintended consequences that will be severely detrimental to agriculture.  The lawmakers’ concerns appear to relate primarily to FDA’s application of FSMA’s small business exemption and the proposed restrictions on the use of biological soil amendments and other conflicts between the proposed rules and current standards by USDA (e.g., the National Organic Program (“NOP”)).  According to the lawmakers, the proposed rules fail to properly define small businesses that would be exempt from certain requirements.  The proposed rules also fail to comply with FSMA’s mandate against establishing requirements that conflict with or duplicate the requirements of other laws and regulations, such as the NOP.

Some of the lawmakers suggest that FDA, rather than finalize the rules, revise the proposed rules and reissue them for public review and comment.  However, in light of the court-ordered deadlines for finalizing the rules (see our previous post here), a “do-over” may not be feasible. 

By Jennifer M. Thomas –

To the extent that Plaintiffs, or interested observers, hoped the District Court for the District of Columbia would seize an opportunity to take FDA to task for failing to prevent or stop drug shortages, they were disappointed by Judge Howell’s Thanksgiving ruling in Carik v. HHS, No. 12-00272 (D.D.C. Nov. 27, 2013). 

On the other hand, FDA may hug itself.  Judge Howell concurred completely with FDA’s argument that Plaintiffs lacked Article III standing because they failed to adequately allege any action by the government with a “causal connection” to their alleged injuries.  In doing so, he found expressly that two pharmaceutical manufacturers had caused the complained-of shortages, not FDA.  Nor did FDA have any ability, let alone a statutory or constitutional “duty to act,” to alleviate the drug shortages.  Finally, Judge Howell determined that the actions of the pharmaceutical companies in managing their drugs in shortage could not be fairly attributed to FDA, since the Agency was not alleged to have significantly encouraged those companies’ drug rationing schemes.

Judge Howell went further in favor of dismissal on Article III grounds even than FDA in its brief, finding that only one of the twenty-five Plaintiffs had adequately alleged injury in fact.  The “possibility that adverse effects may result from taking a diluted dose” of the drug in shortage could not constitute injury in fact where the Plaintiff’s had failed to quantify the increased risk of physical injury, and thus “demonstrate a ‘substantial probability’ that they will be injured.”

Coming on the heels of a major setback for FDA on the drug shortage front in the D.C. Circuit (Cook v. FDA, No. 12-5176 (Jul. 23, 2013)), as we discussed here, FDA may feel vindicated by Judge Howell’s recognition of the Agency’s serious limitations in managing drug shortages, and attribution of responsibility to pharmaceutical companies.   

By John R. Fleder –

On August 8, 2013, we reported on a brief filed by the Department of Justice in United States ex rel. Ge v. Takeda Pharmaceutical Company Limited.  The case involves the defendants’ alleged failure to timely report to FDA adverse drug events associated with certain drugs.

The government’s brief asserted that the court below had erred in relying on FDA’s Citizen Petition procedures as an “alternative administrative mechanism” that bars FCA actions.  The brief also argued that failure to report adverse events to FDA can theoretically form the basis for FCA liability.  The brief stated that pharmaceutical companies must report adverse events associated with their drugs to FDA.  The government indicated that FDA approval is relevant to whether the government can reimburse for drugs under some government programs.  The relator claimed that all of the claims for reimbursement submitted with regard to Takeda’s drugs were “false” because Takeda had not properly filed adverse events reports.  The government concluded that the circumstances where a failure to report an adverse event could form the basis for FCA liability are “rare.”  Indeed, the government stated that simply “alleging that a company failed to comply with FDA’s adverse event reporting requirements is insufficient to state an FCA claim.”  The government further argued that compliance with the FDCA’s adverse event reporting requirements “is not, in itself, a material precondition of payment under Medicare or Medicaid.”  In the government’s view, only when it is determined that the unreported adverse events “are so serious that the FDA would have withdrawn a drug’s approval for all indications had these events been properly reported” would the failure to report be material to the government’s payment decisions, and thus trigger a potential FCA action.

On December 6, 2013, the United States Court of Appeals for the First Circuit affirmed the lower court’s decision dismissing the case.  The Court of Appeals concluded that the Relator’s Complaint was legally deficient under Rule 9(b) of the Federal Rules of Civil Procedure because of the absence of evidence that the defendants’ alleged misconduct resulted in the submission of false claims or the making of false statements.   The Court also ruled that relator had not timely raised certain issues, such as the belated claim that the False Claims Act was violated under a FDC Act misbranding theory.

Unfortunately for those who were hoping for some clarity on the issue of the interplay between the False Claims Act and the FDC Act, the Court circumvented a ruling on that issue by affirming the dismissal on other grounds.  Indeed, the Court made reference to DOJ’s brief only in a short footnote that neither adopted no rejected the approach suggested by DOJ.  Thus, we will have to await another case to obtain clearer rulings from courts regarding the interplay between these two statutes.

By Kurt R. Karst –      

Our hopes that FDA might publish a proposed rule to implement at least some of the changes made to the Hatch-Waxman Amendments to the FDC Act by the Medicare Modernization Act (“MMA”), enacted on December 8, 2003, before the 10-year anniversary of the law were dashed when December 8th came and went without a peep out of the Agency.  We’re now at day 3,655 and counting.  And because this is Hatch-Waxman we’re talking about – where day calculations really count – we should be clear that the 3,655-day period was calculated from and including Monday, December 8, 2003, to and including Monday, December 9, 2013.  By comparison, FDA – and the U.S. Patent and Trademark Office for that matter – took significantly less time to implement the 1984 Hatch-Waxman Amendments:

• Proposed ANDA Regulations (Hatch-Waxman Title I): 1751 days (from and including Monday, September 24, 1984, to and including Monday, July 10, 1989)
• Final ANDA Regulations (Hatch-Waxman Title I): 1023 days (from and including Tuesday, July 11, 1989, to and including Tuesday, April 28, 1992)
• Final ANDA Regulations; Patent and Exclusivity Provisions (Hatch-Waxman Title I): 1911 days (from and including Tuesday, July 11, 1989, to and including Monday, October 3, 1994)
• Proposed Patent Term Restoration Regulations (Hatch-Waxman Title II): 656 days (from and including Monday, September 24, 1984, to and including Friday, July 11, 1986)
• Final Patent Term Restoration Regulations (Hatch-Waxman Title II): 605 days (from and including Saturday, July 12, 1986, to and including Monday, March 7, 1988)

C’est la vie . . . C’est la vie.  Perhaps 2014 – the 30th anniversary of the enactment of the Hatch-Waxman Amendments (on September 24, 1984) – will be the year when we see a proposed rule.  We understand that FDA is quite close to getting something out to the public.

Because we don’t yet have a proposed rule to talk about, we need something to fill the void.  So, we decided on the Paragraph IV notice provisions amended by the MMA.  Earlier this week we addressed “premature notice” (see our post here).  This post addresses the other side of the notice period: late notice and its consequences. 

Under FDC Act § 505(j)(2)(B)(ii), as added by the MMA:

(ii) TIMING OF NOTICE.—An applicant that makes a [Paragraph IV] certification . . . shall give notice as required under this subparagraph—

(I) if the certification is in the application, not later than 20 days after the date of the postmark on the notice with which the Secretary informs the applicant that the application has been filed; or

(II) if the certification is in an amendment or supplement to the application, at the time at which the applicant submits the amendment or supplement, regardless of whether the applicant has already given notice with respect to another such certification contained in the application or in an amendment or supplement to the application.

Prior to the MMA’s enactment, FDC Act § 505(j) provided specific instruction with respect to notice timing only as it concerned ANDA amendments.  Specifically, FDC Act § 505(j)(2)(B) (2002) stated:

(i) An applicant who makes a [Paragraph IV] certification described . . . shall include in the application a statement that the applicant will give the notice required by clause (ii) to –

(I) each owner of the patent which is the subject of the certification or the representative of such owner designated to receive such notice, and

(II) the holder of the approved application under subsection (b) for the drug which is claimed by the patent or a use of which is claimed by the patent or the representative of such holder designated to receive such notice.

(ii) The notice referred to in clause (i) shall state that an application, which contains data from bioavailability or bioequivalence studies, has been submitted under this subsection for the drug with respect to which the certification is made to obtain approval to engage in the commercial manufacture, use, or sale of such drug before the expiration of the patent referred to in the certification.  Such notice shall include a detailed statement of the factual and legal basis of the applicant's opinion that the patent is not valid or will not be infringed.

(iii) If an application is amended to include a [Paragraph IV] certification . . . , the notice required by clause (ii) shall be given when the amended application is submitted.

FDA’s regulation at 21 C.F.R. § 314.95(b), which implemented the statutory notice provision under the Hatch-Waxman Amendments for original ANDAs, states, in relevant part, that an ANDA sponsor must provide notice of its Paragraph IV certification “when it receives from FDA an acknowledgment letter stating that its [ANDA] is sufficiently complete to permit a substantive review.”  As FDA has previously stated, “[t]he term ‘when’ was subject to multiple interpretations by industry, resulting in ANDA applicants providing notice to NDA holders and patent owners at times ranging from immediately upon receipt of an acknowledgement letter to months after such receipt.”  FDA’s regulation at 21 C.F.R. § 314.95(d), which implemented the statutory notice provision under the Hatch-Waxman Amendments for amended ANDAs, states: “[i]f an abbreviated application is amended to include [a Paragraph IV] certification . . . , the applicant shall send the notice required by paragraph (a) of this section at the same time that the amendment to the abbreviated application is submitted to FDA.”

Pre-MMA, FDA and the courts addressed the question of timing of Paragraph IV notice in a couple of cases concerning amended ANDAs (both involving Purepac) for generic versions of NEURONTIN (gabapentin): Purepac Pharmaceutical Co. v. Thompson, 354 F.3d 877 (D.C. Cir. 2004), aff’g TorPharm, Inc. v. Thompson, 260 F.Supp.2d 69 (D.D.C. 2003).  (Further litigation involved a challenge to FDA’s patent-by-patent interpretation of the pre-MMA statute permitting multiple periods of 180-day exclusivity – see here).

In summary, Purepac amended its ANDA with a Paragraph IV certification in late May 2000, but waited until June 13, 2000 to send notice of the certification to the NDA owner/patent owner.  In contrast, TorPharm, another ANDA sponsor, simultaneously amended its ANDA and sent notice to the NDA sponsor/patent on June 13, 2000.  FDA received TorPharm’s amended ANDA on June 16th and deemed the Paragraph IV certification filed on that day.  FDA concluded that the penalty for Purepac’s failure to provide simultaneous notice should be postponement of the effective date of the certification.  Ultimately, FDA refused to nullify Purepac’s notice (as argued by TorPharm) and FDA awarded Purepac 180-day exclusivity because Purepac completed both tasks before TorPharm.  The U.S. District Court for the District of Columbia found this to be a reasonable exercise of FDA’s discretion, and the D.C. Circuit affirmed.

With respect to timely notice and original ANDAs, two Citizen Petitions were submitted to FDA post-MMA concerning pre-MMA 180-day exclusivity for generic versions of two drugs: (1) RISPERDAL (risperidone) Tablets, the subject of an IVAX Citizen Petition, FDA Docket No. 2004P-0520 (Nov. 19, 2004); and DUONEB (albuterol sulfate and ipratropium bromide) Inhalation Solution, the subject of a Mylan Citizen Petition, FDA Docket No. 2006P-0245 (June 12, 2006).  Both petitions contend that Congress effectively directed FDA to apply the same notice rule to original and amended ANDAs.  FDA did not substantively respond to either petition.  In the case of Risperidone Tablets, the patent at issue expired and 180-day exclusivity was granted with respect to a later-listed patent (see here).  In the case of generic DUONEB, FDA apparently resolved the notice issue and granted exclusivity contrary to what was requested in the petition (see here). 

Post-MMA, we’re not aware of an instance in which FDA has publicly resolved a notice dispute concerning an original ANDA pursuant to FDC Act § 505(j)(2)(B)(ii)(I).  But we’re going to make an educated guess here as to how FDA would handle the issue (and how it might be described in proposed regulations to implement to MMA).  Consider the following scenario and the underlying rule that a Paragraph IV certification is perfected when notice is timely sent within the statutory timeframe.

The Reference Listed Drug is listed in the Orange Book with information on a single patent and has been granted 5-year New Chemical Entity (“NCE”) exclusivity.  Thus, the date on which the first ANDA can be submitted to FDA containing a Paragraph IV certification – the so-called “NCE-1 date” – qualifying an ANDA sponsor as a “first applicant” eligible for 180-day exclusivity is known to all potential ANDA applicants.  ANDA Applicant Nos. 1 and 2 submit their applications on the NCE-1 date.  Both ANDAs are received on the same date and the applicants receive notice of that receipt on the same day.  ANDA Applicant No. 1 provides notice of its Paragraph IV challenge within 20 days of receiving FDA’s receipt notice.  ANDA Applicant No. 2 delays sending notice of its Paragraph IV challenge until 23 days after receiving FDA’s receipt notice.  What happens? 

We think FDA will propose that untimely notice postpones the effective date of the Paragraph IV certification (whether in an original ANDA or in the case of an amended ANDA).  That is, with respect to the scenario above, ANDA Applicant No. 1 would be a first applicant eligible for 180-day exclusivity because its ANDA was received as of the date of submission of the ANDA (i.e., the NCE-1 date).  ANDA Applicant No. 2, however, would not be a first applicant eligible for 180-day exclusivity because its ANDA was not received as of the date of submission of the ANDA.  That is, we think FDA would add on an additional 3 days to the initial ANDA submission date, such that the ANDA is considered received as of the NCE-1 date plus 3 days (to account for the untimely notice period).  Are we correct?  We’ll see when FDA finally proposes some MMA regulations implementing FDC Act § 505(j)(2)(B)(ii).

By Kurt R. Karst –      

A Complaint recently filed in the U.S. District Court for the District of Delaware by Otsuka Pharmaceutical Co., Ltd. (“Otsuka”) against Par Pharmaceutical, Inc. (“Par”) concerning notice of a Paragraph IV certification contained in an ANDA Par submitted to FDA for a generic version of SAMSCA (tolvaptan) Tablets raises the issue of so-called “premature notice.”  The issue is not a new one – particularly for Par.

FDA approved SAMSCA on May 19, 2009 under NDA No. 022275 and granted a period of 5-year New Chemical Entity (“NCE”) exclusivity.  Because patents are listed in the Orange Book for SAMSCA, that raises the possibility of submission of an ANDA containing a Paragraph IV certification beginning on the so-called NCE-1 date of May 19, 2013.  It also means that a timely filed patent infringement lawsuit within 45 days of the NDA holder/patent owner having received notice of a Paragraph IV challenge results in a 30-month litigation stay on ANDA approval that lasts until 7.5 years after the date of NDA approval (or until November 19, 2016 in the case of SAMSCA), unless an earlier court decision terminates the stay. 

Although it has been nearly 7 months since the NCE-1 date of May 19, 2013, FDA’s Paragraph IV Certifications List has not yet been updated to reflect receipt (i.e., filing) of an ANDA for generic SAMSCA containing a Paragraph IV certification.  But Otsuka recently filed a Complaint in the U.S. District Court for the District of Delaware in response to a Paragraph IV notice received by Par.  That means either FDA’s Paragraph IV Certifications List has not yet been updated to reflect receipt of an ANDA . . . . or that the list is currently correct and the notice sent by Par with respect to the company’s ANDA No. 206119 is not effective.  Not effective you ask?  Yes, ineffective beacuse it is premature.

Under FDC Act § 505(j)(2)(B)(ii), as added by the 2003 Medicare Modernization Act:

(ii) TIMING OF NOTICE.—An applicant that makes a [Paragraph IV] certification . . . shall give notice as required under this subparagraph—

(I) if the certification is in the application, not later than 20 days after the date of the postmark on the notice with which the Secretary informs the applicant that the application has been filed; or

(II) if the certification is in an amendment or supplement to the application, at the time at which the applicant submits the amendment or supplement, regardless of whether the applicant has already given notice with respect to another such certification contained in the application or in an amendment or supplement to the application.

According to Otsuka, which confirmed with FDA that as of November 14, 2013, Par’s ANDA No. 206119 had not been accepted for review:

Upon information and belief, as of October 10, 2013, Par did not have an ANDA with respect to Otsuka’s SAMSCA® (tolvaptan) that had been accepted for review by [FDA].  The acceptance of an ANDA by the FDA is a prerequisite that must be satisfied before Par can send Otsuka proper notification that an ANDA containing a “Paragraph IV certification” has been filed.  Such a notice letter, if it were valid, would start a time period in which Otsuka must sue for patent infringement in order to obtain a 30-month statutory period during which the FDA cannot approve Par’s ANDA.  Because, upon information and belief, Par’s ANDA had not yet been accepted by the FDA, Par could not send a valid notice letter to Otsuka, and therefore could not trigger Otsuka's statutory right to sue for infringement or commence the 30-month stay.

Shortly after confirming with FDA that Par’s notice letter was premature, Otsuka contacted Par and asked the company to withdraw the Paragraph IV notice.  Among other things, Otsuka cited a 2008 court decision – SB Pharmco Puerto Rico, Inc. v. Mutual Pharm. Co, Inc., 552 F. Supp. 2d 500 (E.D. Pa. 2008) (see here) – which held that a Paragraph IV notice letter sent prior to FDA’s receipt of an ANDA is premature and ineffective.  In that decision, the court also noted that premature certification, if accepted, could lead to manipulation of the Hatch-Waxman scheme by “accelerat[ing] the timing provisions and litigation process well beyond the framework that Congress intended.”  This point is reiterated by Otsuka in its Complaint: “By filing prematurely or notifying the NDA holder or patent owner prematurely, the first ANDA filer may also be able to manipulate the rules surrounding the 30-month stay to its advantage and reach the market sooner than would otherwise be permitted.”

Par declined Otsuka’s request to withdraw the notice (see here), saying that the “Paragraph IV Notice may be necessary to protect Par’s potential first-to-file status.”  Furthermore, according to Par, Otsuka’s reliance on SB Pharmco “is not persuasive” because the court in that case “improperly gave deference to the FDA’s interpretation of [FDC Act § 505(j)(2)(B)(ii)(II)].”  “No deference is owed to the FDA’s interpretation if the statutory language is clear and unambiguous, as is [FDC Act § 505(j)(2)(B)(ii)(II)],” writes Par.  (Of course, in the case of SAMSCA and Par's original ANDA, FDC Act § 505(j)(2)(B)(ii)(I), and not FDC Act § 505(j)(2)(B)(ii)(II), is the operative provision.)   

Interestingly, Par’s notice to Otsuka is not the first time the company has attempted to jump the gun by sending notice before FDA’s receipt of an ANDA as substantially complete.  According to one letter from FDA sent in August 2012, the Agency rebuffed Par for doing the same thing on another drug.  Indeed, we understand that the notice to Otsuka is not even the second time Par has followed an early notice strategy.  This may be a pattern of conduct followed by Par in more than 6 instances.  Will FDA finally more forcefully step in and take action to prevent future premature notices?  We may not know for sure, but the absence of future complaints alleging premature notice could be a sign that FDA had enough of the practice and took action to put an end to it. 

The Food and Drug Law Institute (“FDLI”) will hold is annual – and quite popular – Enforcement, Litigation and Compliance Conference from December 10-11, 2013 at The Westin Georgetown in Washington, DC.  You can register for the conference here.  A copy of the conference agenda is available here.

During the two days of advanced sessions, attendees will hear HHS OIG’s deputy inspector general for investigations discuss prescription drug diversion enforcement efforts, hear compliance directors from all FDA product Centers discuss center-specific developments, and hear how the federal government works across agencies to collaborate on enforcement actions.  Here’s a list of the star-studded cast of government presenters:

• Gary Cantrell, Deputy Inspector General for Investigations, Office of Inspector General, HHS
• Mary E. Riordan, Senior Counsel, Office of Counsel, Office of the Inspector General, HHS
• Beth P. Weinman, Associate Chief Counsel for Enforcement, Food & Drug Division, HHS Office of the General Counsel
• Jill Furman, Deputy Director, Consumer Protection Branch, DOJ
• Robert L. Hill, Executive Assistant, Office of Diversion Control, DEA, DOJ
• Ilisa Bernstein, Deputy Director, Office of Compliance, CDER, FDA 
• Jarilyn Dupont, Director of Regulatory Policy, Office of Policy, OC, FDA
• Annamarie Kempic, Deputy Chief Counsel for Litigation, Office of Chief Counsel, FDA   
• Mary A. Malarkey, Director, Office of Compliance and Biologics Quality, CBER, FDA 
• Daniel McChesney, Director, Office of Surveillance and Compliance, CVM, FDA   
• Michael W. Roosevelt, Deputy Director, Office of Compliance, CFSAN, FDA 
• John Roth, Director, Office of Criminal Investigation, FDA
• Steven D. Silverman, Director, Office of Compliance, CDRH, FDA 
• Ann L. Simoneau, Director, Office of Compliance and Enforcement, CTP, FDA    

In addition to these key panels, attendees will hear from the FDA Office of Chief Counsel during the Inaugural Eric M. Blumberg Memorial Lecture.  (Mr. Blumberg, the Deputy Chief Counsel for Litigation at FDA, died last March of complications from a stroke – see here.)  

Hyman, Phelps & McNamara, P.C.’s John R. Fleder will moderate a panel on Responding to FDA Enforcement Actions.  The panel, which includes David J. Bloch, Principal Legal Counsel, Medtronic, Inc., Mitchell S. Fuerst, Managing Partner, Fuerst Ittleman David & Joseph, PL, and Stephen Gardner, Director of Litigation, Center for Science in the Public Interest, will focus on a range of complex issues, including private enforcement actions through state consumer protection laws, the Lanham Act, False Claims Act, deferred prosecution agreements, and non-prosecution agreements.  The session will present both the plaintiff and defense side of enforcement actions.  Additionally, the panelists will review inspections and warning letters and what FDA enforcement trends may mean for industry members.

By Delia A. Stubbs & John A. Gilbert –

DEA didn’t waste time during its Thanksgiving break.  Monday, in just shy of three weeks of the close of its comment period on its proposed rule, DEA issued a final rule placing perampanel in Schedule III.  We previously reported on DEA’s delay in issuing a Notice of Proposed Rulemaking (“NPRM”) to schedule the drug and the impact on drug manufacturer, EISAI, here, here, and here. 

DEA’s quick turnaround is not surprising in light of EISAI’s recent suit where it requested that the Court of Appeals for the D.C. Circuit issue a writ of mandamus ordering DEA promptly to schedule perampanel.  Perampanel is the active pharmaceutical ingredient (“API”) in EISAI’s drug, FYCOMPA, that FDA approved last year.  FDA has taken the position that the exclusivity clock began to run upon the drug's approval, although EISAI cannot market the drug until it is scheduled by DEA (see our prior post here).  FDA sent its scientific and medical evaluation to DEA in January of 2013, but as of October, the agency had yet to take any discernable action on it.  While the Court declined to grant the writ, shortly after DEA promised to issue a NPRM by the end of the month, the Court warned that “petitioner may once again seek relief in this court should the Drug Enforcement Administration fail to adhere to its envisioned schedule.”  Fear of once again being dragged into federal court may have prompted the agency to move quickly.

The final order scheduling FYCOMPA will not be effective until January 2, 2014.  DEA declined to follow a commenter’s request that DEA make the regulation effective – and thus the drug available – immediately.  DEA reasoned that final orders are required by regulation to become final no less than 30 days after publication and “that the conditions of public health or safety do not necessitate . . . an earlier effective date.”  Id. at 72,014 (citing 21 C.F.R. § 1308.45).  It explained that there are medications currently available with the same indications as perampanel, yet different mechanisms of action, and that delaying effectiveness of the final rule by 30 days will “allow handlers to obtain the appropriate registration with the DEA and to comply with regulatory requirements for handling schedule III controlled substances.”  Id.  For manufacturer EISAI, who has already lost 13 months of exclusivity during DEA’s delay, January 2nd likely can’t come soon enough.   

By Dara Katcher Levy –

We recently became aware of a lawsuit filed against FDA in the Eastern District of New York over the importation of bulk drug product.  In this suit, which also names an individual FDA Compliance Officer, the importer argues that FDA’s actions in refusing a shipment of bulk acetaminophen are overreaching, arbitrary and capricious, unlawful and discriminatory.  The importer is requesting a temporary restraining order that would stay U.S. Customs and Border Patrol’s request for redelivery of the refused shipment, and a declaratory judgment that the acetaminophen that is the subject of the import is exempt from misbranding provisions of section 502(f)(1) of the Federal Food, Drug, and Cosmetic Act.

FDA apparently refused the shipment because of some unidentified policy against importing lawful product for future use or inventory, as well as a failure to document every customer that would be purchasing the finished goods (from the importer’s customer, not the importer).  According to the Complaint, the importer, was seeking to import bulk acetaminophen to distribute to its contract manufacturer customer.  The contract manufacturer provided an end-use letter that stated the acetaminophen would be further manufactured into over-the-counter drug products, and identified one of the brands that would be manufactured from the bulk product.  The bulk acetaminophen, as proposed for import, had been labeled with the statement, “Caution: For manufacturing, processing, or repacking” in accordance with 21 C.F.R. § 201.122.  In addition, the ultimate customer of the contract manufacturer also contacted the FDA prior to the refusal.

After over a month of correspondence, FDA refused the shipment through a formal FDA Notice of Refusal that stated, “DOCUMENTATION NEEDED TO REMOVE THE APPEARANCE OF VIOLATION, SUCH AS, APPROVED USE DOCUMENTATION.  NO APPLICATION, USE OR END-USER TRANSMITTED.  REQUIRED END-USE DOCUMENTATION NOT RECEIVED TO DATE.”  Separately, by email, the Compliance Officer stated that it appeared the active pharmaceutical ingredient would be for future or stock/inventory use and “[c]urrent guidance for bulk APIs does not permit importation for stock/inventory use.” 

OTC drug products are often manufactured by a single manufacturer for many private label distributors.  As long as the finished product is ultimately compliant, FDA’s refusal to permit the import of otherwise lawful bulk drug product simply because a customer for the finished product had not yet been identified at the time of import is difficult to understand, and does not appear to be consistent with the agency’s regulations on drugs intended to be further manufactured.  It would be interesting to see whether an end-use statement that simply stated that the product would be manufactured and labeled in accordance with the pending OTC monograph would have sufficed in securing the release of this shipment.

Next Wednesday, December 12th, the ABA Section of Litigation, Products Liability Committee is sponsoring a live audio program titled “Understanding criminal prosecution of food and supplement companies (and their corporate officers) under the Food Drug and Cosmetic Act: Best practices to avoid becoming the next Jensen Farms.”  The presenters are Jeffrey Steger, Assistant Director of the Consumer Protection Branch, U.S. Department of Justice, and Hyman, Phelps & McNamara, P.C.'s Ricardo Carvajal and Anne Walsh.  The program will be moderated by Sam Felker of Bass, Berry & Sims, and is scheduled from 12:00 – 1:00 p.m. EST.  Registration is available here.

By Allyson B. Mullen & Jeffrey N. Gibbs –

On November 25, 2013, CDRH issued the Final Guidance “Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions” (the “RUO Guidance”) (see our previous posts on the draft guidance here and here).  The draft guidance significantly limited the sale and distribution of “Research Use Only” (RUO) and “Investigational Use Only” (IUO) products.  76 Fed. Reg. 31615 (June 1, 2011).  As we discussed in our previous blog posts on the draft guidance, most of the restrictions set out in the policy were consistent with the current practices of many IVD companies, but in several key areas the agency’s proposals would have substantially curbed the sale of RUO and IUO labeled products.

Most significantly, in the draft guidance, FDA departed from the well-established practice of determining intended use based on the manufacturer’s conduct, by also considering how a customer uses a product.  FDA stated in the draft guidance that a manufacturer must stop sales of its RUO or IUO product to a customer once the manufacturer knows – “or has reason to know” – that the customer is using the product for a diagnostic use, even if the manufacturer makes no diagnostic claims or statements.  In Hyman, Phelps & McNamara, P.C.’s comments to the draft guidance, we recommended that this concept be removed from the final guidance (see here and here). 

In the draft guidance, FDA defended this approach by stating that cessation of sales was necessary since use of RUO and IUO products in clinical diagnostic tests “presented[ed] a serious potential risk to the public health.”  Draft Guidance at 11.  However, in a recent FDASIA Hearing before the House Energy and Commerce Committee’s Subcommittee on Health (the “Committee) Dr. Jeffery Shuren, Director of CDRH, did not defend this position.  USHR21 Energy and Commerce Committee, November 15, 2013, available here (last visited Nov. 17, 2013).  When asked by Congressman Michael C. Burgess, M.D., Vice Chair of the Committee, whether Dr. Shuren had any evidence of patient harm caused by use of RUO products, Dr. Shuren said that while he was aware of companies putting RUO products on the market and then promoting them for clinical diagnosis, there was no evidence of harm.  Id.

With no known harm to patients or the public health, and a questionable legal basis for equating known use with intended use, the agency clearly could not justify the change in policy proposed in the draft guidance.  (Indeed, one could make a stronger argument that heavy restrictions on RUO sales actually would have an adverse impact on public health).   Dr. Shuren testified that the agency received the message loud and clear that the “reason to know” standard needed to come out of the final guidance.  Issued just 8 days later, the final guidance did just that.

With this background, FDA significantly modified the guidance before issuing the final version.  Some of the key differences between the draft guidance the RUO Guidance are:

• The final guidance introduces the concept of a certification program as evidence that the manufacturer is ensuring its customer are using the RUO or IUO product in accordance with its intended purpose.  RUO Guidance at 11.  The concept of a certification program for RUO products was originally introduced in the early 1990s in a draft Compliance Policy Guide (CPG) document issued by FDA.  After many companies implemented such programs, FDA never finalized the CPG and had seemed to move away from this concept in recent years, including having excluded such a concept from the draft RUO guidance.  However, unlike the earlier drafts of the CPG, the final RUO Guidance gives little weight to certification programs.
• The final guidance does not include the concept of registration and listing for foreign manufacturers, which was previously included in the draft guidance.  Draft Guidance at 7.
• The final guidance does not expressly address whether RUO and IUO products are subject to the Quality System Regulation like the draft guidance did.  Id. at 9.  This could suggest that for mislabeled RUO and IUO products FDA will subject them to the requirements in the QSR. 
• As discussed above, the final guidance does not include the concept that if the manufacturer of an RUO or IUO “knows, or has reason to know” that the product is being used in clinical diagnosis that it must take action and cease selling to that customer.  Id. at 10-11.  On the other hand, it does say “a manufacturer who produces only products labeled RUO whose sales force makes routine calls to clinical laboratories that do not perform research or clinical studies may be viewed as demonstrating its intent that its products be used for clinical purposes.”  RUO Guidance at 9.  This sentence may cause some RUO manufacturers to think more carefully about their customer lists.
• The Guidance puts some limits on the support RUO manufacturers can provide laboratory customers.  The guidance says, “provision of certain types of specialized technical support (e.g., assistance in performing clinical validation) to clinical laboratories” would be in conflict with the product’s RUO or IUO labeling.  Id.  However, FDA clarifies in Footnote 10 that specialized technical support “is not referring . . . to generic maintenance support or software updates for an RUO or IUO IVD product.”

One other interesting change between the draft and final RUO Guidance relates to use of RUO and IUO products in pre-market submissions to FDA.  The draft guidance affirmatively stated that a manufacturer could obtain 510(k) clearance for an IVD which used RUO or IUO products as part of the submission.  Draft Guidance at 12.  This language is not in the final guidance.  The significance of that omission is unclear.  However, the timing of the release of this Guidance interestingly coincided with two other important IVD developments.  On November 22, FDA issued a highly publicized Warning Letter to 23andMe, a provider of direct-to-consumer FDA sequencing service.  Also, FDA recently cleared Illumina MiSeqDx Platform for high-throughput DNA sequencing.  One could infer that FDA is signaling through the RUO Guidance and its clearance and enforcement actions that it wants manufacturers of laboratory instrumentation (e.g., sequencers) and reagents, and providers of at least certain laboratory developed tests to obtain FDA pre-market clearance. 

Even with some of the key changes in the RUO Guidance compared to the draft guidance, it is clear that FDA expects commercially available RUO and IUO products to be an area of focus for FDA enforcement.  The RUO Guidance emphasizes that FDA will review the totality of the circumstances when it comes to assessing whether an IVD is properly labeled as RUO or IUO.  This approach is consistent with FDA’s traditional approach to enforcement, although we do not yet know which restrictions may trip up some RUO manufacturers.

• FDA views the RUO and IUO labeling statements as warnings and anything done by a manufacturer or distributor to undercut those warnings may be viewed as problematic. RUO Guidance at 8.
• FDA will be looking at the “objective intent” of the manufacturer to determine if the product is a true RUO or IUO.  Id. at 9. 
• The manufacturer should ensure that all presentations and talks are appropriately labeled with the RUO or IUO statement as applicable.  Id.
• The manufacturer should carefully review its current sales practices, including who the company solicits RUO and IUO business from.  Id. If an RUO/IUO manufacturer is soliciting business primarily from diagnostic laboratories, FDA would consider this off-label promotion.
• The manufacturer should ensure that it is not providing specialized support (e.g., beyond generic maintenance support or software updates) or LDT validation support for its RUO and IUO products.  Id.

During Dr. Shuren’s testimony before the Committee, he stated that the concern with RUO products being used in clinical diagnosis is that a determination (we should say an FDA determination) has not been made as to whether the RUO product is accurate or not.  Dr. Shuren went on to testify that in the instances where the agency has taken action against a manufacturer of an RUO product for clinical diagnostics promotion, it has been where there is an alternative test that has been cleared or approved for the same intended use.  This is helpful insight for industry into FDA’s thinking as it relates to the marketing of RUO and IUO products.

With the issuance of the RUO Guidance FDA’s policy is now articulated.  Of course, the RUO Guidance is just that: guidance.  It is not legally binding.  Still, we expect the agency to be keeping a close eye on RUO and IUO manufacturers and their marketing and sales practices.  The agency says it will take enforcement action based on the totality of the circumstances.  What that actually means remains to be seen.  As with most things with FDA, we will simply have to wait and see.  Thus, 21 years after FDA first proposed an RUO/IUO guidance document; the process has come to an end.  A final RUO/IUO guidance is now in effect.  Yet the original 1992 CPG proposal did spawn an issue that lives on: FDA has the power to regulate LDTs.  And that is an issue that will not be definitively resolved any time soon.