By Allyson B. Mullen –

In 2012, CDRH initiated an action plan to strengthen the medical device surveillance system (we previously reported on this plan here).  As part of this initiative, a multi-stakeholder Planning Board was created with the purpose of “envisioning an MDS with the capability of accurately and systematically evaluating potential medical device safety signals in near real-time, measuring the benefit-risk profile of devices throughout their life cycle, and developing meaningful information to support pre-and postmarket regulatory decision making.” 

The Engelberg Center for Health Care Reform at the Brookings Institution (Brookings) brought this board together in 2014.  On February 24, 2015, Brookings issues a report documenting the board’s recommendations for a National Medical Device Postmarket Surveillance System (MDS) (the report can be found here).  The report sets forth the board’s recommendations on the “mission, principles, and key functions for the MDS.”

The MDS is intended to aggregate significant amounts of both pre-and postmarket information into a single system, including information from claims and administrative systems, patient-generated data, EHRs, and device-specific and clinical care registries.  This information is intended to be useful to a wide variety of stakeholders, including CDRH.  According to the report, the information in the new MDS should have a focus on patients and clinicians.  The information should also be collected with minimal burdens being placed on those required to submit and collect the information.  The report indicates that information should be collected once, but for multiple purposes.  While achieving these lofty goals, the MDS should be adaptable to the future and continuously evolving.

While this report is lengthy (75 pages), it contains very few specifics, including, who will be responsible for/required to submit data to the MDS, what specific information will be submitted, where/how the information will be stored, how FDA will use the data to assess marketed devices.  The report recommends that the MDS be developed, implemented and managed by a joint public-private partnership, not solely by CDRH like current systems.  The report lays out the high-level organizational and governing principles for the partnership.  As one of the overriding goals, the report indicates that the public-private partnership should collaborate with those individuals who will be submitting data to the MDS to develop an effective infrastructure and policies.  Specifically, the board believes that the new MDS should promote use of UDIs and common data standards in all data sources, including those that protect patient privacy.

Perhaps most interesting, the report acknowledges that government funding alone may be insufficient to develop such a new and novel system.  The report suggests charging membership fees for those entities participating in the system, including, “manufacturers, nonprofits, CROs, academic institutions, and others who support MDS’s objectives.”  Although it is not addressed in the report, our view is that manufacturers who would be asked to pay a membership fee would be those wishing to access and utilize the data for its own purposes, and manufacturers would not be charged a “membership fee” in order to submit adverse event information.

Finally, the report sets out a timeline for implementation.  In years 1 and 2, the board proposes that FDA perform fact-finding activities and pilot programs to develop and 5-year implementation plan for MDS.  Then in years 3 through 7, the public-private partnership should be created and it should implement the MDS that is developed through the pilot program.  As we noted in our earlier post on this topic, the information provided on the new MDS has left several key questions unanswered, such as how FDA will use the information in the new MDS, how it will affect premarket requirements, and how would it be used in regulating products that are on the market.  Unfortunately, this new report continues to leave these important questions unanswered.

By Kurt R. Karst –      

Amidst concern that the 2013 sequester could make a repeat appearance and reduce both FDA’s budget from Congress and industry-financed user fees to the Agency, Representatives Anna Eshoo (D-CA) and Leonard Lance (R-NJ) have introduced legislation to exempt FDA user fees from the ravages of sequestration.   Sequestration refers to automatic spending cuts to the U.S. federal budget that went into effect as a result of the Budget Control Act of 2011.  The Congressional Budget Office recently opined that sequestration will not be required for 2015; however, that is by no means certain and depends on several factors (see here). 

The FDA Safety Over Sequestration Act of 2015, or FDA SOS Act (H.R. 1078), would amend the Balanced Budget and Emergency Deficit Control Act of 1985 – the law first establishing sequestration procedures – to exempt user fees collected pursuant to FDC Act Sections 736 (Prescription Drug User Fee Act), 738 (Medical Device User Fee and Modernization Act), 740 (Animal Drug User Fee Act), 741 (Animal Generic Drug User Fee Act), 744B (Generic Drug User Fee Amendments), and 744H (Biosimilar User Fee Act).  “The FDA’s user fees are 100 percent private sector dollars,” wrote Rep. Eshoo in a press release.  “If the intent of sequestration is to limit public spending, withholding private monies is counterintuitive.  Whether one agrees or disagrees with sequestration, private dollars should not be held hostage by the policy.  It discourages investment in medical innovation and denies patients access to timely and potentially lifesaving therapies.”  The FDA SOS Act is supported by several organizations and companies, including PhRMA, BIO, AdvaMed, the Medical Device Manufacturers Association, the California Healthcare Institute, the Leukemia Lymphoma Society, Gilead, Genentech, Patient Services Inc., and the National Health Council.

H.R. 1078 is the second legislative go-around at saving industry user fees from sequestration.  As we previously reported, Reps. Eshoo and Lance introduced a nearly identical bill in July 2013 (H.R. 2725), which was later introduced in the Senate as the FDA User Fee Protection Act (S. 1413).  Neither bill was passed; however, the Consolidated Appropriations Act of 2014 (Pub. L. No. 113-76) permitted FDA in 2014 to use fees that were withheld because of the 2013 sequester.  Enactment of the FDA SOS Act would avoid Congress having to go through that procedure again with respect to FDA. 

By Kurt R. Karst –      

There’s been a lot of activity in the budding biosimilars world this year, and it’s only February.  On the FDA front, the Agency reportedly has 5 Section 351(k) biosimilars applications under review: (1) Sandoz’s version of Amgen’s NEUPOGEN (filgrastim); (2) Celltrion’s version of Johnson & Johnson’s REMICADE (infliximab); (3) Apotex’s version of Amgen’s NEULASTA (pegfilgrastim); (4) Apotex’s version Amgen’s NEUPOGEN; and (5) Hospira’s biosimilar version of Amgen’s EPOGEN (epoetin alfa) (also marketed by Johnson & Johnson as PROCRIT).  Earlier this year, FDA held the first advisory committee meeting for a biosimilar – for Sandoz’s filgrastim (see our previous post here).  A second advisory committee meeting for Celltrion’s infliximab was scheduled for March 17, 2015, but has been postponed “due to information requests pending with the sponsor of the application.”  FDA action on Sandoz’s Section 351(k) application for filgrastim is expected within the coming weeks; however, even if FDA approves the application, it appears that the launch of the product will be delayed.  In a recent court filing, Sandoz agreed that the company “will not launch its biosimilar filgrastim product in the United States until the earlier of April 10, 2015, or a ruling in Sandoz’s favor on Amgen’s Motion.”  And that’s our segue to the litigation front of the biosimilars world, where things remain hot. 

As we previously reported (here and here), last October, Amgen filed a Complaint in the U.S. District Court for the Northern District of California alleging that Sandoz has unlawfully refused to follow certain procedures created by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  In particular, Amgen alleges that Sandoz opted out of the information exchanges at PHS Act § 351 (l)(2)(A)-(l)(5), but that such option does not exist; and that despite Sandoz’s assertions that the company already provided 180-day notice of commercial marketing to Amgen required under PHS Act § 351(l)(8)(A), such notice cannot be provided until at least FDA approval of a Section 351(k) application.  In making these allegations, Amgen asserts three causes of action: (1) unfair competition under Cal. Bus. & Prof. Code § 17200 et seq.; (2) conversion; and (3) infringement of U.S. Patent No. 6,162,427 covering a method of using NEUPOGEN to treat a disease requiring peripheral stem cell transplantation in a patient in need of such treatment.

Earlier this year, Amgen filed a Motion for Judgment on the Pleadings or, in the Alternative, Motion for Partial Summary Judgment.  That triggered Sandoz to file a Cross-Motion for Judgment on the Pleadings and Opposition to Amgen’s Motion for Judgment on the Pleadings (Amgen’s opposition brief and Sandoz’a reply brief are available here and here).  But as the days went by and the date by which FDA is scheduled to act on Sandoz’s Section 351(k) application crept closer (in early March), Amgen finally decided that the company needed to seek emergency relief. 

On February 5th, Amgen filed a Motion for a Preliminary Injunction in a bid to restrain Sandoz from engaging in the commercial manufacture, use, offer to sell, sale within or importation into the U.S. of its biosimilar filgrastim product until the California District Court decides the parties’ Motions for Judgment on the Pleadings (and, if the court resolves those motions in Amgen’s favor, until, the parties have been placed in the position they would be in had Sandoz complied with the BPCIA).  “Sandoz has sandbagged Amgen,” says Amgen in its court filing. “It has refused to provide its BLA and manufacturing information, frustrating Amgen’s ability to determine which of its many patents it can assert against Sandoz.  And Sandoz intends to launch its product immediately upon FDA licensure, rather than waiting the 180 days required by the law. That is why Amgen brings this motion for a preliminary injunction.”  Among other things, Amgen says that “[i]f Sandoz is permitted to launch its product without having provided the information and time to Amgen as the statute provides, Amgen will be irreparably harmed by losing the opportunity afforded it under the BPCIA to exercise its exclusionary patent rights and seek a preliminary injunction before Amgen is injured by the entry of Sandoz’s biosimilar product.”  That irreparable harm will, according to Amgen, come in the form of harm to research and development, harm to new products in their infancy, price erosion for NEUPOGEN (and Amgen’s NEULASTA), and damage to customer relationships and loss of goodwill.

Hogwash!, says Sandoz in it opposition brief filed earlier this week.  Amgen hasn’t established any of the four factors necessary to support a preliminary injunction: (1) whether Amgen will be irreparably harmed in the absence of an injunction; (2) Amgen’s likelihood of success; (3) the balance between the harm to Amgen and the harm to Sandoz; and (4) the public interest.  It’s a chair without any legs – meaning that it’s either held up by magic, or that it must come crashing down to the ground. 

Sandoz argues that Amgen’s Motion for a Preliminary Injunction fails for myriad reasons:

First, Amgen cannot show it is likely to succeed on the merits.  Amgen seeks to convert a “notice” provision for resolving patent disputes into an “exclusivity” provision.  Adopting Amgen’s interpretation would defy Congress’s intent (as expressed in the statute’s plain language) by extending the exclusivity period from 12 years to 12.5 years. . . .

Second, Amgen cannot show irreparable harm for multiple reasons . . . . Amgen claims that it has been harmed because it did not receive Sandoz’s filgrastim application in July 2014, and so it allegedly could not determine what patents it might potentially be able to assert against Sandoz.  But that alleged harm is of Amgen’s own making.  The BPCIA contemplates a maximum of 60 days for a Sponsor to identify any applicable patents after receiving a 42 U.S.C. § 262(k) application.  Amgen cannot deny (and therefore ignores) that Sandoz offered to produce its Application seven months ago in July 2014, and multiple times since then, subject only to reasonable confidentiality protections.  Amgen chose to decline all of those offers. . . .  Amgen’s alleged harms are not only self-inflicted, they run afoul of two other black-letter rules governing preliminary injunctions: neither speculative injuries nor compensable monetary losses qualify as irreparable harm.

Third, the balance of equities heavily favors Sandoz.  Sandoz is poised to launch the first biosimilar filgrastim in the United States, and an injunction would jeopardize the first-to-market advantage in which it has invested years of effort and tens of millions of dollars.  By contrast, denial of the requested injunction would not impose any undue hardship on Amgen. . . .

Fourth, the public interest factor forecloses Amgen’s request.  The BPCIA expressly seeks to balance two key public purposes: innovation and consumer interests.  Amgen has been amply rewarded for its innovation, enjoying 24 years of exclusivity although Congress concluded in the BPCIA that 12 years meets the public’s interest in innovation.

A hearing on the outstanding Motion for Preliminary Injunction and Motions for Judgment on the Pleadings is scheduled for March 13, 2015 at 10:00 AM.

By Kurt R. Karst –      

In a 19-page decision handed down earlier this week by Judge Nancy Torresen of the U.S. District Court for the District of Maine, the court ruled that Maine’s 2013 law, titled “An Act To Facilitate the Personal Importation of Prescription Drugs from International Mail Order Prescription Pharmacies,”  2013 Me. Legis. Serv. Ch. 373 (S.P. 60) (L.D. 171) (West) (the “Maine Pharmacy Act Amendments” or “MPA Amendments”) permitting (as its title suggests) importation of drug products into the U.S. from licensed retail pharmacies located in certain foreign countries (i.e., Canada, Australia, New Zealand, and the United Kingdom), is unconstitutional under the theory of field preemption.  In doing so, Judge Torresen granted a Motion for Judgment on the Pleadings filed by two Maine pharmacists and three Maine trade associations (the Maine Pharmacy Association, Maine Society of Health-System Pharmacists, and Retail Association of Maine), and denied a Motion for Judgment on the Pleadings filed by Maine’s Attorney General (Janet T. Mills) and Commissioner of Administrative & Financial Services (formerly H. Sawin Millett, Jr., and now Richard Rosen). 

The February 23rd decision stems from a September 2013 Complaint filed by the Plaintiffs, as well as then-Plaintiff the Pharmaceutical Research and Manufacturers of America (“PhRMA”), challenging the MPA under several theories (see our previous posts here and here).  PhRMA was tossed out of the lawsuit last May after the district court ruled that the trade organization lacked Article III standing (see our previous post here). 

The State Defendants argue that the MPA Amendments “simply reduce the reach of the MPA,” “that it is within [the State’s] authority as a sovereign to choose not to regulate certain conduct,” and that to hold otherwise “would violate the Tenth Amendment principle that states may not be compelled to administer federal regulatory programs.”  On the other side, the Maine pharmacist and trade association Plaintiffs argue that the FDC Act “creates a comprehensive and ‘closed’ regulatory scheme, which strictly limits the introduction of prescription drugs into interstate commerce,” and that preempts the MPA Amendments under three theories of preemption: (1) field preemption (i.e., when  “[t]he intent to displace state law altogether can be inferred from a framework of regulation ‘so pervasive . . . that Congress left no room for the States to supplement it’ or where there is a ‘federal interest . . . so dominant that the federal system will be assumed to preclude enforcement of state laws on the same subject.’” Arizona v. United States, 132 S. Ct. 2492, 2501 (2012) (quoting Rice v. Santa Fe Elevator Corp., 331 U.S. 218, 230 (1947)); (2) direct conflict preemption (i.e., a form of implied preemption that occurs when there is an inescapable contradiction between state and federal law); and (3) obstacle preemption (i.e., when “the challenged state law ‘stands as an obstacle to the accomplishment and execution of the full purposes and objectives of Congress.’” Arizona, 132 S. Ct. at 2501 (quoting Hines v. Davidowitz, 312 U.S. 52, 67 (1941)).

Focusing on the Plaintiffs’ contention that the MPA Amendments violate the Supremacy Clause, U.S. Const. art. VI, cl. 2, and 42 U.S.C. § 1983, under the theory of field preemption, Judge Torresen first defined the “field” at issue:

The FDCA does not regulate the licensure of pharmacists; it instead leaves that area to individual states.  If the MPA Amendments were truly limited to the regulation of pharmacy licensure, then evidence of “a congressional decision to foreclose any state regulation in the area” would be lacking.

But by its plain language, the MPA Amendments extend beyond the regulation and licensure of pharmacies and pharmacists within Maine.  The MPA Amendments do not, as the State asserts, simply repeal state licensure regulations; the MPA Amendments select five countries whose licensed retail pharmacies “may export” prescription drugs to Maine residents. . . .  [T]he MPA Amendments extend beyond the traditionally local arena of public health and safety and into the traditionally federal spheres of foreign commerce and affairs.  [(Internal citations omitted)]

As such, the properly defined “field” for preemption purposes in the case, said Judge Torresen, is “the importation of foreign pharmaceuticals.”  From there, it was all downhill for the State Defendants, because the relevant question for the court to address was then whether the FDC Act forecloses Maine’s encroachment into the realm of pharmaceutical importation.

Citing the complex new drug approval process Congress created as part of the FDC Act, as well as provisions included as part of the 2003 Medicare Modernization Act concerning the importation of drugs from Canada, Judge Torresen was compelled to conclude that there’s a clear “Congressional intent to tightly control prescription drug importation,” and that the FDC Act “occupies the field of importation of pharmaceuticals from foreign countries” rather than state law.

No matter how they are applied, the MPA Amendments regulate within the field of pharmaceutical importation.  The State has not suggested any limiting construction which would allow a portion of the law to stand, and the parties have not briefed the issue of severability.  It is apparent that removing the portion of the statute that touches on foreign commerce would defeat the purpose of the law. Because they are contrary to clear Congressional intent to occupy the field of pharmaceutical importation, the MPA Amendments violate the Supremacy Clause and are therefore preempted.

It is unclear at this time whether or not an appeal will be made to the U.S. Court of Appeals for the First Circuit.  According to press reports (here), the sponsor of the bill that was enacted as the MPS Amendments, State Senator Troy Jackson, thinks an appeal is in order. 

Moving down the Eastern Seaboard to Capitol Hill, earlier this year Senators John McCain (R-AZ) and Amy Klobuchar (D-MN) introduced S. 122, the Safe and Affordable Drugs from Canada Act of 2015, which would amend the FDC Act to require the Department of Health and Human Services to promulgate regulations within 180 days permitting individuals to import a prescription drug purchased from an approved Canadian pharmacy under certain specified conditions.

By Kurt R. Karst –      

It’s been a long time since we last posted on a Patent Term Extension (“PTE”) controversy  – a little more than a year it seems (see here) – but that doesn’t mean we’re not keeping an eye on decisions coming out of FDA and the Patent and Trademark Office (“PTO”).  We still diligently track issues and cases of interest, whether with respect to so-called “reverse Photocure” issues (see our previous post here, and here for a recent FDA decision in Docket No. FDA-2014-E-0025), first permitted commercial marketing issues (see, e.g., here), or regulatory review period determination issues.  That last topic is the subject of today’s post.

Under 35 U.S.C. § 156, certain patents covering products regulated by FDA are eligible for a PTE if patent life was lost during a period when the product was undergoing regulatory review.  The “regulatory review period” is composed of a “testing phase” and a “review phase” (also referred to as an “approval phase”).  For drugs approved under the FDC Act, the “testing phase” begins on the effective date of an IND, and ends on the date an NDA (or BLA) is initially submitted to FDA.  The “review phase” is the period between the initial submission of the NDA (or BLA) and approval.  (The term of a patent may be extended for a period of time that is the sum of one-half of the time in the “testing phase,” plus all the time in the “review phase,” and minus any of the “regulatory review period” that occurs prior to the patent grant or where the sponsor did not act with due diligence.)   FDA’s regulations implementing the statute’s PTE provisions state that “[t]he approval phase begins on the date a marketing application under section 351 of the Public Health Service Act or section 505(b) of the Act is initially submitted to FDA . . . and ends on the date the application is approved” (21 C.F.R. § 60.22(a)(2) (emphasis added)), and that “[f]or purposes of determining the regulatory review period for any product, a marketing application . . . is initially submitted on the date it contains sufficient information to allow FDA to commence review of the application” (21 C.F.R. § 60.22(f) (emphasis added)). 

Over the years, questions have cropped up as to when the review phase begins – that is, when is an application considered initially submitted to FDA – in the context of “rolling” or modular submissions.  Insofar as NDA and BLA “fast track” submission are concerned, FDA has determined that receipt of the last module (or application component) makes the application complete, and thus “initially submitted” for PTE purposes.  This has been the topic of several letter decisions, including in Docket No. FDA-2005-E-0310 concerning KEPIVANCE, in Docket No. FDA-2009-E-0237 concerning DEXILANT, and in Docket No. FDA-2007-E-0278 concerning ZOLINZA.  FDA has come to a similar conclusion involving modular PMA (medical device) submissions (see our previous post here).

Perhaps most famously, both FDA and the PTO were sued over their determinations as to what it means for an animal drug application to be initially submitted to FDA.  In Wyeth Holdings Corp. v. Sebelius, Wyeth contended that a 16-day approval phase for a New Animal Drug Application reviewed under FDA’s Phased Data Review Policy and Administrative NADA process was unreasonable, and that the NADA was initially submitted to FDA when the company submitted the first technical section to its application.   In May 2010, the U.S. Court of Appeals for the Federal Circuit affirmed a March 2009 decision from the U.S. District Court for the District of Columbia granting summary judgment to FDA and the PTO (see our previous posts here and here). 

The case of U.S. Patent No. 6,087,380 (“the ‘380 patent) covering Boehringer Ingelheim Pharmaceuticals, Inc.’s (“BIPI’s”) PRADAXA (dabigatran etexilate) Capsules offers up a new twist on the question: “When is an NDA subject to a rolling review initially submitted to FDA?” 

PRADAXA is the subject of NDA 022512, which FDA approved on October 19, 2010, and for which the final “piece” of the submission arrived at FDA on December 15, 2009.  Almost two months after receiving that final NDA component, however, FDA, on February 12, 2010, issued a Refuse-to-File (“RTF”) letter refusing to file the December 15, 2009 submission for clinical reasons.  Nevertheless, FDA continued to review other parts of the application (e.g., Chemistry, Manufacturing, and Controls).  On April 19, 2010, BIPI resubmitted the NDA and the application was later accepted for review and approved.

Fast-forward to May 2012, after BIPI timely requested a PTE for the ‘380 patent, and FDA’s publication of a notice in the Federal Register that the regulatory review period for PRADAXA is 2,633 days, of which 2,449 days occurred during the testing phase and only 184 days occurred during the approval phase.  The FDA notice states, in particular, with respect to the approval phase that:

The date the application was initially submitted with respect to the human drug product under section 505(b) of the FD&C Act: April 19, 2010.  The applicant claims December 15, 2009, as the date the new drug application (NDA) for PRADAXA (NDA 22–512) was initially submitted.  However, FDA records indicate that NDA 22–512, received December 15, 2009, was incomplete.  FDA refused to file this application and notified the applicant of this fact by letter dated February 12, 2010.  The completed NDA was then submitted on April 19, 2010, which is considered to be the NDA initially submitted date.

BIPI timely requested reconsideration of the regulatory review period determination asking that the initial submission date of NDA 022512 be corrected from April 19, 2010 to December 15, 2009.  According to BIPI, “[a]ll of the required elements of the NDA were submitted to FDA as of December 15, 2009,” and “[a]lthough FDA issued a [RTF] letter to BIPI on February 12, 2010, the agency continued to review the NDA.” 

FDA did not agree, however, that the continued review of NDA 022512 was material, and did not agree that the NDA could be considered initially submitted on December 15, 2009 as a result of the subsequent RTF determination.  In a Letter Decision that cites legislative history, a regulatory review period determination of a 1994 vintage, and (of course) the Federal Circuit’s Wyeth decision, FDA says:

For determining the regulatory review period, the application filing review provides a measure of whether an application contains all the information necessary for Agency review to begin.  If an application can be filed, then it is considered sufficiently complete.  If the application is sufficiently complete, then the end date of the testing phase of the regulatory review period and the beginning of the approval phase can be declared and the initially submitted date is the NDA receipt date.  However, if the application cannot be filed (RTF), then it is not sufficiently complete and the approval phase has not yet begun. . . .

FDA permitted BI to submit its application on a “rolling review” basis, so that segments of the application that would be reviewed by different disciplines within FDA could be submitted when they were ready.  It was clearly understood, however, including by BI, that the application itself would not be considered to be submitted to FDA until such time as the last segment of the application was submitted for FDA review so that the complete application was before the agency. . . .

Thus, the fact that BI had submitted, and FDA had begun to review, modules of the application —and continued to review them after the application was refused for filing based on the promise that the application would be resubmitted— has no effect on the date that the application is considered to have been “initially submitted” for purposes of 35 U.S.C. 156(g).  While, as the Wyeth court found, this statutory provision may be considered ambiguous, the FDA interpretation is clear, and it is binding here.  Accordingly, no application is considered to be “initially submitted” if it has not been found to be sufficiently complete to meet the filing requirement for an application.

Interestingly, FDA says that BIPI had the chance to secure a date earlier than April 19, 2010 as the date of initial submission, but lost it when the company decided not to raise the rarely used “filing over protest procedures” at 21 C.F.R. § 314.101(a)(3).  According to FDA:

While BI had an opportunity, under FDA regulations, to contest FDA’s position, assert that its application was in fact sufficiently complete to be reviewed, and ask FDA to file the application over protest, BI did not do so.  FDA accordingly refunded 75% of the user fee for this application and awaited submission of additional and corrected data that would permit the application to be considered suffrciently complete such that FDA review of the entire application could commence.  On April 19, 2010, BI submitted the necessary data to complete its application, together with a user fee required for the resubmission of a new drug application.

FDA’s RTF regulation provides that if the Agency issues a RTF decision, “the applicant may request in writing within 30 days of the date of the agency’s notification an informal conference with the agency about whether the agency should file the application,” and that “[i]f, following the informal conference, the applicant requests that FDA file the application (with or without amendments to correct the deficiencies), the agency will file the application over protest . . . , notify the applicant in writing, and review it as filed.”  In that case, “the date of filing will be the date 60 days after the date the applicant requested the informal conference.” 

Although it’s unlikely that FDA’s decision means that we’ll see a rush of “filing over protest” actions by NDA and BLA sponsors, it’s certainly a tool to keep in mind if the PTE calculus warrants such an action.

By Ricardo Carvajal –

The question (in the title of this post) occurred to us in preparing for FDLI Food Week 2015, taking place as this is written.  When FDA issued its Pathway to Global Product Safety and Quality in 2011, the agency set forth this ambitious objective:  “Over the next decade, FDA will transform itself from a domestic agency operating in a globalized world to a truly global agency fully prepared for a regulatory environment in which product safety and quality know no borders.”  As we noted in a prior posting, a fundamental obstacle to this objective could well be a lack of additional funding, without which FDA contends that it “will be unable to… adequately assure the safety of imported food by building and implementing the import safety system mandated by FSMA.”

Funding limitations aside, there are challenges inherent in the rapid expansion of FDA’s footprint in the past four years to encompass constituencies over which the agency historically has exercised more limited oversight.  As noted by FDA, “[f]or the first time, importers will have explicit responsibility to verify that their foreign supplies have adequate preventive controls in place and that the food they ship to the U.S. is otherwise safe.”  Also for the first time, the agency will actively regulate farms (through the produce safety rule) and restaurants (through the menu labeling rule).  Fully implementing each of these initiatives will require the agency to devise appropriate enforcement strategies.  That is a critical piece of the puzzle without which the regulated industries will have difficulty assessing how best to target their compliance efforts – but one that might not be in place for some time to come.

By Jamie K. Wolszon –

Amidst the winter storms that have struck the East Coast this January and February, there has been, and will continue to be, a flurry of developments related to FDA efforts to actively regulate Laboratory-Developed Tests (LDTs).  Those developments include a White Paper authored by prominent constitutional and Administrative Procedure Act (APA) litigators on behalf of the American Clinical Laboratory Association (ACLA) challenging FDA’s statutory authority to regulate LDTs as medical devices; a January 8-9 public workshop hosted by FDA to obtain feedback on the Draft Guidances; the submission of hundreds of written comments to FDA; and an upcoming February 20 workshop hosted by FDA to discuss a white paper on next generation sequencing (NGS).  We provide a round up of those and other events below.

January 5: Deadline for LDT Comments to House Energy & Commerce Committee.

We previously reported that the House Energy & Commerce Committee, which has jurisdiction over FDA, has issued a “white paper” announcing that as part of its efforts to prepare a draft discussion legislative package in early 2015 related to the overall 21st Century Cures Initiative, that it seeks input on specific questions related to the FDA LDT proposed Framework.  The Committee sought comments by January 5.  Two major medical organizations – the American Medical Association and the Association of Molecular Pathology (AMP) – submitted comments to the Committee expressing significant concerns with the Draft Guidances.  We previously reported that on January 27, the Committee released the nearly 400 page draft discussion legislative package.  The discussion draft did not address LDTs. 

January 7: ACLA Unveils Tribe and Clement LDT White Paper.

On January 7, a day before FDA’s public workshop to discuss the draft guidances, ACLA unveiled a white paper authored by two distinguished constitutional and APA litigators Laurence H. Tribe and Paul D. Clement.  The timing of this can hardly be coincidental.  We previously reported that ACLA had retained Mr. Tribe and Mr. Clement to help the organization oppose the framework, a move perceived as a shot across FDA’s bow.  In the white paper, Mr. Tribe and Mr. Clement argued that: (1) FDA lacks the statutory authority to regulate LDTs, which are services, as medical devices; (2) FDA is violating the APA by proceeding through guidance instead of notice-and-comment rulemaking; (3) FDA’s Draft Guidances would stifle innovation and interfere with the practice of medicine.  Alan Mertz, President of ACLA, mentioned the white paper in his statement on January 8 at the FDA public workshop on the Draft Guidances.

January 8-9: FDA Public Workshop on Draft Guidances. 

At the January 8-9 FDA Public Workshop on Draft Guidances there was significant opposition expressed to the draft guidances. Even some of the groups that supported the draft guidances still expressed reservations, such as need for clarification on how risk categorization would be done and how the Quality System Regulation (QSRs) would be applied.  Some of the points expressed at the workshop include:

• Many speakers stated that the Draft Guidances would have unintended consequences, hurt patient access and innovation and interfere with practice of medicine
• Public health, state, and small reference laboratories stated that if FDA finalizes the Draft Guidances in their current format, some of those laboratories would cease to exist, and many tests will no longer be offered.
• ARUP Laboratories representative Edward Ashwood gave a blistering presentation using words such as “outrage, ”naïve,” “misguided,” “overreach, and “reprehensible”  to describe the draft guidances.  
• Kelly Slone of National Venture Capital Association (NVCA) said draft guidances would discourage venture capital in LDTs 
• Ms. Slone stated that LDTs already receive significantly less venture capital due to regulatory uncertainty and reimbursement issues.
• Many speakers stated that FDA has not provided evidence of harm caused by LDTs
• Curtis Hanson of the Mayo Clinic said his laboratory has performed over 21 million tests without so much as one sentinel adverse event.  In his introduction, Jeffrey Shuren, CDRH Director, talked about anecdotal reports of harm but provided no new evidence of the risks associated with LDTs.  FDA has apparently still not provided the evidence of harm that was requested back in September.
• Many speakers stated that FDA does not have resources to review influx of submissions it would receive if agency finalized the framework
• Curtis Hanson of the Mayo Clinic noted that his laboratory alone offers over 1,600 LDTs
• Some speakers stated that FDA clearances or approvals do not necessarily mean better tests
• Examples include 510(k)-cleared Lyme Disease tests (high false negatives) (two Lyme groups spoke, one of which noted that the LDT had better performance than the 510(k)-cleared version) and the recently approved Vemurafinib-Responsive BRAF V600K Melanoma companion diagnostic (reportedly misses mutations found by the LDT)
• Many speakers stated that FDA should go through notice-and-comment rulemaking and not use guidance
• Several speakers stated that FDA should allow use of research use only RUO products as components of LDTs
• Rare Disorder Exemption
• Several commenters said the 4,000 test limitation is too narrow and should be expanded to either 4,000 cases or 200,000 cases as in the Orphan Drug Act.  It is very likely that FDA will not adopt a 4,000 test cap, but it is entirely unclear what cap they will select instead.
• Definition of health care system
• With regard to LDTs for Unmet Needs and Traditional LDTs, one of the factors to consider whether the exemption applies is whether it is for use by a health care facility laboratory (such as one located in a hospital or clinic) for a patient that is being diagnosed and/or treated at that same health care facility or within the facility’s healthcare system.  There was considerable discussion during the meeting of how to interpret that definition of healthcare system and the impact of various definitions on patient access.
• Modifications
• Many speakers stated that it is common practice within laboratories to modify FDA-cleared or approved tests to serve their patients, so the provision within the guidance requiring additional submissions to FDA for certain modifications will pose difficulties.  Some laboratories explained how the results would be worse if modifications were not allowed; an example came from a public health lab talking about tissue samples for sexually transmitted infections.  
• Multiple speakers identified a need for a clear explanation of risk-categorization before final guidance
• Several speakers called for clarity on application of QSRs prior to final guidance, specifically a cross-walk comparing CLIA and QSR requirements

A number of organizations stressed that FDA should reissue the Framework in draft to allow for further comments, since the agency will need to make multiple changes. 

For those interested in soaking up additional details about the public workshop.  FDA has provided a Transcript of the public workshop.

The FDA’s proposal did generate some support as well, with proponents arguing that FDA regulation was necessary to ensure test safety and that it does not matter to patients whether a test is an LDT or a kit.

February 2: FDA Deadline for Written Comments.

On February 2 (coincidentally Groundhog’s Day) written comments to FDA related to the Draft Guidances and the January 8-9 public workshop were due to the agency.  As of February 17 at midnight, regulations.gov listed 235 comments submitted to the Framework draft guidance: Of those, 144 comments were posted, including comments from ACLA, the American Association for Clinical Chemistry, state public health laboratories and departments of health (including the Wadsworth center in New York, the only state that requires LDTs to be approved), the Biotechnology Industry Organization, which represents biotech companies, organizations representing patients, insurers, NVCA, individual laboratories, medical centers and hospitals (such as the American Hospital Association), representatives of kit manufacturers (such as the Advanced Medical Technology Association), accreditation bodies (such as the College of American Pathologists), the Coalition for 21st Century Medicine, AMP, and HPM. 

February 20: FDA Public Workshop to Discuss NGS.

Multiple LDTs utilize NGS technology.  A number of speakers during the FDA public workshop expressed concern that FDA regulation of LDTs would hamper introduction of NGS.  FDA issued a discussion paper on potential approaches to regulate NGS, and has announced that it will be holding a February 20 public workshop to obtain feedback on the NGS discussion paper.  How the agency will approach tests that use this technology is a key aspect of any regulatory framework to regulate LDTs.  This is also important as a bellwether for how FDA will handle new technologies that do not fit the traditional model.

May 4: Discussion of Draft Guidances at ACLA Annual Meeting.

Although hopefully we will see the end of winter weather well before this time, on May 4, Mr. Tribe, Mr. Clement, Viet Dinh, Partner at the same law firm as Mr. Clement and Professor of Law at Georgetown University Law Center, and Elizabeth Mansfield, Director of Personalized Medicine at FDA’s Center for Devices and Radiological Health, will discuss the Draft Guidances at ACLA’s annual meeting.  It should be entertaining.

By Frank J. Sasinowski & Andrew J. Hull* –

Even though we often blog on orphan drug developments (see two of our most recent posts here and here), many may be unaware of the origin of the term “orphan.”  Today, we may think that the term “orphan” was created by the Orphan Drug Act of 1983 (“ODA”).  The ODA incentivizes the development of drugs to treat rare or “orphan” diseases.  The ODA, however, provides absolutely no explanation for its use of the word “orphan.”  Instead, it is necessary to go back further into history to understand the term’s origin.

The first written use of “orphan” in the context of therapeutic drugs was in a 1968 editorial comment entitled “Therapeutic Orphans” and published in The Journal of Pediatrics by Harry Shirkey, M.D. (see a reprinted copy of the article by the American Academy of Pediatrics here).  Dr. Shirkey, a pediatrician in the Children’s Hospital in Birmingham, Alabama, was writing about the inequality that he saw in the development of drugs to treat children.  Since few drug developers found it worth the cost of studying the efficacy and safety of drugs in children, Dr. Shirkey argued that, “[b]y an odd and unfortunate twist of fate, infants and children [were] becoming ‘therapeutic or pharmaceutical orphans.’”  As a result of these lack of studies, most drugs contained disclaimers stating that the drugs should not be used in children, but, nevertheless, often children were prescribed these drugs with little to no knowledge of possible adverse reactions or any estimate of benefit.  Dr. Shirkey decried this abandonment, or “orphaning,” of the pediatric population, stating that “[i]t seems unfair that the use of some drugs will be denied based on relatively infrequent use and small sales potential.”

After the publishing of Dr. Shirkey’s editorial comment, others began to apply “orphan” to other types of diseases that were similarly abandoned or orphaned.  For example, many began to use the term to describe diseases that primarily affected those in less-developed parts of the world.

In the 1970s, the FDA began to investigate what it saw as a gap in the development of therapies for certain patient populations.  In June 1979, an interagency taskforce issued a report to the Secretary of Health, Education, and Welfare (predecessor to Health and Human Services) addressing the lack of development of “significant drugs of limited commercial value.”  The taskforce found that many drugs essential for diagnosis or treatment of “rare diseases” were not available mainly because “research, development and production are deemed too expensive relative to expected economic return.” 

The taskforce on significant drugs of limited commercial value was chaired by FDA’s Associate Director for New Drug Evaluation, Marion J. Finkel, M.D.  After publication of the report, Dr. Finkel was named as FDA’s first Director of Orphan Products Development in 1982, and, in this position, she played an instrumental role in FDA’s implementation of the ODA.  Additionally, it was Dr. Finkel who championed use of the term “orphan” exclusively for therapies for rare diseases.  Accordingly, even though she did not coin the term, we have Dr. Finkel to thank for our use today of the term “orphan.”  Additionally, we can also be grateful that her doing so moved us away from the less euphonious term: “significant drugs of limited commercial value” (imagine a law entitled the “Significant Drugs of Limited Commercial Value Act of 1983”!).

The development of the term “orphan” in the context of developing cures for rare diseases and conditions has had a long and interesting evolution.  At each step of the process, however, one thing has remained the same: those involved in creating and developing this term have been motivated by their concern for patients with rare diseases.  Together, these individuals have worked to create a better system that advances the development of drugs for patients suffering from ORPHAN diseases.

* Admitted only in Virginia.  Work supervised by the Firm while D.C. application pending.

By Karla L. Palmer –

Following our blogpost describing the four human drug compounding draft guidance documents and draft Memorandum of Understanding (MOU) that FDA released last Friday, FDA formally published the documents in the Federal Register on February 19th.   Interested persons should note the docket numbers in the notices so they can post comments (due 90 days from today for the four draft guidances and 120 days after today’s publication for the draft standard MOU).  FDA also finally withdrew the draft MOU that it issued in January 1999 (to our knowledge no state had signed it).  That 1999 draft, which received over 6,000 public comments, defined “inordinate amounts” as when the number of compounded drugs dispensed or distributed interstate annually is equal to or greater than 20 percent of all drugs dispensed by the facility, and contained other controversial provisions.  Recall that under FDCA Section 503A, states have a choice of either signing an MOU with FDA, or human drug compounders within that state acting pursuant to Section 503A must limit out of state shipments to 5 percent of all prescription orders dispensed or distributed by the pharmacy or physician.  

Concerning the new draft “standard” MOU, FDA consulted with NABP (as statutorily required), and already received 31 public comments on the new MOU after it promulgated draft guidance for Section 503A compounders in December 2013.  FDA reiterated today that it does not intend to enforce the 5 percent limit on interstate distribution of compounded human drug products until after FDA has finalized the MOU and made it available to the states for their consideration and signature.

After considering any comments on the new draft standard MOU, FDA will determine how long it will allow states to “consider whether to sign the [final] MOU before FDA begins to enforce the 5 percent limit in those states that have not signed an MOU.” Nonetheless, the Agency proposes a 180-day period after the final standard MOU is made available for signature.  After that, FDA will enforce the 5 percent limit in States that have not signed the MOU.

The Notice sets forth key provisions of the new draft standard MOU, and compares it to the 1999 version where appropriate.  Some highlights:

Investigation of Complaints — States must investigate complaints related to compounded products distributed out of state, including adverse drug experiences and product quality issues, and take action as necessary to identify public health risks.  States must notify FDA in 72 hours of a “potential public health risk or immediate safety concern,” such as a report of a “serious adverse drug experience” or “serious product quality issue,” and maintain records for three years.  Definitions of these terms, included in the MOU appendix, are taken from relevant sections of FDA’s regulations for manufactured drugs (21 C.F.R.  §§ 310.305 and 314.81).

Unlike the 1999 version, the new MOU is clear that states are only required to investigate complaints for compounds distributed from their state into another state, and are not required to investigate potential FDCA violations.  The new draft MOU also is clear that the types of complaints states should investigate include any adverse drug experience (not just serious adverse drug experiences) and product quality issues that, if left uncorrected, “could lead to potential public health risks or safety concerns.”  FDA states that even “nonserious” adverse drug experiences and product quality issues may be indicative of significant problems at the facility.

Distribution of Inordinate Amounts: “The 30 % Limit” — The new draft MOU requires states to review compounding records during pharmacy inspections to determine whether the physician, pharmacist or pharmacy’s interstate distributions are “inordinate,” and to notify FDA of that determination.  Distributions are “inordinate” if “the number of units of compounded human drug products distributed interstate during any calendar month is equal to or greater than 30 percent of the number of units of compounded and non-compounded drug products distributed or dispensed both intrastate and interstate by such pharmacist, pharmacy, or physician during that calendar month.”  FDA does “not intend to consider” prescriptions dispensed to a patient or patient’s agent where that patient carries the drug across state lines after dispensing at the compounding facility.  Note that the 1999 MOU draft considered a 20 percent total annual interstate limit, and interstate quantities of individual drugs (including different dosage strengths of same active ingredient) could not exceed five percent even if the total distributed interstate was less than the 20 percent.  Unlike the new version, the 1999 draft also excluded from its “inordinate” percentage determination “local” interstate distribution to patients within 50 miles of the compounding pharmacy, and interstate distribution in response to a public health emergency or catastrophic event.  Importantly FDA discussed that a “distribution” now occurs when a compounded drug leaves the facility where it was made, regardless of whether the drug is also deemed to be “dispensed.”

Although comments on the 1999 draft and the 2013 Section 503A draft guidance objected to defining “inordinate” or placing percentage restrictions on interstate distributions, FDA proposed the following reasons for its 30 percent limit definition of “inordinate”:

• Congress imposed strict restrictions on the distribution of drug products compounded under Section 503A to protect the public health and integrity of the drug approval process.
• Congress did not intend for compounders to become manufacturers operating a substantial portion of its business interstate. 
• Congress recognized that Section 503A compounders are primarily subject to state oversight.  States face challenges if substantial amounts of the compounded products are distributed out of state. 
• The 5 percent limit in Section 503A is a “baseline measure,” leaving FDA (with assistance from NABP) to address whether a limit higher than 5 percent would be appropriate, provided states agree to appropriately investigate compounded products distributed outside of the state. 
• FDA currently believes the 30 percent limit balances access with the need to protect the public health and the drug approval system.
• FDA also considered that patients can now obtain compounded human drug products from outsourcing facilities, which may mitigate access concerns.
• Addressing contiguous states, FDA believes that the 30 percent limit on inordinate amounts is “high enough that special calculations to address interstate distribution between contiguous States or over short distances are not needed.”  FDA added that the draft also excludes from the 30 percent limit those patients that carry the dispensed product across state lines.
• The draft does not exclude from the calculation of “inordinate amounts” interstate distributions in response to a public health emergency or catastrophic event. FDA believes the 30 percent limit affords “adequate opportunity for interstate distributions.”  FDA notes that outsourcing facilities “may be able to compound drugs in an emergency and drugs on FDA’s drug shortage list, further mitigating access concerns.”

A few final points.  It is plain from the notice that FDA does not expect to negotiate with states different provisions of the MOU.  It believes that a standard MOU will prevent a patchwork enforcement approach.  FDA also rejected comments seeking to exempt non sterile drug products and home infusion pharmacies from interstate limits.  FDA stated Congress did not exempt particular drugs or entities from the 5 percent limit; FDA believes that the 5 percent limit and the MOU limit on inordinate amounts “are important to distinguish pharmacy compounding from conventional manufacturing in the guise of compounding, and to protect consumers and the integrity of the drug approval process.”  FDA’s efforts to regulate compounding have proven controversial over the years, and many FDA proposals have triggered significant criticisms. The draft MOU is unlikely to be an exception to this pattern.

By Kurt R. Karst –       

Without even knowing what we’re talking about, it’s probably safe to say that any company would immediately answer “Yes!” to the question posed in the title to this post.  But that’s exactly what FDA is asking some ANDA applicants to do to facilitate the creation of a single, shared Risk Evaluation and Mitigation Strategy (“REMS”). 

FDC Act § 505-1 provides FDA with the authority to require a proposed REMS from an NDA sponsor if the Agency determines that such a strategy “is necessary to ensure that the benefits of the drug outweigh the risks of the drug.”  A REMS may include various elements, such as a Medication Guide, patient package insert, and/or communication plan.  In addition, under FDC Act § 505-1(f), FDA may require that a REMS “include such elements as are necessary to assure safe use of the drug, because of its inherent toxicity or potential harmfulness.”  The Elements To Assure Safe Use (“ETASU”) of such a drug include, among other things, certain restricted distribution, procurement, and dispensing systems. 

ANDAs for generic versions of RLDs with an approved REMS must have the same Medication Guide (if there is one) and the same or a comparable ETASU REMS.  Specifically, FDC Act § 505-1(i)(1)(B) states:

A drug that is the subject of an [ANDA] and the listed drug shall use a single, shared system under [FDC Act § 505-1(f)].  The Secretary may waive the requirement under the preceding sentence for a drug that is the subject of an [ANDA], and permit the applicant to use a different, comparable aspect of the elements to assure safe use, if the Secretary determines that—

(i) the burden of creating a single, shared system outweighs the benefit of a single, system, taking into consideration the impact on health care providers, patients, the applicant for the [ANDA], and the holder of the [RLD]; or

(ii) an aspect of the [ETASU] for the applicable listed drug is claimed by a patent that has not expired or is a method or process that, as a trade secret, is entitled to protection, and the applicant for the [ANDA] certifies that it has sought a license for use of an aspect of the [ETASU] for the applicable listed drug and that it was unable to obtain a license.

ETASU REMS have been a difficult pill for some ANDA applicants to swallow.  Such REMS have resulted in litigation over the ability of some generic drug companies to obtain product sample to conduct bioequivalence testing (see our previous post here).  And once those studies are conducted, the baseline requirement for a single, shared REMS has further complicated things (see our previous post here).

FDA has apparently taken on the role of facilitator in negotiations for a single shared system.  But before FDA will facilitate such negotiations, the Agency is asking ANDA applicants for permission to disclose certain information to the NDA RLD sponsor, and to hold FDA harmless for any repercussions such disclosure might cause.  That’s a lot to ask of an ANDA sponsor. 

A copy of the disclosure letter FDA has been asking ANDA applicants to sign is provided below.  Although it asks for permission to share only the existence of an ANDA number, it’s the following sentence about which folks might have the greatest concern: “FDA may not be able to withhold information and documents containing such information under 5 U.S.C. 552(b)(4) or FDA’s regulations.”  Of course, almost any document an ANDA applicant sends to FDA contains the application number.  So it seems that the potential exists for almost any ANDA correspondence to become public.

FDA Letter to ANDA Applicants     

Instructions to ANDA applicant: Prepare the following disclosure authorization letter on applicants letterhead. Prominently identify the submission containing the disclosure letter with the following wording in bold capital letters at the top of the first page of the submission:

ANDA ###### REMS CORRESPONDENCE

[ANDA NUMBER]
John R. Peters, M.D.
Acting Director, Office of Bioequivalence
Office of Generic Drugs
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

        RE:  FDA Sharing of Non-Public Information concerning [ANDA NUMBER] with [NDA SPONSOR] and ANDA applicants]

Dear Dr. Peters:

On behalf of [ANDA APPLICANT], the applicant of the above-referenced regulated product(s), I authorize the United States Food and Drug Administration (FDA) and its staff to share the information described below with [NDA SPONSOR] and any abbreviated new drug application (ANDA) applicants for [DRUG] for the purpose of facilitating the development of a single shared system REMS for [DRUG].  I understand that the information may contain confidential commercial information within the meaning of 18 U.S.C. § 1905 and 5 U.S.C. § 552(b)(4) that is exempt from public disclosure.  I agree to hold FDA harmless for any injury caused by FDA’s sharing the information with thc parties referenced above.

Information to be shared: The existence of [ANDA NUMBER].  I understand that, after disclosure, FDA may not be able to withhold information and documents containing such information under 5 U.S.C. 552(b)(4) or FDA’s regulations.

Authorization is given to FDA and its staff to disclose the above-mentioned information without deleting confidential commercial information.  As indicated by my signature, I am authorized to provide this consent on behalf of [ANDA APPLICANT] and my full name, title, address, telephone number, and facsimile number is set out below for verification.

Sincerely,
(Signature)
(Printed name)
(Title)
(Telephone & Facsimile Numbers)

By Kurt R. Karst –      

Last year we posted on the possible effect of Inter Partes Review (“IPR”) on the forfeiture of 180-day exclusivity eligibility under the so-called failure-to-market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) added by the 2003 Medicare Modernization Act.  With no decision yet from the U.S. Court of Appeals for the Federal Circuit on the matter (or from FDA), however, the interplay between IPR and 180-day exclusivity remains an open question.  But in an upcoming law review Note slated for publication this October in the Michigan Law Review, Brian Apel, a law student at Michigan, argues that under the current wording of the statute, IPR – as well as Post-Grant Review (“PGR”) – “will likely prove ineffective for later-filing generics at triggering the failure to market provision.”

By way of background, the Leahy-Smith America Invents Act (“AIA”) created two procedures to replace inter partes reexamination of a patent: IPR and PGR.  Both procedures allow for administrative patent challenge proceedings at the U.S. Patent and Trademark Office (“PTO”) before the Patent Trial and Appeal Board that serve as a parallel or alternative to district court litigation to adjudicate patentability of issued patents.  Whereas PGR is available immediately after patent issuance, IPR becomes available only after the period for PGR has passed. 

The FDC Act’s failure-to-market provisions are one of the six forfeiture provisions added to the statute by the MMA.  Together, the six forfeiture provisions, which borrow heavily from the pre-MMA law, were designed to make the 180-day market exclusivity incentive work more effectively within the Hatch-Waxman framework. 

Under the failure-to-market forfeiture provisions, there must be two events (i.e., “bookends”) to calculate a “later of” event.  The first bookend date (under FDC Act § 505(j)(5)(D)(i)(I)(aa)) is the earlier of the date that is 75 days after ANDA approval or 30 months after ANDA submission.  The other bookend date (under FDC Act § 505(j)(5)(D)(i)(I)(bb)) is “the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a [Paragraph IV] certification qualifying the first applicant for the 180-day exclusivity period,” one of three events occurs – two of which are relevant here:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

The (AA) and (BB) court decision events under item (bb) can be triggered in patent infringement litigation by “the first applicant or any other applicant (which other applicant has received tentative approval).”

Another of the six forfeiture provisions – the so-called “collusive agreement” forfeiture provision at FDC Act § 505(j)(5)(D)(i)(V) – addresses the effect on 180-day exclusivity when a first applicant enters into a settlement agreement with the NDA holder and/or owner of the patents listed on the listed drug.  It provides that eligibility for 180-day exclusivity is forfeited if:

The first applicant enters into an agreement with another applicant under this subsection for the drug, the holder of the application for the listed drug, or an owner of the patent that is the subject of the [Paragraph IV certification], the Federal Trade Commission or the Attorney General files a complaint, and there is a final decision of the Federal Trade Commission or the court with regard to the complaint from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the agreement has violated the antitrust laws (as defined in section 12 of Title 15, except that the term includes section 45 of Title 15 to the extent that that section applies to unfair methods of competition).

In his Note, Mr. Apel focuses primarily on the failure-to-market and collusive agreement forfeiture provisions, and argues that as a result of court and FDA decisions, both provisions have failed to live up to their potential as Congress originally intended.

In steps the AIA and the new IPR and PGR post-grant proceedings.  Can these proceedings be used to trigger a forfeiture of exclusivity eligibility?  Mr. Apel confronts the question head-on, looking at the statutory text, legislative history, judicial precedent, and practical application.  Ultimately, he concludes that if the question came to a court or to FDA, neither would be likely to construe the failure-to-market provisions to include IPRs or PGRs.  Why?  Because the failure-to-market provisions use the term “declaratory judgment action” and IPRs and PGRs are simply not a “declaratory judgment action.”  However, writes Mr. Apel, there is decent support for going the other way.  The strong estoppel effect of IPRs and PGRs gives them the effect of a district court action, and Congress intended to trigger the failure-to-market provisions upon resolution of the patent dispute.  Nevertheless, Mr. Apel predicts that those arguments cannot overcome the unambiguous text of the statute, especially in a highly regulated field, and that the statute would need to be amended:

Neither a court nor FDA is likely to adopt a broad enough construction of the failure to market statute to accommodate the new USPTO proceedings.  Thus, amending the failure to market provision to include administrative proceedings would remove the uncertainty in the field and help refocus the Hatch-Waxman Act towards its originally-intended balance.

The Federal Circuit has just started issuing decisions in the first IPRs to ever be filed, but none have concerned pharmaceutical patents that could otherwise be the subject of Hatch-Waxman litigation.  FDA’s recently-published proposed rules (see our previous post here) don’t shed any new light on the matter either, though 180-day exclusivity forfeiture is not the focus of FDA’s proposal.  In any case, practitioners will have to continue to wait as cases move through the system and issues are posed to FDA.

By Karla L. Palmer –  

As it did on the eve of another holiday weekend last July (see our previous posts here and here), on this past Friday (the 13^th), FDA released the long-awaited draft Memorandum of Understanding (MOU) addressing interstate shipment of compounded preparations under FDCA Section 503A and four other compounding draft guidance documents.  See FDA’s Press Release here, which also includes a handy link to all five drafts.

The four draft guidances address: (1) considerations for entities who wish to register under Section 503B; (2) drug repackaging by pharmacies, outsourcing facilities, federal facilities and hospital systems; (3) mixing, diluting, or repackaging biological products; and, (4) Section 503B adverse event reporting.  Neither the guidances nor the draft MOU have been published in the Federal Register (but publication is likely imminent).  Once published, interested parties have 90 days to comment on the draft guidance documents and, according to the FDA press release, 120 days to comment on the draft MOU.  Recall, however, that FDA’s Section 503A final guidance dated July 2, 2014 stated: “FDA does not intend to enforce the 5% limit on interstate distribution until after FDA has finalized an MOU and made it available to the states for their consideration and signature.  The Federal Register notice that will announce the availability of the draft MOU will specify the time period during which the MOU will be made available to the states to sign.  After this time period expires, FDA intends to begin enforcing the 5% limit in states that have not signed the MOU.”  July 2, 2014 Section 503A Guidance at 6 (emphasis added).  Thus, it is still unclear when FDA will begin Section 503A’s 5% limit on interstate shipments of compounded preparations in those states that do not sign an MOU.

A brief summary of each draft guidance document and MOU is below:

(1)        “For Entities Considering Whether to Register As Outsourcing Facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act”  

This guidance lists eleven “conditions” for qualifying for the exemptions under Section 503B (i.e., FDCA’s new drug, adequate directions for use, and track and trace requirements).  It also clarifies that a facility can only qualify for the exemptions if all of the facility’s compounded drugs are compounded in accordance with Section 503B.  If a compounder does not intend to compound all drugs at the facility in accordance with Section 503B – including cGMP – then it should not register as an outsourcing facility.  The guidance similarly clarifies the law for those facilities that compound both office use and patient-specific preparations:  Even patient-specific preparations must meet cGMP requirements (no exceptions).

An outsourcing facility should also consider the following:

• To meet the “outsourcing facility” definition, it must be engaged in sterile drug compounding.  
• The definition of compounding under Section 503B(d)(1) does not include repackaging (but repackaging is addressed in another draft guidance, below).
• For purposes of 503B, a drug including a sterile drug does not include a biological product under Public Health Service Act (PHS) Section 351 or an animal drug under FDCA Section 512 (but biological products are also addressed in another draft guidance).
• A facility should not register as an outsourcing facility if the only activities conducted at the facility are repackaging, compounding non-sterile or animal drugs, or mixing, diluting, or repackaging biological products subject to licensure under Section 351 of the PHS Act, because none of the products would qualify for the exemptions under Section 503B.  It seems such activities could only be conducted by pharmacies pursuant to patient specific prescriptions.  .  
• Facilities that only compound non-sterile drugs are not eligible for the exemptions from the federal laws’ requirements that any new drug be distributed only after FDA approval, adequate directions for use, and track and track requirements; nevertheless, if the facility compounds sterile and non-sterile drugs, then those non-sterile products are eligible for exemptions in Sections 505, 502(f)(1), and 582 if the drugs are otherwise compounded in accordance with Section 503B.  

(2)        “Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities”

This guidance defines “repackaging” compounders: The act of “taking a finished drug product from the container in which it was distributed by the original manufacturer and placing it into a different container without further manipulation of the drug.”  Repackaging also includes placing contents of multiple finished drug containers (e.g., vials) into one container, “as long as the container does not include other ingredients.”  FDA notes that, “if the drug is manipulated in any other way, including if the drug is reconstituted, diluted, mixed, or combined with another ingredient,” then it is not considered repackaging.  FDA’s draft guidance describes the conditions under which FDA does not intend to take action for violations of the law when pharmacies, federal facilities or outsourcing facilities repackage certain drug products.  In other words, in these situations, FDA will exercise what it has traditionally called its “enforcement discretion” not to sanction or punish these facilities for engaging in what FDA describes as illegal acts.

The draft guidance explicitly does not address repackaging of animal drugs, repackaging by entities that are not state-licensed pharmacies, drugs administered at the point of care, and dispensing solid dosage forms directly to individual patients in amounts less than in the original container.   FDA notes that drug packaging is a part of the drug review and approval process; repackaging may affect the sterility of the product and other characteristics that could adversely affect the safety and efficacy of the drug.

The guidance addresses FDCA Section 506F, dealing with hospitals within health systems repackaging drugs in the event of drug shortages to extend supply when certain statutory conditions are met (page 4).  Section 506F will terminate when the guidance becomes final.   

FDA describes conditions under which it will exercise enforcement discretion in the context of drug repackaging.  Some of the highlights:

• The repackaged drug must be an approved drug unless that drug is on FDA’s shortage list.
• The drug must be repackaged by a pharmacy, federal facility or outsourcing facility, and under the direct supervision of a pharmacist.
• If repackaged by a pharmacy or federal facility (but not an outsourcing facility), the drug must be pursuant to a prescription or order for an individually identified patient.  It may be repackaged in advance of a prescription or order (but not dispensed) if that amount does not exceed the amount repackaged in the previous, consecutive  14-day period, and based on a history of receipt of prescriptions or orders over a consecutive 14-day period for such repackaged drug products.
• Except for single-dose vials, the drug must be repackaged in a way that does not conflict with approved labeling.
• The repackaged product must be assigned a beyond use date (BUD) (which is the date included on the label within which the repackaged drug must be used)  as detailed in the draft guidance, considering the drug’s stated in-use time, USP guidelines, or cGMP depending on whether the drug product is an approved drug product, the type of facility and drug product (pages 6-8).  
• The drug may not be sold or transferred by an entity other than the entity that repackaged the drug.  In other words, repackaged drugs may not be distributed by wholesalers or middlemen.
• Repackaged drugs may only be distributed in states in which the facility meets all applicable state requirements.
• Drugs repackaged by outsourcing facilities must include required information on their labels and meet other requirements of 503B (pages 8-9).
• FDA will not take action against repackagers of approved or unapproved drug products on FDA’s shortage list, provided the facility meets all conditions of the draft guidance, during the period of shortage and for 30 days after the period ends.  When this draft guidance and guidance concerning repackaging biological products becomes final, Section 506F (hospital repackaging in times of shortages) will no longer apply. 

(3)        “Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application”

This draft guidance describes the conditions under which FDA intends to exercise enforcement discretion when pharmacies, federal facilities or outsourcing facilities mix, dilute or repackage specific biological products without an approved BLA, or when such facilities or physicians prepare prescription sets or allergenic extracts (used to treat allergies) without an approved BLA.

FDA notes that under the FDCA, such products otherwise may not legally be marketed, and the Act’s compounding provisions do not address biological products subject to licensure under Section 351 of the PHS Act.

The guidance addresses the following:  

• Except as provided for single-dose vials (as described in the guidance), repackaging must not conflict with approved labeling.
• For a single dose vial that is mixed/diluted/repackaged into multiple units, it must be done in a way that does not conflict with labeling other than statements designating product as a single-use vial/dose (page 9; 9 n.15). 
• Specifically concerning Avastin, which is packaged in a single-dose vials: “This condition could be satisfied even if Avastin is repackaged into multiple single dose syringes,” despite the fact that label of the approved product states, “single-use vial…discard unused portion.”  The repackager must adhere to other approved labeling (e.g., regarding the appropriate diluent and storage conditions) (page 9).
• Products must adhere to very stringent BUDs specified in the draft guidance due to susceptibility of biological products to contaminants (page 9). 
• If mixed, diluted or repackaged by a pharmacy or federal facility, the BUD cannot be longer than the in-use time indicated on the package or four hours (whichever is shorter); or up to 24 hours if microbial challenge studies are performed (as described in the guidance appendix);
• If mixed or diluted by an outsourcing facility, then the BUD cannot be longer than the in-use time or four hours (whichever is shorter); or up to 24 hours if microbial challenge studies are performed, as described in the guidance appendix.
• If repackaged by an outsourcing facility, then, as an alternative to the above, the BUD may not exceed the shorter of five days or the expiration of the biological product being repackaged, if the outsourcing facility performs container-closure compatibility studies consistent with 21 C.F.R. § 211.94.   
• Products may not be sold or transferred by an entity other than the facility that mixes the product, and must meet state requirements.  Sale or transfer does not include administration in a health care setting.
• Outsourcing facilities must comply with FDA reporting and labeling provisions, but the NDC number for the original licensed biologic product should not be placed on the repackaged  product (page 11, 12).
• Secondary packaging (i.e., the bag, box, or other package in which the products are distributed) must include active and inactive ingredients; directions for use, including dosage and administration and information to facilitate adverse event reporting.
• Must be accompanied by a copy of the prescribing information that accompanied the original FDA-licensed biological product (page 12).
• The outsourcing facility must reports serious adverse events to FDA.
• Concerning prescription sets and allergenic extracts, FDA does not intend to take action for violations of section 351 of the PHS Act or FDCA section 502(f)(1), if the pharmacist, federal facility or outsourcing facility meets conditions for extracts/BLAs in the guidance.  Conditions are set forth at pages 13-15. 

(4)         “Adverse Event Reporting For Outsourcing Facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act” 

Under Section 503B, outsourcing facilities are required to submit adverse event reports to FDA. Failure to report is a prohibited act.  The draft guidance describes a “serious adverse drug experience” and “unexpected adverse drug experience” under 21 C.F.R. § 310.305.  It reminds registrants they must report all serious, unexpected adverse events “associated with” their compounded drugs.  It also “strongly recommends” reporting of all “serious adverse drug experiences” (assuming this means reporting whether or not such event is “unexpected”  (page 4). 

The guidance sets forth considerations for event reporting, which should include an investigation of the following four data elements and submission of an “Alert Report’ as soon as possible but not later than 15 calendar days after receiving information about the event:

1. An identifiable patient
2. An identifiable reporter
3. A suspected drug product
4. A serious adverse event

The guidance describes the four data elements in detail (pages 5-7) and tells how to report the events to FDA (pages 7-8).  FDA is currently modifying its processes to specifically identify and accept electronic reports from outsourcing facilities.  Until the electronic system is available, outsourcing facilities should provide reports of adverse events to FDA in hard copy (page 8).  Reports should be maintained by the facility for ten years. 

(5)         Draft Memorandum of Understanding Between a State and FDA Addressing Interstate Distribution of Compounded Human Drug Products under Section 503A 

Released with no accompanying guidance or explanation (which we hope is forthcoming), the draft MOU describes a state’s responsibilities for investigating and responding to complaints related to compounded human drug products distributed outside the state.  The MOU sets forth clear notification requirements for complaints. 

The draft also defines interstate distribution of “inordinate amounts” of compounded human drug products:  “The number of units of compounded human drug products distributed interstate during any calendar month is equal to or greater than 30% of the number of units of compounded and non-compounded drug products distributed or dispensed both intrastate or interstate during that month.”  FDA does not intend to include prescriptions dispensed to a patient/patient’s agent; if the patient/patient’s agent carries the drug across state lines after dispensing. (MOU  III(b)(4)).  Recall that the 1998 version of the draft MOU, which states never signed, used a 20% ratio.  The MOUN provides that states will review compounding records during inspections to determine compliance with the 30% ratio.  The MOU explicitly does not prohibit FDA from taking action against a non-compliant pharmacy, although the primary responsibility for investigations will lie with the state.    

Notwithstanding the interminable length of this blogpost, it is not a complete analysis of the draft guidance documents.  We will continue to update as more information becomes available.     

By Kurt R. Karst –

Earlier this month in a post concerning the Orange Book we mentioned our love of data and discussed how solid figures can reveal some interesting conclusions.  After all, it’s rather difficult – and dangerous – to come to a conclusion without having as many facts and as much data as possible.  Or, as Sir Arthur Conan Doyle wrote in The Adventure of the Copper Beeches, one of the Sherlock Holmes series of stories: “‘Data! Data! Data!’ he cried impatiently.  ‘I can’t make bricks without clay.’”  Indeed!  And the clay we have to play with today to make some bricks are the latest data from FDA’s Office of Orphan Products Development (“OOPD”) on orphan drug designations and approvals.

Although FDA’s agency-wide performance management system, known as FDA-TRACK, provides some information on orphan drug designations and approvals, that system is not up-to-date.  So we have to get our data from other sources – primarily (though not exclusively) from FDA’s Orphan Drug Designations and Approvals database.  As we’ve done in some previous years, we culled information from that database, which OOPD populates with data on a rather frequent basis.   The database is also constantly being refined to better reflect what orphan drug designations have been granted, what orphan drugs have been approved, and what the relevant periods of orphan drug exclusivity apply to.   We understand that the database will be revamped soon (perhaps later this year) to make it a more useful and user-friendly resource. 

The three metrics we’ve historically followed are: (1) the number of orphan drug designation requests received by OOPD; (2) the number of orphan drug designation requests granted by OOPD; and (3) the number of orphan drugs approved.  In 2014, records were shattered for all three metrics, with an astounding 467 designation requests (a nearly 35% increase over 2013), an astonishing 293 orphan drug designations granted (a nearly 13% increase over 2013), and a whopping 49 orphan drug approvals (a 53% increase over 2013).  Wow!  That’s an amazing output for FDA’s orphan drug program (and, in particular, for OOPD).

Below are three tables – one for each metric – showing the year-by-year numbers since 1983.

When we add up all of the numbers since 1983, FDA has approved 511 orphan drugs, granted 3,280 orphan drug designations, and received 4,738 orphan drug designation requests.  Of the 511 approvals, some drugs have been approved for more than a single rare disease, and sometimes a single orphan drug designation has been the platform for multiple orphan drug approvals (and multiple periods of 7-year exclusivity).

So what does it all mean?  Well, clearly orphan drugs are trending up – way up!  And there’s no indication of a slowdown any time soon.  (In fact, we understand that OOPD is already on pace to break the 2014 record for the number of orphan drug designation requests received by the Office.)  The data also show that the Orphan Drug Act has been an overwhelming success (for both patients and the drug and biotechnology industries).  Of course, a successful program breeds copycats.  We’ve seen that with the creation of orphan drug programs in other countries modeled after the Orphan Drug Act.  It’s also happening on out own backyard, however.  Consider, for example, the Generating Antibiotic Incentives Now Act (“GAIN Act”) (FDC Act § 505E), and the Dormant Therapies Act provisions included in the draft 21st Century Cures Act (see our previous post here).  The roots for both of those items can almost certainly be traced back to the Orphan Drug Act. 

By James E. Valentine* & Anne Marie Murphy –

The National Institutes of Health (“NIH”) just extended the comment period for its Notice of Proposed Rulemaking on clinical trial registration and results submission (“NPRM”) until March 23, 2015.  As we previously reported, the NPRM proposes to expand and clarify many of FDAAA’s requirements for submitting registration and summary results information for specified clinical trials of drugs, biologics, and devices and for pediatric postmarket surveillances of a device to ClinicalTrials.gov. 

This month-long extension will provide current and future “responsible parties” of “applicable clinical trials,” as well as other stakeholders, additional time to weigh in on NIH’s proposed changes (e.g., requiring results for trials of products that are not approved), as well as areas where the Agency has requested specific feedback (e.g., whether to require lay and/or technical results summaries).  For a synopsis of the changes proposed in the NPRM, see our previous posts here and here.  Comments can be submitted to docket number NIH-2011-0003 at Regulations.gov.

*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.

By Kurt R. Karst –

For those in the generic drug industry who attended the Generic Pharmaceutical Association’s (“GPhA’s”) annual meeting in Miami, Florida earlier this week, the message from Office of Generic Drugs (“OGD”) Director Dr. Kathleen “Cook” Uhl in her Generic Drug User Fee Amendments (“GDUFA”) progress report was clear: We have a lot of work to do, but progress is being made.  Of course – and to borrow the tagline from one of the industry’s giants (Mylan) – “seeing is believing.”

We’re now well into the second quarter of Fiscal Year 2015, which corresponds to GDUFA year 3 cohort applications.  For that cohort, FDA agreed to review and act on 60% percent of original ANDAs within 15 months from the date of submission.  (Those goals are ratcheted up in Fiscal Year 2016 [year 4 cohort] and Fiscal Year 2017 [year 5 cohort] where FDA agreed to review and act on 75% of original ANDAs within 15 months, and 90% of original ANDAs within 10 months, respectively.)  GDUFA includes other performance goals for Fiscal Year 2015, including with respect to Prior Approval Supplements (“PASs”) and Controlled Correspondence.

Although we’re still far away from the first 15-month GDUFA goal dates for original ANDA submissions (i.e., January 2016), it’s clear that OGD has been working hard to put in place a system to ensure that goals will be met.  (And by meeting goals, we mean approvals, not complete response actions.)  For example, OGD has surpassed GDUFA hiring goals (as shown in the table below from Dr. Uhl’s presentation), enhanced the Office’s information technology systems to realize various efficiancies, made significant changes to the Office’s structure, aligned other FDA components necessary to a successful (and prompt) ANDA review system, and published numerous guidance documents and manuals of policies and procedures (see, for example, our previous posts here, here, and here). 

OGD’s efforts have thus far have resulted in some pretty impressive progress for cohort year 3 submissions and for other goal-related Fiscal Year 2015 submissions.  Consider, for example, the information in the slides below from Dr. Uhl’s presentation.

Two items in particular in these slides stand out to us: (1) the average time for FDA’s initial review and acceptance of an ANDA is now less than 30 days (specifically, 27 days); and (2) a large number of ANDAs are still the subject of Refuse-to-Receive (“RTR”) actions.  That last bit is something that folks should be able to correct with little effort.  Most of the RTR letters from FDA cite inadequate or improper payment of GDUFA user fees, inadequate stability data, dissolution data or bioequivalence data (even failed studies), and incomplete or untimely responses to minor deficiency communications. 

While OGD certainly seems to be progressing well with GDUFA year 3 cohort submissions, the Office’s ability to “move the freight” on pre-GDUFA submissions, as well as year 1 cohort (Fiscal Year 2013) and year 2 cohort (Fiscal Year 2014) submissions (the so-called “GDUFA donut hole”), is still a work in progress and an ongoing issue of concern for the generic drug industry. 

To give readers a sense of the amount of pre-GDUFA and donut hole freight OGD has to move, below is a series of slides from Dr. Uhl’s presentation showing some pretty large numbers:

The following two slides from Dr. Uhl’s presentation show that OGD is making some progress, but there’s clearly still a lot of work to be done.

So, how will OGD hold itself accountable and assuage generic drug industry concerns (and concerns that are likely growing with FDA’s recent announcement – here at page 65 – that the median ANDA approval time was a whopping 42 months in Fiscal Year 2014, and is predicted to remain at that level for the next two fiscal years)?  The answer seems to be: assign Target Action Dates (“TADs”) to all pre-year 3 cohort applications. 

TADs are a relatively recent OGD creation that the Office has reportedly been assigning to some ANDAs for several months now as a sort of dry run for meeting GDUFA performance goals.  A TAD is not a GDUFA action date, but rather an internal OGD deadline for action on an application.  At the GPhA annual meeting, Dr. Uhl announced that OGD will extend the TAD initiative to all pre-year 3 cohort applications – and notify  ANDA applicants of the assigned TAD.  OGD will roll out the enhanced TAD initiative over the next several months, as discussed in the slides below.