By Kurt R. Karst –      

The once nascent biosimilars industry took off in 2015 with the first biosimilar approval (ZARXIO [filgrastim-sndz], which FDA licensed on March 6, 2015 under BLA 125553), myriad court decisions interpreting the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) (see our previous post here), and the release of highly anticipated FDA guidance on Nonproprietary Naming of Biological Products (see our previous post here), as well as other guidance (here, here, here, and here).  Congress also entered the mix with the introduction of the Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015 (H.R. 1576) (see our previous post here) and with recent directives included as part of the 2016 Consolidated Appropriations Act (in explanatory statements here, here, and here), including with respect to FDA’s efforts to address biosimilarity and interchangeability:

The agreement acknowledges some progress in FDA’s effort to address issues with products that are biosimilar to and interchangeable with FDA-licensed biological drug products. In August of this year, the FDA issued draft guidance and a proposed rule regarding naming of these products. However, the agreement remains concerned that FDA needs to provide the public with a greater opportunity to review and comment on all regulatory standards for the approval and oversight of biosimilar drugs. Therefore, FDA is directed to provide the Committees with an estimated timeline by which the agency will finalize all pending draft biosimilars guidance documents and regulations. The Committees expect to receive this report no later than 60 days after enactment.

And then there’s the recent gear up for reauthorization of the Biosimilar User Fee Act (“BsUFA”). FDA held a public meeting on that topic on December 18, 2015.

The year that was (2015) also saw an uptick in the number of citizen petitions submitted and responded to by FDA concerning a variety of biosimilar and BPCIA implementation topics. There was the first response to a biosimilars 505(q) Citizen Petition (Docket No. FDA-2014-P-1771) that addresses the sharing of aBLA (or Section 351(k) application) information (see our previous post here). There was also a second Citizen Petition submitted to FDA as a 505(q) petition (Docket No. FDA-2015-P-2000) challenging FDA policies on biosimilar labeling (see our previous post here).  As we close out 2015, and as we move into what will likely be a very active 2016 insofar as biosimilars are concerned, AbbVie Inc. (“AbbVie”) has given us fodder for one last post in 2015 about biosimiliars (unless, of course, there’s a surprise decision or announcement later this week).

On December 16, 2015, AbbVie submitted a Citizen Petition (Docket No. FDA-2015-P-4935) to FDA concerning Agency determinations of interchangeability – the step after mere biosimilarity is demonstrated – between a brand-name reference product and its biosimilar (or “biogeneric”) counterpart. AbbVie wants three things from FDA. First, FDA should “ensure that applicants seeking interchangeability determinations meet the ‘Safety Standards for Determining Interchangeability’ set forth in PHSA section 351(k)(4) with respect to each condition of use for which the reference product is licensed, regardless of whether the applicant intends to label its product for every such condition of use” (emphasis added). Second, AbbVie requests that FDA “clarify that the statutory standards for establishing interchangeability differ in both kind and scope from the standard for establishing biosimilarity.” Third, FDA should convene a Part 15 hearing to obtain public input on interchangeability, says AbbVie, and then “issue guidance or regulations that address this important public health issue.”

AbbVie’s petition comes on the heels of Amgen Inc.’s (“Amgen”) announcement the of the submission of an aBLA to FDA for a biosimilar version of AbbVie’s blockbuster biological product HUMIRA (adalimumab). According to press reports, Amgen’s aBLA for its product, dubbed ABP 501, includes data and information based on studies in patients with rheumatoid arthritis and plaque psoriasis – just two of the many indications for which HUMIRA is licensed – as well as “[d]ata to support the switching of patients from Humira to ABP 501.” “Switching” is the key word in that quote, as it seems to imply efforts to demonstrate interchangeability between HUMIRA and Amgen’s ABP 501. After all, the BPCIA amended the PHS Act to provide the following at PHS Act § 351(k)(4) concerning interchangeable biological products:

(4) SAFETY STANDARDS FOR DETERMINING INTERCHANGEABILITY.—Upon review of an application submitted under this subsection or any supplement to such application, the Secretary shall determine the biological product to be interchangeable with the reference product if the Secretary determines that the information submitted in the application (or a supplement to such application) is sufficient to show that—

(A) the biological product—

(i) is biosimilar to the reference product; and

(ii) can be expected to produce the same clinical result as the reference product in any given patient; and

(B) for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

According to AbbVie, the public health, the text and structure of the BPCIA, and the legislative history of the BPCIA all clearly support – and, in fact, mandate – that before FDA issue a determination of interchangeability with a reference product, the Agency must determine that “the two products [are] interchangeable for every condition of use for which the reference product is licensed” (emphasis in original), and notwithstanding that a biosimilar/interchangeable biological product may not be licensed for all reference product uses (i.e., is “skinny labeled”) because of patent or non-patent exclusivities.

Pointing to state laws enacted over the past few years governing the substitution of biosimilar biological products, AbbVie says that those laws do not differentiate interchangeable biosimilars according to approved use, thereby raising the possibility that a product will be substituted for the reference product for a use for which interchangeability has not been assessed and that could jeopardize patient health:

State laws governing pharmacy substitution of biological products generally direct the pharmacist to dispense a biological product that FDA has found interchangeable with the reference product. Neither federal nor state law requires the pharmacist to determine whether the product to be substituted is labeled for (let alone determined to be interchangeable for) the prescribed use in question. The assumption of these state laws is that an interchangeable biological product is functionally the same as a generic drug—it is therapeutically equivalent for all uses.

FDA therefore needs to ensure that biological products listed as substitutable are in fact interchangeable for all indications and conditions of use for which the reference product is labeled and thus might be prescribed. Any other approach risks the possibility that a physician will prescribe the branded product and the pharmacist will dispense a biological product that is not interchangeable for the patient’s condition.

Turning the the text of the statute (and later, to its legislative history), AbbVie focuses on four words at PHS Act § 351(k)(4) (reprinted above) to make its case: “in any given patient.”

Section 351(k)(4)(A) permits an interchangeability determination only if the biological product in question is biosimilar and (separately) “can be expected to produce the same clinical result as the reference product in any given patient.” As the Supreme Court has explained, “the word ‘any’ has an expansive meaning, that is, ‘one or some indiscriminately of whatever kind.’” Further, “given” means “known; stated; [or] specified.” When paired together, the words “any given” take on an extraordinarily broad, idiomatic meaning akin to “every” or “all” (e.g., “on any given Sunday” or “at any given time”). Thus, the plain meaning of “any given patient” in section 351(k)(4)(A) is all known, stated, or specified patients. Further, because it is juxtaposed with “the reference product,” the phrase “any given patient” must be understood to mean all patients for whom the reference product is known, stated, or specified. Under the plain terms of section 351(k)(4)(A), therefore, a biological product can be deemed interchangeable only if it can be expected to produce the same clinical result as the reference product in any patient for whom the reference product is specified—meaning any patient covered by any approved reference product condition of use. [(Emphasis in original.)]

AbbVie points to other statutory language – at PHS § § 351(k)(2)(A), (k)(4)(B), and (k)(6) – and to events in 2006-2007, including precursor legislation and FDA statements, to buttress the company’s argument. “This history compels the conclusion that Congress rejected the option for applicants to make selective interchangeability showings,” says AbbVie.

AbbVie’s position raises the possibility that reference product changes after licensure of a interchangeable product, such as the addition of a new reference product indication, could make interchangeability determinations listed in the Purple Book fluid: there one day and gone the next day. But AbbVie takes a page out of the Orange Book to address that situation:

AbbVie believes that a previously issued interchangeability determination should not be disturbed absent significant scientific questions regarding the continuing validity of the determination following a product change. We believe that the Orange Book preface points to a path forward for handling these situations that will respect the law, adequately protect the public health, and minimize disruption to established products and markets. The Orange Book suggests that therapeutic equivalence ratings for generic drugs may be changed, but only “as a result of new information raising a significant question as to bioequivalence.” Applying a similar approach in the BPCIA context, a previously issued interchangeability determination for a biological product would not be altered unless a manufacturing change or a new condition of use raises significant scientific questions (that were not answered satisfactorily) about the continuing validity of the determination. This, AbbVie believes, should be a rare occurrence.

AbbVie makes several other points throughout the 21-page Citizen Petition that make it worth a read and that may garner public comment. Although AbbVie includes in its petition a 505(q) certification – which, if operative, would trigger an FDA response within 150 days – the company notes that it is unlikely to be classified by FDA as such because, to the best of the company’s knowledge, “no applicant has yet submitted to FDA a BLA seeking licensure as an interchangeable biological product.” However, as noted above, that may not be the case given Amgen’s aBLA for ABP 501.

By James E. Valentine & David B. Clissold – 

In an annual update presented at the FDA/CMS Summit on December 14, 2015, Dr. John Jenkins, Director, Office of New Drugs, the Center for Drug Evaluation and Research (CDER or the Center), provided metrics and insights into the Center’s drug reviews and approvals for 2015, including PDUFA goals, IND activity, new molecular entity (NME) submissions and approvals, and utilization of expedited programs. These bloggers will discuss the topics we found most noteworthy. Several of Dr. Jenkins’ slides are presented below and the full presentation can be found here.

First Cycle Review Rates are at Historic Highs

The first action approval rate for CDER’s NME NDAs and BLAs is currently sitting at 95% with 25 applications pending of those received in Fiscal Year (FY) 2015. This comes after a sharp increase since FY 2010, when first action approvals were at 56%.

When further broken down, Priority Review NME applications in 2015 were approved at a rate of 93% in the first cycle, and have been consistently above 80% since FY 2011. Meanwhile Standard Review NME applications in 2015 are at 100% after hovering between 58% and 85% since FY 2011. However, the median time to approval has increased slightly, likely because under “the Program” (previously discussed here), a filing review takes place over the first two months after an NDA/BLA is submitted, and that time is “off the clock” with respect to the PDUFA timelines.

Why are first cycle approvals so high? Dr. Jenkins made clear in his presentation that “CDER has not changed its interpretation of the statutory standard for approval” and that the Center is “not a ‘rubber stamp.’” Since the standard has not changed, then we must ask: what has? This is likely a multifactorial answer.

First, let’s consider “the Program,” which is designed to improve planning before application submission, increase the number of complete applications at the time of submission, enhance communication and transparency between the applicant and review team during review, and allow for additional review time when amendments are made. One important component of “the Program” is the pre-NDA/BLA Meeting (Pre-Submission Meeting). The purpose of this meeting is to discuss the format and content of the anticipated application, including labeling, presentation of data, dataset structure, and acceptability of data for submission. As a result, CDER likely informed some number of applicants that their information would not be accepted for review because of certain deficiencies (e.g., the need for another pivotal trial, or unresolved manufacturing issues). Thus, applications that may have been submitted in the past were not, and those that were submitted were better positioned to meet FDA’s expectations at the time of the filing decision. Deficiencies that had previously been relegated to Complete Response letters (or Refusal to File letters) could be addressed before submission or, the FDA agreed during the Pre-Submission Meeting, through amendments during the review itself, which could extend the time of that first cycle review.

Now let’s take a closer look at some key characteristics of the 41 NME approvals in Calendar Year 2015; all but five of these drugs were approved on the first cycle (88%).

*Repatha was counted as half because its application was submitted with two indications, of which only one received Orphan Drug Designation.

The first four rows of the table above represent FDA’s four expedited programs for serious conditions. FDA clarified in modifications to the CDER Desk Reference Guide in Fall 2014, that “the Program” can accommodate expedited review times for drugs in one of its expedited programs while still meeting its program commitments, and Dr. Jenkins’ data appears to support that conclusion. Drugs approved on the first cycle utilized at least one of those programs at a higher rate than drugs approved, but not on the first cycle (69% vs. 20%, respectively). These programs, especially the “all-hands-on-deck” Breakthrough Therapy program, provide additional attention and interactions with FDA. These interactions provided sponsors with the opportunity to obtain additional input from FDA regarding drug development programs and the ultimate content of the application, as well as the opportunity to discuss with or “sensitize” FDA to issues that could make the review of an application particularly challenging.

The final two rows in the table above represent two factors that may have affected FDA’s benefit/risk analysis. A greater proportion of drugs approved on their first cycle were first in their class, increasing the likelihood that they are for diseases with treatments that have less favorable benefit-risk profiles or have no available treatment options. Lastly, about half of all drugs approved on their first cycle were for rare conditions while no drugs approved on a subsequent cycle were. As analyses conducted by HP&M attorneys have found, FDA demonstrates extraordinarily reasonable flexibility in its review of applications for orphan drugs.

Orphan NME and New Biologic Approvals are at an All Time High

Not only are orphan drugs playing a role in first cycle review approvals, but orphan drug approvals themselves are at an all time high. As of December 9, 2015, CDER has already approved 19 orphan NME and New Biologics in the calendar year. CDER approved 17 NDA/BLA for orphan drugs in calendar year 2014. Together, this may signal a jump in the number of orphan NME and New Biologic Approvals relative to past years. This is very promising for rare disease patients and the companies that are investing in developing drugs for these diseases, which are often severe and/or life-threatening, but poses a series of unique challenges, such as small patient populations to enroll in clinical trials and large information gaps in the understanding of the underlying science (e.g., pathophysiology, natural history).

NDA Review Times Vary by Division

When it comes to review times, review division matters. The chart below plots each division’s median NDA review time against the percentage of NDAs that qualified for Priority Review. As might be expected, the divisions with the most Priority Review applications (Oncology and Anti-Viral) have the shortest review times. Somewhat surprising is the number of review divisions with median NDA review times in excess of 350 days, even after factoring in a number of Priority Review NDAs for most of those divisions. Only three divisions (Bone, Reproductive and Urologic; Psychiatry; and Dental and Dermatologic) received no Priority Review NDAs.

Breakthrough Therapy Designation Program Metrics Indicate Continued Strong Interest but Low Success in Getting Designated

The Breakthrough Therapy Designation (BTD) program has suffered from a lack of clarity due to subjective criteria, even with the issuance of a final guidance in May 2014 and a MAPP in March 2015. Purportedly, the pace of requests and percentage of applications granted designation have remained steady. From the start of the BTD program in December 2012 through November 2015, CDER received 307 requests for BTD, of which 95 (31%) have been granted. So far 20 of the applications that received BTD have been approved.

However, of the 307 requests, 48% have been denied, 14% withdrawn, and 7% are pending. Dr. Jenkins’s presentation provided some common reasons for denial of BTD requests:

• Evidence does not include clinical data;
• Evidence is too preliminary to be considered reliable (e.g., small numbers of patients or inadequate duration of follow up);
• Failure to demonstrate “substantial” improvement over available therapy vs. “expected” incremental benefit of development programs;
• Reliance on a novel biomarker or surrogate endpoint without sufficient evidence to support benefit to patients;
• Post-hoc analyses of failed studies.

The number of BTD requests and granted designations is highest in the oncology, antiviral, and hematology divisions (see chart below).

By Kurt R. Karst –      

Congress has been busy in the lead-up to the holiday!  In addition to the recently-enacted 2016 Consolidated Appropriations Act, which saddles FDA will meeting myriad requests and new requirements, a host of lawmakers from the U.S. House or Representatives recently sent out three letters (here, here, and here) seeking answers and documents on various generic drug review and FDA inspection issues. 

Complex Generics

The first letter, dated December 10, 2015, requests that the Government Accountability Office (“GAO”) conduct a study to assess the FDA approval pathway for reviewing generic versions of so-called Non-Biologic Comples Drugs (“NBCDs”).  A similar request was made earlier this year as part of the “Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015” (H.R. 1576) (see our previous post here). 

NBCDs, like sodium ferric gluconate and liposomal doxorubicin hydrochloride, “are drugs of non-biological origin with an active ingredient that has molecular diversity,” where “scientific analytic methodologies are unable to fully identify the molecular structures and physiochemical properties of the active ingredient,” and where “the natue of the active ingredient is not understood sufficiently to identify all the molecular components that produce the therapeutic effect of the drug, and the mechanisms of action that produce such effect,” says the letter.  NBCDs are approved under Section 505 of the FDC Act instead of under Section 351 of the PHS Act, but the lawmakers suggest that FDC Act regulation may not be sufficient.  “The current regulatory pathway used for generic approval of small molecule drugs is being used for the evaluation of NBCDs.  Given the complex natures of these large molecule drugs, we seek GAO’s input on whether the current statutory pathway for generic NBCDs is adequate to guarantee patient safety,” says the letter.

If GAO’s study concludes that meeting FDC Act approval standards presents unique challenges for generic NBCD products, then the lawmakers request that the GAO address certain questions in consultation with appropriate public and private entities, including:

1. 1.What degree of characterization of the proposed generic version and the reference product should be required in order to determine the safety and effectiveness of the generic version;
2. 2.What degree of similarity should be required to deem that the active ingredient of the proposed generic version is the same as the active ingredient of the reference product;
3. 3.What types of evidence should be required to demonstrate that the proposed generic version is bioequivalent to the reference product;
4. 4.What requirements should be established with respect to the comparability of the manufacturing process for the proposed generic version and the manufacturing process for the reference product;
5. 5.Whether and to what extent clinical evidence is needed to demonstrate that there is no difference in immunogenicity between the proposed generic version and the reference product; and
6. 6.Whether and to what extent other clinical evidence is needed to demonstrate that the proposed generic version is as safe and effective for patients as the reference product.

If GAO has to answer the questions above, then the lawmakers request that GAO assess whether the FDC Act’s ANDA process is sufficient and to recommend “whether and when FDA should develop a public policy document offering comprehensive, general principles on the evidence necessary to obtain the FDA’s approval of generic drug applications that use such reference products.” 

Interest in the approval of generic versions of NBCDs has been increasing over the past several years, and such products have been the topic of numerous Citizen Petitions and research (see here).  Under the Performance Goals and Procedures FDA agreed to as part of the 2012 Generic Drug User Fee Amendments (“GDUFA”), the Agency said that it would look into complex drug substances as part of the Agency’s Regulatory Science Plan.  Each Fiscal Year thereafter, FDA has outlined Regulatory Science Priorities including complex generics.  For example, FDA’s GDUFA Regulatory Science Priorities for Fiscal Year 2016 include the following:

Equivalence of complex drug products includes research into making generic versions available in all product categories, including complex drugs with unique characteristics.  FDA spends an increasing amount of time reviewing and developing policy for complex drug products, and future generic products will need to demonstrate equivalence to increasingly complex RLDs.  This scientific research supports the development of guidance and policy that clarifies the Abbreviated New Drug Application (ANDA) pathway for complex products, such as drug-device combinations, transdermal systems, implants and parenteral microspheres, nanomaterials (e.g. liposomes and iron colloids), and products that contain complex mixtures and peptides.  New FY 2016 priorities include transdermal irritation studies and research into human factors studies that will aid in evaluation of product substitutability and robustness for drug-device combinations.

FDA Inspections

In a second letter, dated December 18, 2015, a group of four lawmakers from the House Energy and Commerce Committee ask the GAO to take a look at and assess FDA’s foreign inspectional activities.  A 2010 GAO report concluded that while FDA was making efforts to improve the Agency’s inspectional activities, more progress was needed (see our previous post here).  Since then, FDA has formed the Office of Global Regulatory Operations and Policy and has looked to partner with other agencies and organizations to strengthen inspectional activities.  In 2012, the FDA Safety and Innovation Act gave FDA new authorities to improve the drug supply chain and directed FDA to take a risk-based approach to domestic and foreign inspections.  Despite these changes, however, the lawmakers remain sceptical and concerned about FDA’s progress in addressing global supply chain issues.  “[W]e are concerned that there is still inadequate oversight with regards to these foreign drug plants, not to mention an unequal playing field compared to U.S. drug manufacturers that are subjected to more frequent and rigorous inspections,” write the lawmakers, who also note that only two FDA drug inspectors are reportedly assigned to oversee 700 drug manufacturing facilities in China. 

Given these lingering concerns, the lawmakers ask the GAO to “revisit these issues [from the 2010 report] and assess FDA’s activities and accomplishments” in certain areas, including:

• Foreign Drug Inspections – How has FDA implemented the risk-based inspection frequency in selecting foreign drug manufacturing facilities for inspection as required in Section 705 of FDASIA?  Has it finalized the development of the risk-based schedule?  In addition to the risk factors outline in the statute, what other criteria, if any, did FDA identify as necessary for establishing the risk-based schedule?  When did FDA begin to use the risk-based schedule?  How many surveillance inspections of foreign establishments has the agency conducted over the last 5 years?  How does the rate of inspections of foreign drug manufacturing establishments compare to domestic drug manufacturing establishments?  What is the average inspection frequency for domestic drug manufacturing establishments and foreign drug manufacturing establishments?  What is the status of FDA’s cadre of staff dedicated to foreign drug inspections – how many staff members and how many inspections have they conducted?

• FDA’s Foreign Offices – What are the specific accomplishments of these offices?  How many inspections of drug manufacturing establishments have these offices conducted?  In what ways have the offices improved relationships with foreign regulators and manufacturers?  Why has FDA closed some of these offices, which only opened a few years ago?  What is the agency’s plan to fill the many vacancies in the remaining offices?  Does it continue to experience difficulties in obtaining visas for its staff.  Any what accounts for the agency’s delay in implementing recommendations made by your office five years ago?

ANDA Review Efficiency

In a third letter, dated December 15, 2015, a group of 12 lawmakers ask Acting FDA Commissioner Stephen Ostroff, M.D., for a trove of documents relating to ANDAs.  The request is apparently related to recent price increases for certain generic drugs that have captured the attention of Congress as of late, as well as to reports of alleged declining market competition.  We also suspect that Congress wants the information as the generic drug industry gears up for creation of the second iteration of GDUFA.

The list of requested documents is long.  There are 15 general requests, some of which have multiple subparts.  (The folks in FDA’s Office of Generic Drugs almost certainly have to feel like Rodney Dangerfield’s Thornton Melon in that famous examination day scene from “Back to School.”)  The lawmakers want, among other things, information on median ANDA approval times, Refuse-to-Receive decisions (including rescissions), ANDA Target Action Date assignments, industry communications, documents and communications concerning barriers to generic drug entry, user fee funding accountability, and on and on. 

FDA is supposed to respond to the request no later than 5PM pn January 6, 2016.  It’s not quite the the present anyone from FDA had hoped for this season. . . . But, like Thornton Melon, we know the Agency will pull through. 

The American Conference Institute’s (“ACI”) popular FDA Boot Camp, now in its 27th iteration, is slated to take place at The Carlton Hotel in New York, New York from March 9-11, 2016.  The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.

The 27th edition of the FDA Boot Camp has been reworked to provide attendees not only with the essential background in FDA regulatory law to help you in your practice, but also key sessions showing how this regulatory knowledge can be applied to situations encountered in real life.  Highlights of the new program include the “Ripped from the Headlines” session that will update attendees on the key developments in the FDA regulatory bar, and the interactive Post-Conference Case Study Working Groups.

A stellar cast of presenters will share their knowledge and provide critical insights on a host of topics, including:

• The organization, jurisdiction, functions, and operations of FDA
• The essentials of the approval process for drugs, biologics, and devices, including: INDs, NDAs, BLAs, OTC Approval, 510(k) submissions, and the PMA process
• Clinical trials for drugs and biologics and the clearance process for devices
• The classification of devices and the concept of “risk-based” classification
• The role of the Hatch-Waxman Amendments in the patenting of drugs and biologics
• Labeling in the drug and biologics approval process
• cGMPs and other manufacturing concerns relative to products liability
• Proactive adverse events monitoring and signal detection
• Recalls, product withdrawals, and FDA oversight authority  

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will present with a panel of experts and provide an overview of the Hatch-Waxman Amendments and the Biologic Price Competition and Innovation Act (“BPCIA”).  Mr. Karst will also head one of the workshops new to the ACI FDA Boot Camp program in 2016. Titled “Hatch-Waxman and BPCIA in the Trenches: Deconstructing and Constructing an Exclusivity Dispute,” Mr. Karst will deconstruct, in a step-by-step manner, a complex exclusivity dispute, analyzing FDA’s and the disputing parties’ various (and sometimes evolving) positions on exclusivity.  Relevant court decisions will also be analyzed and their practical and future effects discussed.  After the exclusivity case analysis is completed, attendees will have the opportunity to construct their own exclusivity dispute by choosing from various base facts.  Once the case is constructed, Mr. Karst will lead attendees through the exclusivity analysis.  Sounds like fun, eh?

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 15% discount. The discount code is: P15-999-FDA16.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

By Jamie K. Wolszon & Jeffrey N. Gibbs –    

As 2015 draws to a close, the world of laboratory-developed test regulation continues in high gear. One major event featured the Center for Devices and Radiological Health (CDRH) Director Jeffrey Shuren testifying last month before the House Energy & Commerce Committee Subcommittee on Health. Dr. Shuren stated that the Agency intends to issue a final framework under which FDA would actively regulate LDTs in 2016, although he could not pinpoint when in 2016 the final guidance would be issued.

The legislative hearing provided an opportunity for subcommittee members, Dr. Shuren, and the Centers for Medicare & Medicaid Services (CMS) official in charge of managing the Clinical Laboratory Improvement Amendments of 1988 (CLIA) program, an opportunity to critique legislative proposals under which most of the premarket reviews of LDTs would occur under an expanded CLIA program, with only a limited role for FDA. Those legislative proposals have reportedly been presented to members of the Senate Committee on Health, Education, Labor & Pensions. By contrast to those competing CMS-focused proposals, the subcommittee has circulated a legislative discussion draft which would give FDA responsibility for premarket review of all “in vitro clinical tests”—regardless of whether they are LDTs or kits—using a different standard than the one currently employed. CMS would retain jurisdiction over laboratory operations such as personnel and laboratory procedures.

The day before the November 17, 2015 hearing, FDA issued a report of 20 case studies of particular LDTs and types of LDTs that it believes illustrate the need for FDA oversight of LDTs. The report appears to have been issued as a response to a request from the same congressional subcommittee at its September 9, 2014 hearing for examples of instances where LDTs had caused harm. This report has drawn its own criticism. The Association for Molecular Pathology (AMP) released a critique on December 13, 2015, which enumerated alleged flaws in the FDA report.

In another development, in October 2015, FDA issued eagerly-awaited Federal Register notices (here and here) announcing that the Agency will allow sponsors to offer direct-to-consumer (DTC) carrier screening tests without 510(k) clearance for multiple autosomal recessive disorders (excluding tests for Cystic Fibrosis, which will continue to need 510(k)s) if the company and the test adhere to detailed special controls. In a series of letters to labs (here, here, here, and here), FDA also expressed its concerns over the LDT tests that they were offering. Thus, on the LDT front, the FDA giveth – exempting a broad swath of DTC LDTs without 510(k)s, and taketh – challenging labs that offered other types of LDTs.

Returning to the November 17, 2015 health subcommittee hearing, “Examining the Regulation of Diagnostic Tests and Laboratory Operations,” the hearing was markedly different from the subcommittee’s prior hearing on FDA oversight of LDTs on September 9, 2014. As we previously reported, at that hearing, the subcommittee members grilled Dr. Shuren for hours. The November 17, 2015 hearing was much friendlier to the Agency. While a few of the subcommittee members challenged whether FDA should have any role in the regulation of LDTs, the majority of the members seemed to accept the premise that FDA should have some role. Also, unlike the prior hearing, which included testimony from members of both the laboratory and medical device communities, this hearing only had two witnesses: Dr. Shuren and Patrick Conway, Deputy Administrator for Innovation and Quality & Chief Medical Officer, Office of the Administrator, CMS. Dr. Conway manages the CLIA program.

We previously reported on two legislative proposals – one by AMP and another by laboratory accreditor the College of American Pathologists – under which either CMS or its designee would perform most of the premarket reviews of LDTs through an expanded CLIA program. As previously reported, those two proposals are similar to each other in many respects. For instance, both exempt low-risk tests from premarket review, would give CMS or third-party reviewers sole authority to review moderate-risk tests, and FDA would only get involved for high-risk tests (all high-risk tests under the CAP proposal and a subset of high-risk tests under the AMP proposal). AMP submitted a letter for the record of last month’s congressional hearing supporting its legislative proposal.

By contrast to the CLIA-centric approach in those legislative proposals, in October 2015, the House Energy & Commerce Committee circulated a discussion draft that would create a new center for in vitro clinical tests, which would report to the FDA Commissioner. Under this proposal, FDA would use a new standard – reasonable assurance of analytical validity and clinical validity – in reviewing all high-risk in vitro clinical tests, regardless of whether the test is offered by a laboratory or as a distributed product. The current standard for PMAs is reasonable assurance of safety and effectiveness. Premarket review of the test would fall to FDA; CMS would be in charge of laboratory operations.

Dr. Shuren and Dr. Conway testified during last month’s congressional hearing that legislative proposals where FDA conducts the premarket review for some tests, and CMS conducts the premarket review for other tests, would lead to duplication and inconsistency. Dr. Conway repeatedly stated that CMS does not have the resources or expertise to conduct premarket review of LDTs. In response to a question, Dr. Conway said that giving CMS responsibility for premarket review could cause a backlog that would stifle innovation.

As for FDA’s resources, Dr. Shuren mentioned that laboratories are “at the table” as part of the current negotiations between industry and FDA related to the upcoming medical device user fee reauthorization. In a December 7, 2015 letter sent by the subcommittee with questions for the record, Rep. Blackburn (R-TN) asked Dr. Shuren to provide additional detail about those user fee negotiations. “To what extent in the ongoing MDUFMA IV negotiations have any discussions included projections or proposals taken into account the anticipated increase in workload or resource needs required for regulating…LDTs within the MDUFMA program? If so, please provide the Committee with such estimates for workload and resource needs. If not, when does the FDA expect to release such estimates?”

In that same letter, Rep. Blackburn asked Dr. Shuren for timelines on the internal reviews that will precede the release of the final guidance. “Please provide the Committee with the date when [CDRH] expects to complete the Center’s internal work on the final guidance and submit to the FDA Commissioner and/or Health and Human Services and/or the Office of Management and Budget for review and approval.” The letter requests that FDA respond by close of business December 21, 2005.

Dr. Shuren did not discuss during the hearing how the final version of the framework will differ from the proposed version. He did clarify that most modifications to LDTs that had already gone through FDA premarket review would not trigger new review. “Only big changes” would require a new submission to the agency, he testified. Specifically, he said that modifications to intended use or alteration of performance specifications could trigger a new review. Of course, the size of the change is in the eye of the beholder: what is “big” to FDA may seem trivial to a lab.

Dr. Shuren provided as examples of moderate-risk tests ones for cystic fibrosis, herpes and heart failure. He said that most moderate-risk tests would be subject to FDA premarket review; however, there would be some moderate-risk tests for which special controls would suffice. He provided carrier screening as an example of a moderate-risk test where FDA does not require premarket review (other than CF).

Both Dr. Shuren and Dr. Conway expressed concern about the “deemed approved” provisions in some legislative proposals. The concept of the deemed approved provisions is that FDA or CMS or its designee would have a certain amount of time to act on a submission; if the entity did not act within a certain time, the test would be “deemed” approved/cleared. Dr. Shuren said that he is concerned that faced with such a provision, FDA would either allow a test on the market without fully vetting the test, or in the alternative, deny a good test because it does not have enough time to resolve questions. This does not seem to have been the outcome for Investigational Device Exemption applications, which similarly have a “deemed approved” provision. Dr. Shuren also stated that there is no way for a patient to know whether a test came to market because it was deemed approved because the agency ran out of time.

Asked how long it would take to review a moderate-risk LDT, Dr. Shuren responded that the current total time for FDA review of moderate-risk LDTs is “a little over 100 days.” This statement is somewhat odd because FDA currently only reviews LDTs if a sponsor voluntarily seeks approval or clearance (or in a few instances because of FDA pressure to do so). In addition, the FDA “total time” excludes the chunk of time sponsor spends responding to FDA. The average FDA review times for IVDs have been among the longest of any product category. Rep. Michael Burgess (R-TX), in his questions for the record, asked Dr. Shuren to provide details about FDA review metrics including “the number of IVD pre-market applications, de novo application, and 510(k) applications approved by the FDA annually” and “of these applications, how many are applications for modifications of IVDs previously approved or cleared by the FDA.”

Dr. Shuren also stated that FDA has “never proposed to regulate the practice of medicine” and there “actually is a statutory provision that prohibits us from doing so.” This citation to that statutory provision is interesting; some critics have argued that the agency has largely ignored that statutory provision when it comes to LDTs.

Thus, 2015 is ending on a noisy note on the LDT front. Of course, if FDA issues a final guidance in 2016, then 2015 will seem like a whisper in comparison.

Hyman, Phelps & McNamara, P.C.’s Jeffrey K. Shapiro participated in a panel discussion at a recent Food and Drug Law Institute conference that focused on the regulation of digital health software. Mr. Shapiro’s talk emphasized the limits of FDA’s expertise and the need for caution to prevent over regulation of digital health software from impeding innovation that can help improve healthcare. Mr. Shapiro’s talk, and follow-up correspondence on the topic, has garnered significant attention, and is discussed further in recent trade press articles (here and here) (Reproduced with permission from Medical Devices Law & Industry Report, 10 MELR 01 (Jan. 6, 2016). Copyright 2016 by The Bureau of National Affairs, Inc. (800-372-1033).)

By Riëtte van Laack –

The Supreme Court of California recently concluded that federal law does not preempt claims against allegedly intentional misrepresentations of organic status of a food. According to the Court, the Organic Foods Production Act of 1990 (OFPA) only preempts state law on matters related to organic certification, not private actions against alleged misuse of the “organic” label.  

According to the complaint, Herb Thyme, the defendant, has several conventional farms and one farm that is certified organic. Plaintiff alleges that Herb Thyme brings its conventionally grown and organic products to the same facility where they are processed together. According to Plaintiff, the organic and conventional product are mixed and sold with the same “Fresh Organic” label. In other words, Plaintiff claims that the Herb Thyme markets non-organic product as organic, not that Herb Thyme’s organic farm did not comply with the organic requirements.

As we previously reported, the Court of Appeals previously determined that the express preemption provision was narrower than the claims here. The California Supreme Court agreed. However, the California Supreme Court disagreed regarding obstacle preemption. Herb Thyme argued that state private actions were an obstacle to the federal purpose. The Supreme Court did not see any such obstacle.

The opinion includes a detailed description of the history of organic standards in support of the Court’s conclusion that the OFPA was intended to create national standards for production, labeling and sale of organic products; not to prevent consumer actions under state law against the fraudulent labeling of conventionally produced products as organic. The court notes that states may have their own organic program provided it is approved by the National Organic Program (NOP). California has its own organic program, the California Organic Products Act of 2003. This state law incorporates by reference federal regulations under the Organic Products Act. Additionally, it grants authority to the Secretary of the Department of Food and this state program authorizes anyone to file a complaint about noncompliance, and various state authorities may bring enforcement actions and impose penalties.

The Court did not find any evidence to support express or obstacle preemption of private actions under state law. The OFPA sets the national standards for the term organic and certification procedures. However, it does not create “exclusivity” regarding actions related to misuse of the organic label. According to the Court, state consumer fraud lawsuits further the purpose of the law, they promote avoiding consumer deception, build consumer trust in a standard definition of “organic,” and protect legitimate organic producers from unfair competition. If the Court were to find obstacle preemption it “would render organic labeling uniquely immune from suits for deception because of legislation Congress passed, in part, to prevent food from being ‘deliberately mislabeled as “organic.”’ . . . [The law] cannot be interpreted, under the guise of obstacle preemption, as shielding from suit the precise misconduct [the law] sought to eradicate.” Finding no preemption, the case will be remanded. 

By Ricardo Carvajal –

Answer:  They were all designated as high priority items in a Nutrition Program Review (NRP) Report prepared by CFSAN staff for the Center Director in December 2014.  (We compiled the report and its attachments into a single PDF, which we repaginated for the reader’s convenience.)  Unlike the highly publicized activities of CFSAN’s Chemical Safety Review, the activities of the NRP have stayed low on the radar, and the NRP Report was not made widely available to the public.  Our summary analysis of the Report is based on a copy obtained through the FOIA.

Commissioned by then-CFSAN Director Michael Landa, the NRP’s purpose was “to examine the nutrition and nutrition-related activities within CFSAN and recommend how they could be enhanced to more optimally benefit the public health,” in light of “reasonable resource constraints” and existing statutory authority.  The NRP was motivated in part by recognition that nutrition-related morbidity and mortality is estimated to far exceed morbidity and mortality associated with food contamination – historically the primary focus of FDA’s foods program, and almost certain to remain so with the advent of FSMA and associated funding.  The NRP was led by a Steering Committee (SC) comprised of key FDA personnel, and developed its recommendations based on interviews of agency staff and a range of external sources, including consumer advocates and the food industry. 

For purposes of the NRP, the SC broadly defined “nutrition and nutrition-related activities” to include “all activities intended to support growth, maintain health, and reduce the risk of chronic diseases, nutrient deficiencies, and other nutrition-related problems through a nutritionally healthy food supply and diet.”  Activities within the scope of the NRP included “assessments, education and outreach, economic analysis, food supply monitoring, research, and compliance.”  Covered chronic diseases and conditions included “obesity, nutrient inadequacy, inadequate growth, heart disease, site specific cancers, diabetes, hypertension, osteoporosis, age-related macular degeneration, neural tube defects, and dental caries.”

One of the principal objectives of the NRP was to develop a proposed strategic framework for FDA’s nutrition program.  The Report notes that CFSAN’s nutrition-related activities focus on providing information to consumers, with the assumption that they’ll use that information to make choices that contribute to better health, and encouraging product reformulation.  The NRP recommended that these activities be focused on achieving public health outcomes, notwithstanding the difficulty of ascertaining whether those goals are met.  Under the proposed strategic framework, the “top-level results” of CFSAN’s nutrition program over the next 10 years would be:

• Reduce rates of nutrition-related risk factors for chronic disease;
• Improve rates of optimal nutritional status among adults; and
• Ensure rates of optimal growth and development in infants and children.

Accordingly, the Report proposes the inclusion of the following nutrition-related objectives in the Office of Foods and Veterinary Medicine’s upcoming 10-year strategic plan: facilitate dissemination of information to help consumers choose healthier diets; monitor scientific developments, as well as changes in composition of marketed foods and their impact on consumers’ health; and encourage product reformulation “to promote a healthier food supply.”  In furtherance of those objectives, the Report includes the following “recommendations for improvement,” tiered in order of priority:

Tier 1

• Conduct a comprehensive evaluation of the nutrition program to establish a baseline against which to measure future evaluations;
• Reduce consumption of sodium through “voluntary and gradual” reduction, and of trans fat through revocation of GRAS status of PHOs (the Report also mentions engaging with industry “to consider how and whether foods could be reformulated to reduce saturated fats”);
• Begin planning to engage in FOP labeling to ensure that “labels are useful to consumers and not misleading regarding the healthfulness of the food,” perhaps through issuance of a regulation mandating a “single national system” or guidance establishing basic principles;
• Address the “growing and sometimes egregious problem of products making unsubstantiated therapeutic drug-type claims” by claiming medical food status – but without stifling “development of legitimate medical foods”;

Tier 2

• Address “growing concern” about the potentially misleading use of dietary guidance statements, such as the use of such statements on products that have “negative nutritional attributes” or “lack meaningful amounts of foods to which the statements pertain”;
• Develop a “regulatory structure” to ensure that structure/function claims are adequately substantiated, “given their great potential to mislead consumers”;
• Monitor scientific developments pertaining to “bioactive food components” such as probiotics and added fibers, and consider how to address the validity of related structure/function claims.

The Report includes other recommendations pertaining to consumer studies, consumer education, laboratory and clinical research, and collaboration with other government agencies and the private sector.

In looking back over the past year, it’s clear that FDA has pursued some activities consonant with the Tier 1 recommendations described above, such as revocation of GRAS status for PHOs and continued targeting of products the agency believes to be unlawfully marketed as medical foods – but those activities were underway when the NRP Report was generated.  At this point, the ultimate fate of the Report is unclear.  It may be that the Report’s recommendations will be incorporated into the next OFVM strategic plan, given that the benefits of the proposed initiatives are estimated to far outweigh the costs, and also far exceed the benefits of the agency’s food safety initiatives.  Alternatively, the Report might be shelved and forgotten – more time will tell.

By Larry K. Houck –

The Centers for Disease Control and Prevention (“CDC”) have published draft guidelines for prescribing opioids for chronic pain and opened a docket seeking public comment. Proposed 2016 Guideline for Prescribing Opioids for Chronic Pain, 80 Fed. Reg. 77,351 (Dec. 14, 2015). The docket will accept comments until January 13, 2016. We blogged on the draft guidelines on October 12, 2015, listing the guidelines that the CDC presented during the September 16, 2015 webinar. At that time we noted that the CDC did not intend to make the draft guidelines available to the public. CDC Opioid Prescribing Guidelines; Excluding Stakeholders is Wrong Path. The CDC has now cured this obvious shortcoming and agreed to publish the draft guidelines for public comment. The CDC guidelines are just the latest contribution to the ongoing debate about the appropriate treatment of pain and, while they are voluntary, we expect them to be very influential on opioid therapy for chronic pain. We therefore believe that the CDC has made the right decision in publishing the guidelines and providing stakeholders with the opportunity to weigh in before they are finalized.

The CDC states physicians across all treatment specialties “believe that opioid pain medication can be effective in controlling pain but agree that physical dependence, tolerance, and addiction are common consequences of prolonged use” and that opioids are often overprescribed for patients with chronic noncancer pain. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. Primary care providers (family physicians and internists), says the CDC, are concerned about the misuse of opioid pain medication and patient addiction, and opine that they have received insufficient training on prescribing opioids. Id.

The draft guidelines provide opioid prescribing recommendations for primary care healthcare professionals who are treating patients with chronic pain, that is, pain lasting longer than three months or past the time of normal tissue healing, in outpatient settings. The guidelines apply only to patients eighteen years or older with chronic pain unrelated to active cancer treatment, and outside of palliative and end-of-life care. The CDC states that the guidelines are intended to improve communication between providers and patients about the benefits and risks of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks, including abuse, dependence, overdose, and death, associated with long-term opioid therapy. Id. The Federal Register notes that “The Guideline is not a federal regulation; adherence to the Guideline will be voluntary.” 80 Fed. Reg. at 77,351.

The draft guidelines are generally the same as those presented during the September 16th webinar with minor variations. The differences appear to be mostly the addition of the qualifier “for chronic pain” as if to reiterate that the guidelines do not apply in all circumstances. CDC has organized the guidelines into three general areas: (1) when to initiate or continue opioids for chronic pain; (2) opioid selection, dosage, duration, follow-up, and discontinuation; and (3) assessing risk and addressing harms of opioid use. The current draft guidelines are:

Determining When to Initiate or Continue Opioids for Chronic Pain

1. Nonpharmacologic therapy and nonopioid pharmacological therapy are preferred for chronic pain. Providers should only consider adding opioid therapy if expected benefits for both pain and function are anticipated to outweigh risks to the patient.
2. Before starting opioid therapy for chronic pain, providers should establish treatment goals with all patients, including realistic goals for pain and function. Providers should not initiate opioid therapy without consideration of how therapy will be discontinued if unsuccessful. Providers should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety.
3. Before starting and periodically during opioid therapy, providers should discuss with patients known risks and realistic benefits of opioid therapy and patient and provider responsibilities for managing therapy.

Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation

4. When starting opioid therapy for chronic pain, providers should prescribe immediate-release opioids instead of extended-release/long acting (ER/LA) opioids.
5. When opioids are started, providers should prescribe the lowest effective dosage. Providers should use caution when prescribing opioids at any dosage, should implement additional precautions when increasing dosage to ≥ 50 morphine milligram equivalents (MME)/day, and should generally avoid increasing dosage to ≥ 90 MME/day.
6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, providers should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three or fewer days usually will be sufficient for most nontraumatic pain not related to major surgery.
7. Providers should evaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy for chronic pain or of dose escalation. Providers should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid therapy, providers should work with patients to reduce opioid dosage and to discontinue opioids.

Assessing Risk and Addressing Harms of Opioid Use

8. Before starting and periodically during continuation of opioid therapy, providers should evaluate risk factors for opioid-related harms. Providers should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, or higher opioid dosages (≥ 50 MME), are present.
9. Providers should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving high opioid dosages or dangerous combinations that put him or her at high risk for overdose. Providers should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months.
10. When prescribing opioids for chronic pain, providers should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs.
11. Providers should avoid prescribing opioid pain medication for patients receiving benzodiazepines whenever possible.
12. Providers should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016.

The CDC has also cured another criticism of the draft guidelines by making a number of relevant documents and materials available as part of the docket. The documents and materials provide needed transparency to the CDC’s development of the guidelines and should promote a much needed discussion in this complicated area. These documents include the Peer, Stakeholder and Constituent Review Summaries and the Clinical and Contextual Evidence Review Appendices.

As we noted in October, the draft guidelines are reasonable and should help progress the public discussion on appropriate pain treatment. Some of them are commonsensical, constitute good medical practice, and apply to the prescribing of any medication, not just opioids or controlled substances. However, they are not without controversy and other stakeholders have been critical of the CDC’s position. See, e.g., Letter to the Honorable Fred Upton, Chairman, House Energy and Commerce Committee, U.S. House of Representatives, from Robert Twillman, Executive Director, American Academy of Pain Management (Oct. 20, 2015). We questioned the CDC’s lack of transparency and not allowing input from interested stakeholders including prescribers, pharmacists, regulators, and especially patients. The final guidelines will potentially greatly influence practitioners and patients so it is appropriate that the CDC provide stakeholders and the public with an opportunity to comment on the draft guidelines.

There has been increased enforcement against physicians for failing to adhere to their primary responsibility to ensure that a prescription must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his professional practice. See, e.g., 21 C.F.R. § 1306.04(a). The same is true for action against pharmacies that have failed in their corresponding responsibility to ensure that prescriptions are dispensed only for a legitimate medical purpose. See, e.g., The Medicine Shoppe; Decision and Order, 79 Fed. Reg. 59,504 (Oct. 2, 2014). The CDC guidelines at one level could be viewed as providing criteria or clarifying these standards. However, we would caution physicians, pharmacists, and regulators that legitimate medical treatment may on occasion conflict with strict adherence to the guidelines. There may, for example, be instances where a patient requires more than 50 or 90 morphine milligram equivalents per day. Thus, stakeholders will need to evaluate to the extent that these voluntary guidelines are consistent with appropriate medical practice.

By David C. Gibbons & Jeffrey N. Wasserstein – 

Pacira Pharmaceuticals, Inc. (“Pacira” or the “Company”) announced today that it had reached agreement with FDA to settle its First Amendment challenge regarding the promotion of its drug, EXPAREL. As we discussed in a previous post, Pacira filed a Complaint in the U.S. District Court for the Southern District of New York on September 8, 2015, seeking to prevent FDA from bringing an enforcement action against the Company for its truthful and nonmisleading speech concerning EXPAREL, and then filed a Motion for Preliminary Injunction. The central issue was whether FDA could limit the scope of a generally approved product to only those specific uses in which the drug has been studied and approved. As the litigation progressed, the court issued a revised Scheduling Order on October 22, indicating that the parties were in settlement negotiations. The instant lawsuit has now been resolved in a joint Stipulation and Order (“Settlement Agreement”) that was filed yesterday, December 14.

The Settlement Agreement contains a number of important provisions. These include: 

• The Warning Letter issued to Pacira on September 22, 2014, was formally withdrawn and FDA issued a letter clarifying the reasons for its withdrawal (“Rescission Letter”). Stipulation and Order at 2, Pacira Pharms., Inc. v. FDA, No. 15-7055 (S.D.N.Y. Dec. 14, 2015), ECF No. 45.
• In conjunction with the Settlement Agreement, FDA approved a labeling supplement, including revisions to EXPAREL’s U.S. Prescribing Information intended to “describe accurately the scope of the indication initially approved by FDA, which will avoid confusion by the FDA or any other entity about the scope of EXPAREL’s approval by FDA . . . .” Id. at 3 (emphasis added). 
• Confirms the broad scope of EXPAREL’s indication “for use in a variety of surgeries not limited to those studied in [EXPAREL’s] pivotal trials.” Id.

We consider these provisions now, in turn. In the Rescission Letter, FDA stated that it determined there was “ambiguity” in EXPAREL’s approved labeling regarding the scope of the product’s indication. FDA ultimately determined that the use described in the label “broadly referred to ‘surgical sites’” and was not limited to the two types of surgeries studied in the pivotal trials supporting EXPAREL’s NDA approval. FDA stated that, in light of its determination, it rescinded the Warning Letter on October 13, 2015, and removed the Warning Letter from FDA’s website on the same day. See our previous post (here) when FDA “unpublished” the Warning Letter to Pacira.

Consistent with FDA’s determination in the Rescission Letter, FDA approved changes to EXPAREL’s label. Notably, the revised label does not contain the statement: “EXPAREL has not been demonstrated to be safe and effective in other procedures.” See EXPAREL (bupivacaine liposome injectable suspension) Label, NDA 022496, 16 (Nov. 2014); Stipulation and Proposed Order, Exhibit 1.

Both the Rescission Letter and the revised label confirm that EXPAREL’s use encompasses a broad range of surgeries, not limited to the clinical studies included in the label. Also, importantly, FDA stipulated that this broad use of EXPAREL does not represent the approval of a new indication, but rather clarifies EXPAREL’s use, “as initially approved” at the time EXPAREL’s NDA was approved, back in 2011, thus exculpating Pacira from prosecution or potential False Claims Act liability related to its past, current, and future promotion of EXPAREL for specific surgery types that are encompassed by its general indication.

There are several key takeaways from this settlement. First, clearly this represents a victory for Pacira and paves the way for the Company to continue its promotional efforts directed towards the use of EXPAREL in specific surgeries, as it had done prior to receiving the Warning Letter in September 2014.

Second, we believe there may be broader implications to this settlement for products bearing general indications in their label. As we noted in our previous post concerning this litigation, medical device companies frequently face this “general versus specific use” issue because it is not uncommon for a medical device to receive clearance for a general use. Therefore, device companies may have found a victory here as well, particularly if the approval or clearance was predicated on clinical studies.

Finally, at the end of a tumultuous year that saw FDA face multiple First Amendment challenges (see our Amarin posts here and here), the ability of FDA to effectively ban off-label promotion has been seriously called into question. Following unfavorable decisions in Caronia and Amarin, FDA took a new tack by settling the Pacira matter, making concessions favorable to the Company. We note that FDA’s Center for Drug Evaluation and Research has identified, as one of its “front burner” priorities for 2016, the need to “[r]e-evaluate our regulation of drug advertising and promotion in light of current jurisprudence around the 1st Amendment: ongoing, progress made, but more work needed.” Janet Woodcock, CDER 2016 Priorities, at 10. Indeed more work is needed and we are encouraged that FDA is working with industry stakeholders to arrive at solutions that ultimately benefit patients by giving healthcare providers greater access to more information, as it did here in Pacira. Hopefully, in 2016 and beyond, we will see less litigation and more openness that will forestall the need for legal action. But, if not, the U.S. District Court for the Southern District of New York has proven a helpful forum for First Amendment challenges by pharmaceutical manufacturers.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is pleased to announce that Melisa M. C. Moonan has joined the firm as Of Counsel.

Ms. Moonan advises clients on medical device regulatory issues. She joined the firm after close to six years as Associate Chief Counsel for Regulatory Affairs at Welch Allyn, a medical device manufacturer. In that role, Ms. Moonan was responsible for guiding the company in meeting FDA and Global Regulatory Authorities’ requirements for medical devices, including obtaining premarket registrations and assuring postmarket compliance. She advised management across company departments including Regulatory, Quality, R&D, Marketing, and Operations on premarket strategy and submissions, state licensing, traditional and social media marketing campaigns, quality systems issues, Medical Device Reporting, field actions and reporting, inspections and 483 responses, and writing and reviewing agency submissions generally. She also helped spearhead the company’s global product materials compliance effort including on REACH and California Proposition 65 compliance, and advised the company on regulatory issues related to acquisitions. Ms. Moonan won a number of company awards for her work on product development projects, registrations, and 483 responses.

Prior to Welch Allyn, Ms. Moonan was in private practice as an FDA Counsel at two major law firms, and served as Associate Chief Counsel for Biologics in FDA’s Office of Chief Counsel from 1994-1998. At FDA, Ms. Moonan successfully litigated food, drug, and FOIA cases, and advised CBER on rules and policies related to regulation of the blood supply, medical devices, diagnostics, and therapeutics, including working on the regulations and policies for ASRs, HCT/Ps, and blood establishment software.

Ms. Moonan graduated with honors from the University of Maryland School of Law, and earned a Bachelor of Arts in History from Brown University. She is admitted to practice in the District of Columbia and Maryland.

By Kurt R. Karst –  

Last week, the folks over at the Big Molecule Watch Blog broke the news that the U.S. District Court for Southern District of Florida (Judge James I. Cohn) ruled on a Motion for Preliminary Injunction (supplemented) filed by Amgen, Inc. and Amgen Manufacturing Limited (collectively “Amgen”) in litigation with Apotex Inc. and Apotex Corp. (collectively “Apotex”) over Apotex’s biosimilar version of Amgen’s NEULASTA (pegfilgrastim), approved under BLA 125031 (see our previous post here).  Amgen sought to enjoin Apotex from marketing its pegfilgrastim biosimilar biological product until 180 days after Apotex notifies Amgen of FDA licensure of the biosimilar application (referred to as a “Section 351(k) BLA” or as an “abbreviated BLA”, or “aBLA”).  In a December 9, 2015 Order, the court granted Amgen’s request.  Apotex immediately appealed the decision to the U.S. Court of Appeals for the Federal Circuit.  

The District Court’s decision is the first decision dealing with the 180-day notice of commercial marketing provision at PHS Act § 351(l)(8)(A) created by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) since the Federal Circuit ruled in a highly fractured July 21, 2015 decision (Amgen Inc. v. Sandoz Inc., 794 F.3d 1347 (Fed. Cir. 2015)) that aBLA licensure is required before an “operative notice” of commercial marketing can be given (see our previous posts here and here).  (The Federal Circuit also ruled that the so-called “patent dance,” starting with the provisions at PHS Act § 351(l)(2), is not mandatory.)  In Sandoz, however, Sandoz did not partake in the patent dance.  Apotex decided otherwise and engaged Amgen in the dance.  Apotex, like Sandoz before it, provided what it argued was notice of commercial marketing, but that notice came before any aBLA licensure.  (And, in fact, Apotex’s application has not yet been licensed.)    

In his December 9, 2015 decision, Judge Cohn repeatedly refers to the BCPIA instead of the BPCIA.  This mix-up – and one that we have been guilty of as well (and perhaps the biologics counterpart to saying Wax-Hatchman instead of Hatch-Waxman) not only provides us with fodder for a cute headline – whereby commercial marketing notice (“C”) must always follow the patent dance (“P”) under the BPCIA (at least if a biosimilar applicant decides to go down that path) – but it also underscores how illusive the meaning is of the BPCIA’s patent dance and notice provisions.  

Amgen relied heavily on the company’s Preliminary Injunction papers in the Federal Circuit’s Sandoz decision.  “The Federal Circuit’s decision in [Sandoz] renders Apotex’s April 17, 2015 notice of commercial marketing ineffective, because that notice was given before FDA approval of Apotex’s application,” wrote Amgen.  “Apotex’s position is directly at odds with these statutory purposes.  If Apotex were correct and an Applicant could, at its whim, eliminate the notice period by ‘choosing’ not to provide notice under paragraph (l)(8)(A), then the ‘RPS would be left to guess . . . when commercial marketing would actually begin,’ [Sandoz, 794 F.3d at 1358], and would have to monitor public sources even to find out when FDA approves the Applicant’s aBLA, would have to sprint to court to seek a temporary restraining order just to secure time to seek a preliminary injunction, and would present the court far less than a ‘fully crystallized controversy’ and deprive the court of the ‘defined statutory window’ in which to ‘fairly assess the parties’ rights prior to the launch of the biosimilar product.’”  This would result in chaos, argued Amgen, instead of the ordered, timed process intended by Congress.

Apotex argued that notice is required only where an aBLA applicant fails to provide the reference product sponsor with a copy of its application and manufacturing information under PHS Act § 351(l)(2)(A).  But Amgen said that that’s not what the Federal Circuit said:

[T]he Federal Circuit’s holding [in Sandoz] that “paragraph (l)(8)(A) is mandatory” contains no exception for Applicants who comply with paragraph (l)(2)(A), and in fact the court clearly held that “Paragraph (l)(8)(A) is a standalone notice provision,” and that “nothing in paragraph (l)(8)(A) conditions the notice requirement on paragraph (l)(2)(A) or other provisions of subsection (l).”  Thus, Apotex’s provision of the disclosures called for by paragraph (l)(2)(A) does not drive the outcome here; Apotex must still give notice under paragraph (l)(8)(A) once FDA approves its aBLA.  Amgen is entitled to enforce that obligation, just as the Federal Circuit enforced it against Sandoz in granting an injunction pending appeal under Fed. R. App. P. 8A and then extending that injunction until September 2, 2015, precisely 180 days after Sandoz provided post-FDA-approval notice of commercial marketing under paragraph (l)(8)(A). [(Internal citation omitted)]

In his 9-page Order granting Amgen’s Motion for Preliminary Injunction, Judge Cohn came down squarely on the side of Amgen, rejecting each of the arguments proffered by Apotex:

Apotex would have this Court limit the Sandoz decision, and the mandatory nature of [PHS Act § 351(l)(8)(A)], to instances where the applicant did not comply with [§ 351(l)(2)] and make the notice provision of [§ 351(l)(8)(A)] optional in instances where the applicant did comply with [§ 351(l)(2)].  This scenario was addressed by Judge Chen in his dissent to the Sandoz decision: “While the result in the latter scenario comes from the plain language of the statute, not so with the former.  Nothing in the statute supports this peculiar outcome.”  This Court agrees.  The scenario proposed by Apotex would result in confusion and uncertainty, as well as inconsistent results, depending on which route a subsection (k) applicant chooses to travel.  Nothing in the statute or the Sandoz decision leads to or supports such a result; neither the statute nor the Sandoz decision condition the 180 day notice provision of [§ 351(l)(8)(A)] upon a subsection (k) applicant’s compliance with [§ 351(l)(2)].

As noted above, Apotex immediately appealed Judge Cohn’s decision to the Federal Circuit.  Although Apotex may not have any better luck with that Court than the company had with the Florida District Court, we suspect the endgame here is to try and get the U.S. Supreme Court to take up the issue (if that Court does not take it up in a different appeal, perhaps an appeal of the Sandoz decision, or in one of the other pending cases where Judge Cohn's decision has already been submitted as supplemental authority). 

By Alan M. Kirschenbaum –

If you’re looking for Holiday reading, CMS has a gift for you!

OMB’s Office of Information Regulatory Affairs (OIRA) has completed its review of a long-awaited CMS final regulation implementing significant changes to the Medicaid Drug Rebate Program.  Completion of the review was announced on OIRA’s website here.  It typically takes a lengthy regulation from several days to two weeks after OMB release before it is posted for pre-publication review.

We’ll be posting a notice in the FDA Law Blog when the rule is released, and following its release, we’ll be preparing a memo to summarize it.  We’ll also be conducting a webinar on the rule in collaboration with KPMG’s government pricing group.  The date and other details will be announced on this blog in the near future. 

By Alexander J. Varond –

On December 8, 2015, FDA approved two new therapies: Vonvendi (BLA 125577) for von Willebrand disease and Kanuma (NADA 141-453) for lysosomal acid lipase (LAL) deficiency. These approvals bring the number of new molecular entities and new therapeutic biological products approved this year to 42 (surpassing FDA’s 41 approvals in 2014). With Kanuma’s approval, FDA also issued its 6th rare pediatric disease priority review voucher to Alexion Pharmaceuticals.

The Kanuma pediatric voucher brings the number of vouchers issued since the 1-year sunset clause was triggered in March 2015 to a total of 3. In addition to the uptick in pediatric voucher issuances, the number of companies reporting that they secured rare pediatric disease designation (an optional first step on the path towards a pediatric voucher) has also markedly increased.

Priority Review Vouchers Issued

The two tables below list the vouchers that have been issued to date.

Table 1:         Tropical Disease PRVs

Table 2:         Rare Pediatric Disease PRVs

Despite the tropical disease voucher program’s approximately 7-year existence, it has been utilized much less frequently (3 vouchers/7 years = 0.4 vouchers/year) than the 3‑year old pediatric voucher program (6 vouchers/3 years = 2.0 vouchers/year). Tropical disease vouchers were first available to applications approved in September 2008, and pediatric vouchers were first available to applications submitted after October 2012.

Recently Issued Pediatric Vouchers

A short description of FDA’s three most recent approvals yielding pediatric vouchers is provided below.

Xuriden’s approval is remarkable in that the drug is intended to treat an extraordinarily rare condition, hereditary orotic aciduria. In fact, the rare metabolic disorder has a patient population of approximately 20 patients worldwide! Hereditary orotic aciduria is a rare metabolic disorder associated with blood abnormalities, urinary tract obstruction, failure to thrive, and developmental delays. The drug was evaluated in a single arm, 6-week, open-label trial in 4 patients with hereditary orotic aciduria, ranging in age from 3-19 years old and a 6-month extension trial. The study assessed changes in patients’ prespecified hematologic parameters. FDA also relied on 19 case reports from published literature.

Strensiq’s approval was for perinatal/infantile and juvenile-onset hypophosphatasia (HPP). HPP is a rare, genetic, metabolic disease characterized by defective bone mineralization. Patients also experience devastating progressive effects on multiple systems of the body, leading to severe disability and life-threatening complications, including profound muscle weakness. The most severe form of the disease occurs in newborns at a rate of approximately 1 in 100,000 births. Cases appearing in childhood and adulthood are generally less severe and occur more frequently. Four prospective, open-label studies included 99 patients with infantile- or juvenile-onset HPP on therapy for up to 6.5 years. Efficacy in patients with infantile-onset HPP was supported by improvements in overall survival at 1 year of age, ventilator-free survival at 1 year of age, skeletal manifestations, and growth compared to a natural history cohort. Efficacy in patients with juvenile-onset HPP was supported by favorable results in growth, skeletal manifestations, and gait/mobility compared to a natural history cohort.

Kanuma’s approval was for LAL deficiency, also known as Wolman disease and cholesteryl ester storage disease (CESD). Patients with LAL deficiency suffer from build-up of fats within in cells, leading to cardiovascular and liver disease and other complications. Similar to HPP, LAL deficiency presents both during infancy in a more severe form (as Wolman disease) and in childhood or later in a less severe form (as CESD). CESD is 10-25 times more prevalent than Wolman disease. Efficacy in patients with Wolman disease was supported by a historically controlled trial in 9 infants on significant differences in the survival rates at 12 months of age. Efficacy in patients with CESD was shown in a 20-week double-blind, placebo-controlled trial in 66 pediatric and adult patients on improvements in LDL-cholesterol levels and other disease-related parameters. Patients in the CESD trial were 4-58 years old (71% were less than 19 years old).

By James C. Shehan –

In a citizen petition (Docket No. FDA-2015-P-4529) posted earlier this week, a group of fifteen institutional investors asked FDA to require that all approved prescription drug labeling for biosimilar and interchangeable biological products follow the “same labeling” approach that the agency applied to Sandoz's Zarxio and to hold a Part 15 public hearing on this issue as well as any other related issues being debated by the FDA and connected to biosimilars.

The investors want FDA to make two decisions about the labeling of biosimilar and interchangeable products: 1. That the label not contain information about the clinical trials conducted by the biosimilar sponsor; and 2. That the label not indicate that the product was approved under the biosimilar pathway. The investors note that an AbbVie citizen petition (Docket No. FDA-2015-P-2000) from this summer (see our post here) requested FDA to take the opposite actions. Repeating arguments made by others, the investors assert that the information that AbbVie wants in the label is available elsewhere from a “multitude of other sources including the Purple Book, FDA’s own documents regarding licensure of the product, and published peer-reviewed literature. The investors also argue that European experience with biosimilars demonstrates that “same labeling” is not incompatible with patient safety.

The stated motivation for the requested labeling actions is that biosimilars are “an attractive investment opportunity” and a safe alternative to specialty drugs “whose cost threatens the financial sustainability of the markets” in which the investors operate. The investors are concerned that labeling issues may hinder biosimilar growth in the marketplace, that “[p]olicies that … hamper the introduction or wide acceptance of biosimilars” will discourage the development of biosimilars, and that consequently investors such as themselves will lose out on the investment opportunity of biosimilars.

The investors want the requested hearing to cover three topics: 1. The implications of labeling rules for biosimilar innovation and investment in the U.S.; 2. The European experience with biosimilars, including "same labeling," "patient tracking," and patient safety; and 3. Stakeholder views on how different approaches to labeling may affect prescribing, dispensing, and patient use of biosimilars and interchangeable biologic products. They suggest that prescribers, dispensers, patients and investors should be invited to attend, and that the European experience with biosimilars be reviewed in detail.

The investors state that “to date there has not been an opportunity” for the kind of discourse offered by the suggested hearing. FDA did hold a hearing in May 2012 (transcript here) that covered existing biosimilar draft guidances and a whole host of issues regarding BPCIA implementation. But perhaps the agency will be open to another hearing, given the ever-expanding roster of parties interested in biosimilar issues.