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.

By Riëtte van Laack –

Although it has taken some time, the Food Safety and Inspection Service (FSIS) of the USDA published a final rule establishing a mandatory inspection program for “catfish (“fish of the order Siluriformes and products derived from these fish.”) This rule implements provisions of the 2008 and 2014 Farm Bills, which amended the Federal Meat Inspection Act (FMIA) to define “catfish” as an “amenable species” making is subject to mandatory continuous inspection by FSIS.

For those who may be confused about how FSIS came to have jurisdiction over “catfish” while FDA retains jurisdiction over other fish, here is a brief history. In 2008, the Farm Bill included a provision amending the FMIA, to give FSIS jurisdiction over “catfish as defined by [FSIS].” In 2011, FSIS issued a proposed rule regarding inspections, but postponed making a decision on defining catfish.

Under the FDC Act, the term “catfish” may only be used for fish classified within the family Ictaluridae (a provision added by the 2002 Farm Bill). However, if FSIS were to use that definition, the rule would not apply to certain fish imported from Vietnam, which, although not “catfish” as defined by the FDC Act, apparently are often marketed as such. Three years later, the Farm Bill of 2014 resolved any uncertainty and amended the FMIA to replace “catfish as defined by [FSIS]” with all “fish of the order Siluriformes.” On Thanksgiving eve, FSIS announced the final rule.

Fish of the order Siluriformes from families other than Ictaluridae, which are subject to this rule, must be labeled with an appropriate common or usual name other than catfish (which remains reserved for fish from the family Ictaluridae). However, for purposes of this blog post, we use the term “catfish” for all fish of the order Siluriformes.

Once the final rule takes effect, domestic and imported “catfish” will be subject to FSIS jurisdiction. As a result, “catfish” slaughter will be subject to continuous inspection. Labels for “catfish” and “catfish” products will be subject to FSIS pre-market approval and FSIS labeling requirements (which are similar but not identical to FDA requirements). Ingredients used in “catfish” products must not only be safe, but they also must be “suitable.” Notably, ingredients may not be used unless authorized by FSIS regulations or included in the agency’s list of safe and suitable ingredients. Furthermore, only “catfish” from countries that FSIS has determined have an inspection system equivalent to the U.S. system may be exported to the United States. Moreover, all imported “catfish” will be subject to reinspection by FSIS.

The effective date of the final rule is March 1, 2016. From that date forward, all “catfish” will be subject to FSIS jurisdiction. However, the date of full enforcement is September 1, 2017. During the 18-month “transition” time, FSIS will provide guidance to the industry, start continuous inspection at “catfish” slaughter establishments and inspect “catfish” processing facilities at least once every quarter. Also, countries that wish to continue exporting “catfish” to the United States must submit their application for an equivalency determination during this 18-month period. Provided the application has been submitted, a country may continue to export fish products to the United States until FSIS determines that the exporting country’s inspection system is not equivalent to the U.S. system.

The legislative amendments transferring jurisdiction of “catfish” products to FSIS purportedly were intended to ensure their safety. However, the Government Accountability Office has repeatedly stated that the transfer of jurisdiction over catfish to FSIS and the creation of a catfish inspections office in the USDA is one of the government’s most wasteful and duplicative programs, and recommended against it.  Also, opponents of assigning “catfish” to FSIS have asserted that this action is essentially a trade barrier, and appear prepared to challenge it before the WTO. Thus, the government could find itself having to defend the action on public health grounds, while presumably continuing to stand behind the adequacy of FDA’s seafood program as it applies to fish other than “catfish.” Stay tuned for further developments.  

By Jay W. Cormier –

On December 8, 2015, FDA issued a complex set of approvals for a unique product, Kanuma (sebelipase alfa).  Kanuma is indicated for the treatment of a rare disease known as lysosomal acid lipase (LAL) deficiency.  The list of distinguishing descriptors for the Kanuma application is lengthy:  Kanuma received orphan product designation, received breakthrough therapy designation, was given priority review, and was granted a rare pediatric disease priority review voucher.

There is a lot to discuss about the Kanuma approval, and we will try to keep it high-level in the interest of our readers’ time. . .

Approval of Genetically Engineered Chickens

Kanuma is a biologic that is manufactured by chickens that express the biological product in its egg whites.  Along with the Kanuma BLA approval, then, FDA’s Center for Veterinary Medicine also issued a new animal drug approval for the chickens that have been genetically engineered to produce the human protein in their eggs. 

The “Kanuma Chickens” represent the third genetically engineered animal that FDA has approved via its new animal drug authorities.  The first such approval was for a goat that produces a human biologic in its milk, which was approved in 2009 (see our post on the Atryn Goats here).  The second was the genetically engineered AquAdvantage Salmon, which FDA approved last month for use as a food-producing animal (see our post on the salmon approval here).  The Kanuma Chickens are the second CVM approval for an animal engineered to produce a pharmaceutical product, and the first approval of a genetically engineered chicken.

We note that although in 2014 FDA approved a biological product produced in genetically engineered rabbits (here), FDA did not issue a new animal drug approval for the animals.  We assume that no animal approval was issued because the rabbits are neither produced nor housed in the United States (we note that this was the company’s argument to FDA regarding why it need not seek an animal drug approval for the rabbits – see here). 

Priority Review Voucher

As we have analyzed previously (here), the value of a priority review voucher to a company fortunate enough to have one is escalating quickly.  This represents the sixth such voucher granted by FDA, and the going price for the fourth voucher was $350 million. 

Another interesting issue is that FDA granted the pediatric rare disease priority review voucher for a product that is intended to treat a rare disease, but one that affects both pediatric and adult populations, and one where the data supporting approval included studies in the adult population.  Whether this is a one-off case or represents a loosening of how FDA limits the scope of what diseases are deemed to be “pediatric rare diseases” is yet to be seen.

Use of Historical Controls

As we have discussed with our readers previously (here), FDA’s views regarding the use and validity of historical controls has changed over time and is currently an area of increasing focus within FDA.  One conclusion of recent FDA actions has been that FDA is moving away from accepting historical controls for registration, Phase 3, studies.  But, the Kanuma approval relied heavily on historical controls for its pediatric indication.  Before drawing too many conclusions about historical controls writ large, in the case of the pediatric form of LAL deficiency, pediatric cases almost always resulted in death by 24 months of age, whereas treated subjects survived.  With that clear of a difference, the data is pretty compelling no matter your view on the validity of historical controls.

By Kurt R. Karst –      

Earlier this week, Public Citizen announced the release of a report, titled “House Orphan Drug Proposal: A Windfall for Pharma, False ‘Cure’ for Patients,” that takes aim at a particular provision in the 21st Century Cures Act (H.R. 6) that the U.S. House of Representatives passed in July 2015.  The report comes out at a time when the debate over drug pricing in Congress has reached fever pitch, and shortly after the publication of an article in the American Journal of Clinical Oncology alleging that companies are exploiting the Orphan Drug Act, which President Ronald Reagan signed into law on January 4, 1983 (and that some have referred to as one of the most successful pieces of FDA legislation in the history of food and drug law).  

Section 2151 of the Cures Act, titled “Extension of Exclusivity Periods For A Drug Approved For A New Indication For A Rare Disease Or Condition,” but known more popularly as the “Orphan Product Extensions Now Act,” or “OPEN Act,” would amend the FDC Act to provide a 6-month extension of exclusivity periods – what we’ve referred to as “exclusivity stacking” – for a drug approved for a new indication for a rare disease or condition (i.e., so-called “repurposed” drugs).  The OPEN Act is intended to increase the number of rare disease therapies and to address off-label reimbursement problems faced by rare disease patients.  We previously discussed the OPEN Act in posts here and here.

According to Public Citizen, “the current orphan drug approval system is hardly in need of a stimulus, as companies are pursuing, and achieving, orphan drug approvals at record rates.”  Moreover, says Public Citizen, the OPEN Act “is emblematic of the false hope offered more broadly by the 21st Century Cures legislation.”  Specifically, the OPEN Act would, according to Pubic Citizen:

result in higher drug prices for both orphan and non-orphan diseases: Conservatively, the provision would cost the public close to $4 billion, but given the structure of the financial incentive, the cost could easily approach $12 billion.  The new incentive would further distort existing incentives by encouraging pharmaceutical companies to spend money repurposing old drugs, rather than investing in truly innovative new drug development.  And it encourages more investment in a flawed system that effectively lowers FDA standards for approval and allows for considerable abuse.  Worst of all, the costs of the new incentive would fall not only on taxpayers but also on the backs of patients with common, non-orphan diseases, who will be denied potentially life-saving, affordable generic medicines for six additional months.

Just last month, several folks from the Johns Hopkins University School of Medicine penned a piece for the American Journal of Clinical Oncology, titled “The Orphan Drug Act: Restoring the Mission to Rare Diseases,” alleging that companies are “gaming” the orphan drug system established by the Orphan Drug Act “to use the law for mainstream drugs.”  According to the authors, although the Orphan Drug Act has been successful in getting therapies approved for otherwise overlooked populations, “evidence demonstrated that the [Orphan Drug Act] is often abused.”  The authors point to drugs and biologics approved for a rare disease, but that are used more broadly (for prevalent conditions and diseases) as evidence of this alleged abuse.  (We’ve seen these and other criticisms of the Orphan Drug Act before, which led to the introduction of legislation that was not ultimately enacted – see, e.g., here.) 

In the end, the authors of the article say that the Orphan Drug Act needs to be reformed . . . and they make some suggestions: “(1) increased submission scrutiny to ensure that benefits are allocated to drugs truly intended to treat orphan disease; (2) stratified benefit systems; (3) decreased exclusivity periods when benchmark profits are achieved; (4) decrease benefits to drugs that reach a much larger target populations [sic]; and (5) increased price transparency.” 

So it seems that orphan drugs are under attack from both ends of the spectrum: on the one hand, drugs approved for prevalent uses repurposed for rare conditions, and, on the other hand, approved orphan drugs repurposed for prevalent conditions.   

By Josephine M. Torrente & Etan J. Yeshua –

In September, FDA proposed a significant limitation on the way drug sponsors can appeal FDA decisions, and yesterday Hyman, Phelps & McNamara, P.C. (HP&M) formally requested that the Agency reverse course. In a draft guidance document issued in September, FDA stated that advice from review divisions to drug sponsors as formalized in meeting minutes and in advice letters would no longer be appealable to officials above the review division. Until now, the Agency routinely accepted requests for such appeals through its “formal dispute resolution” (FDR) procedures.

Requests for formal dispute resolution – which involve critical drug development issues ranging from Phase 3 study endpoint selection, to the need for carcinogenicity studies, to the adequacy of impurity characterization – make it possible for a sponsor to ensure that advice it receives from a review division (particularly advice with which the sponsor disagrees) has been vetted and approved by senior officials at the Agency. But FDA’s proposed new practice (as demonstrated by one example in the comment we submitted yesterday) would require that a review division repeat the same advice no fewer than five times over multiple years before that advice would be appealable. This is an untenable position for the Agency to take.

As we stated in our comment to the draft guidance document:

[O]ur firm has drafted dozens of FDR requests for clients and has also advised numerous other clients that pursuing FDR was not advisable based on the facts or circumstances of their cases . . . [A] failure to resolve such disputes efficiently and effectively has the palpable potential to hinder the availability of promising drugs and biologics and, ultimately, public access to them – sometimes for many years and sometimes forever.

Just last week, the Agency stated in a separate draft guidance document that, “It is critical to efficient drug development for sponsors to ascertain FDA’s views on the applicable statutory and evidentiary requirements well in advance of submission of an application.” We couldn’t agree more: timely use of the dispute resolution process can give a sponsor confidence that a review division’s advice is “FDA’s view” and is not merely an initial determination liable to be overturned later in the development process.

However, unless the Agency reverses its new position on the reviewability of a division’s advice, a sponsor who questions or disagrees with the scientific or regulatory feedback it receives from a review division would be faced with two risky and untenable options: either stake its development plan on the division’s controversial advice, or reject the division’s advice and pursue the path that the sponsor believes is scientifically and legally warranted. In either case, the sponsor would be taking on significant and preventable risk. Rather than allowing scientific and regulatory disputes to be appealed in a timely manner, the new FDA practice would require the sponsor to wait until FDA rejects or refuses to file the IND, NDA, or BLA in order to determine that the division’s advice had been vetted and approved by more senior officials at the Agency. By then, much may have been wasted: large numbers of patients participated in unnecessary placebo-controlled trials; years of patent life on the product were lost; and millions of dollars were spent on trials that could have been avoided had the dispute resolution process been available earlier.

To prevent wasted efforts by patients, investigators, sponsors, and the Agency itself, HP&M’s comment, which you can read here, requests that FDA revise its guidance document and continue its long-standing practice of accepting requests for formal dispute resolution when the dispute arises. We hope the Agency will do so.

By Riëtte van Laack –

On December 4, 2015, the California Office of Environmental Health Hazard Assessment (OEHHA) added Aloe vera, non-decolorized whole leaf extract and Goldenseal root powder to the list of “chemicals known to the State of California to cause cancer for purposes of the Safe Drinking Water and Toxic Enforcement Act of 1986” commonly known as the Proposition 65 (or Prop. 65) list. On the same day, OEHHA published a document with its responses to the comments.

OEHHA’s responses clarify various aspects. The basis for the addition of these substances to the Prop. 65 list is their identification as “possibly carcinogenic to humans” with sufficient evidence of carcinogenicity in experimental animals by the International Agency for Research on Cancer (IARC). OEHAA claims, that as a result, the science is not open for discussion; OEHHA must add these substances to the Prop. 65 list. The listing of these chemicals is not “route-specific,” i.e., it applies to all routes of exposure including oral ingestion and topical application. The original notice of intent to list the aloe vera did not include the qualification that only non-decolorized whole leaf extract is a potential carcinogen.

Businesses now have 12 months to either reformulate their products or provide a “clear and reasonable” warning before knowingly and intentionally exposing anyone to these substances. If the past is any indication, plaintiff attorneys will be ready with notices of violation when the 12 month period expires.