In recent years, the level of scrutiny on foreign pharmaceutical manufacturing facilities in countries like China and India has skyrocketed—along with the demand and dependence of western countries on the supply of goods coming from those facilities. With the international pharmaceutical supply chain imperiled like never before, what can drug manufacturers do to protect themselves?

This free webinar, presented by Dechert LLP and Hyman, Phelps & McNamara P.C., will discuss recent pharmaceutical supply chain developments and what steps companies need to take to prevent and remediate compliance issues in the context of:

• The uptick in investigations in China and India.
• The potential impact of adverse regulatory actions against nonconforming facilities.
• Threats Posed by Bribery and Corruption.
• Anti-corruption compliance issues from U.S. and Asian perspectives.
• “War stories” from recent investigations.

When

Wednesday, June 22, 2016
12:00 p.m. – 1:00 p.m. ET

Where

This presentation will be simulcast via Webex as a webinar.  Please click here to register. 

Speakers

Douglas B. Farquhar
Director
Hyman, Phelps & McNamara PC
Washington, D.C.

Mark I. Schwartz
Of Counsel
Hyman, Phelps & McNamara PC
Washington, D.C.

Jeremy B. Zucker
Partner
Dechert LLP
Washington, D.C.

Lewis Ho
Partner
Dechert LLP
Hong Kong

Kareena Teh
Partner
Dechert LLP
Hong Kong

Application for accreditation of this program for Continuing Legal Education (CLE) in California, Massachusetts, New Jersey, and New York is currently pending.

For questions, please contact Reiko Tate (reiko.tate@dechert.com).

By Allyson B. Mullen –

On June 10, FDA issued the draft guidance, “Dissemination of Patient-Specific Information from Devices by Device Manufacturers.”  At a mere six pages long, this guidance is not tipping the scales by any means, but its few short pages contain some important information for device manufacturers interested in providing patient-specific information from devices.

The draft guidance notes that patients are becoming more involved in their health. Accordingly, patients are seeking to obtain information “recorded, stored, processed, retrieved, and/or derived from a medical device.”  The draft guidance defines such patient-specific information as:

any information unique to an individual patient or unique to that patient’s treatment or diagnosis that, consistent with the intended use of a medical device, may be recorded, stored, processed, retrieved, and/or derived from that medical device. This information may include, but is not limited to, recorded patient data, device usage/output statistics, healthcare provider inputs, incidence of alarms, and/or records of device malfunctions or failures. This information does not include any interpretations of data aside from those interpretations of data normally reported by the device to the patient or the patient’s healthcare provider. Generally, categories for patient-specific information may include, but are not limited to: (1) data a healthcare provider inputs to record the status and ongoing treatment of an individual patient or (2) information stored by the device to record usage, alarms, or outputs (e.g., pulse oximetry data, heart electrical activity, and rhythms as monitored by a pacemaker). Patient specific case logs entered into a medical device by a healthcare provider may be included under this definition.

The draft guidance indicates that FDA will consider reports of patient-specific information as labeling, which must comply with the FDC Act. If a device manufacturer intends to begin providing reports of patient-specific information, according to the draft guidance, it may do so “without obtaining additional premarket review.”  We find this point interesting for various reasons, including that it is made without any distinction for the device’s classification.  According to the draft guidance, no additional premarket review is required even if the device recording, storing, processing, retrieving, and/or deriving the patient-specific information is a class III device.

The draft guidance provides some broad considerations for device manufacturers planning to report patient-specific information:

• Provide adequate content to ensure the information presented is interpretable and useful to the patient;
• Consider providing supplementary instructions, materials or references to aid patient understanding of the data;
• Provide comprehensive and contemporary information, including all reasonably available patient-specific information;
• Provide relevant context, including for example, how a parameter was measured and recorded; and
• Indicate whom to contact with questions regarding the data (e.g., the patient’s healthcare provider for questions about the data and/or the device manufacturer for questions about the device).

These considerations appear relatively straight forward and based on common sense to us, but FDA felt they were worth putting in a draft guidance. If FDA were to regulate laboratory developed tests, then this new guidance, if adopted, could affect the way in which labs generate reports to patients.

By Riëtte van Laack –

On May 31, 2016, the Food Safety Coalition submitted a Petition to the Food Safety Inspection Service (FSIS) to amend regulations requiring safe food handling instructions (SHI) on certain meat and poultry products.

The Federal Meat Inspection Act (FMIA) and the Poultry Products Inspection Act (PPIA) authorize FSIS to mandate that meat and poultry products bear label information “to assure that . . . the public will be informed of the manner of handling required to maintain the article in a wholesome condition.” Pursuant to this authority, the FSIS has issued regulations, 9 C.F.R. §§ 381.125; 317.2(l), specifying a safe handling statement or instruction that alerts consumers that raw and partially cooked meat may contain pathogens, and detailing what are considered safe food handling practices – at least as of 1994. These regulations mandate that the label for raw and partially cooked meat and poultry include the following statements:

“This product was prepared from inspected and passed meat and/or poultry. Some food products may contain bacteria that could cause illness if the product is mishandled or cooked improperly. For your protection, follow these safe handling instructions.”

“Keep refrigerated or frozen. Thaw in refrigerator or microwave.” (Any portion of this statement that is in conflict with the product's specific handling instructions may be omitted, and a graphic illustration of a refrigerator must be displayed next to the statement.);

“Keep raw meat and poultry separate from other foods. Wash working surfaces (including cutting boards), utensils, and hands after touching raw meat or poultry.” (A graphic illustration of soapy hands under a faucet must be displayed next to the statement.);

“Cook thoroughly.” (A graphic illustration of a skillet must be displayed next to the statement.); and

“Keep hot foods hot. Refrigerate leftovers immediately or discard.” (A graphic illustration of a thermometer must be displayed next to the statement.)

For example:

According to Petitioners, there is much evidence that these safe handling instructions are no longer sufficient.

Petitioners ask that FSIS revise the regulations to include:

• An end-point temperature for raw and partially cooked product categories as well as any “rest time” requirement;
• Instructions to use a thermometer to verify that the product has reached the recommended internal temperature;
• Information on safe handling practices to minimize risks associated with improper sanitation, handling, storage, and temperature control for meat, poultry and catfish products;
• Include the four “check your steps” (clean, cook, separate and chill) safe food handling graphics instead of the graphics currently displayed; and
• A web address for additional information on cooking recommendations.

In addition to revising the contents of the SHI, Petitioners ask that FSIS revise the regulation to mandate the use of “easily legible type located away from curved or seamed areas of packages” and use of “Use bold or large font for end-point temperatures and ‘rest time’ instructions.”

Petitioners contend that FSIS is aware of the need to revise the SHI and in fact has performed consumer studies as to consumers’ understanding of certain label statements. FSIS has recently initiated a second round of consumer perception studies. However, the Petitioners do not want FSIS to further delay revisions and ask that FSIS proceed with rulemaking now.

In addition to revising the SHI for meat and poultry, Petitioners request that FSIS issue a new regulation mandating a SHI statement for catfish. The latter request presumes that catfish will remain under FSIS inspection instead of reverting back to FDA inspection.

By Riëtte van Laack

As we reported previously, in 2013, Health Science Funding, LLC (HSF) filed what might be the first medical food lawsuit against FDA.  Plaintiff markets a medical food for women with lupus, Prastera® DHEA.  Medical foods may be marketed without pre-market approval by FDA.  In fact, as HSF learned, FDA will not approve or review the label for a medical food or any other food before marketing, even if the company requests that FDA do so.

In 2013, seemingly unwilling to live with the uncertainty as to whether FDA would disagree with HSF’s determination that Prastera qualifies as medical food under the Orphan Drug Act Amendments of 1988, 21 U.S.C. §360ee(b)(3), HSF filed a complaint asking that the Court declare that Prastera is a medical food and enjoin FDA from taking action against Prastera in the future.  The Court did not seize the “opportunity to create a legacy” provided by HSF’s lawsuit and, in November 2013, after various communications with the parties dismissed the case without prejudice.

HSF apparently concluded that the Court closed the case because FDA had agreed to let the company market its medical food and to refrain from any enforcement action in exchange for HSF’s stay of its request for Declaratory Judgment.  FDA inspected the firm 1.5 years later, and, apparently, threatened seizure.  HSF believed that was inconsistent with this “agreement.” 

After several failed attempts to get FDA to commit to refrain from taking enforcement action, HSF again went to Court.  HSF filed a new complaint, again requesting that the Court issue a declaratory judgment and enjoin FDA from taking enforcement action. 

The Court granted FDA’s motion to dismiss. This time, the Court issued an opinion which clarifies that the case was premature.  As FDA had not taken any final agency action, HSF’s claims were not ripe.  The court found that FDA had only informally advised HSF that Prastera does not appear to meet the requirements for a medical food.  FDA had “not enforced, nor made any attempt to enforce [the Federal Food, Drug, and Cosmetic Act] against Plaintiff or its product[].”  Thus, there was no agency action, let alone final agency action, for the Court to review.  For similar reasons, the Court determined that HSF had no standing to bring a claim for injunctive relief. 

Because the Court concluded that it has no jurisdiction, it did not need to address the other issues FDA raised in its motion to dismiss, such as what constitutes a medical food and whether FDA’s interpretation of the medical food definition is valid.  Like any other company, HSF has to live with the uncertainty as to whether FDA will determine that its product does qualify as a medical food and, if not, whether and when the Agency will decide to take an enforcement action against the product. 

FDA is no friend to the medical food category, and this case further illustrates the marketing uncertainty surrounding virtually all medical foods.  FDA’s issuance of recent final guidance, that is in conflict with the broad statutory definition of medical foods has negatively impacted the future of this market category.  Nevertheless, regulatory risk for most medical foods, while unavoidable, can be effectively managed.  However, asking FDA for approval or suing the Agency is not part of such strategy.

by Jennifer Newberger - 

Since September 1995, FDA and CMS have operated under an interagency agreement (IA) regarding Medicare coverage for investigational devices.  That same month, CMS also published a rule that permitted Medicare coverage of certain devices with an approved investigational device exemption (IDE) in place.  The rule established the process by which FDA would assist CMS in determining which investigational devices should be covered under Medicare.  The process was based on placing devices into one of two categories:  Category A, for “Experimental/ Investigational” devices, or Category B, “Non-experimental/Investigational” devices.  Categorization depends upon the level of risk associated with the device.  Category B devices present a lower level of risk, based on information available at the time of the categorization demonstrating that an initial level of safety and effectiveness has already been established.  See   42 C.F.R. § 405.201 et seq.

Under the regulation and the IA, CMS uses FDA’s categorization to determine whether an investigational device may receive coverage under Medicare.  For Category B devices, Medicare may cover both the device and “routine care items and services.”  For Category A devices, however, CMS only reimburses the routine care items and services, but not the device itself. 

In 2013, CMS revised the definitions for Category A and B devices as follows:

• A Category A device is “a device for which ‘absolute risk’ of the device type has not been established (that is, initial questions of safety and effectiveness have not been resolved) and the FDA is unsure whether the device type can be safe and effective.”

• A Category B device is “a device for which the incremental risk is the primary risk in question (that is, initial questions of safety and effectiveness of that device type have been resolved), or it is known that the device type can be safe and effective because, for example, other manufacturers have obtained FDA premarket approval or clearance for that device type.”

Over time, it became apparent that not all devices necessarily fit into either Category A or Category B.  This was especially true for the following types of devices:

• Devices that had been studied in early feasibility studies, but had undergone modifications that raised significant new safety questions.

• Devices for which additional data became available since the original categorization of the device indicating that certain safety issues had been resolved.

Due to changes made to the original iteration of the device, it may have been appropriate to change the initial categorization of the device.  Unfortunately, neither the rule nor the IA provided FDA with the authority to change the categorization of a device once made. 

To address these issues regarding categorization, FDA and CMS entered into a Memorandum of Understanding (MOU) dated December 2, 2015.  On June 1, 2016, one day before the MOU was to go into effect, FDA issued a draft guidance document to implement the MOU.  Upon finalization, the “policies and framework in this guidance will represent the Agency’s current thinking on categorization.”

The draft guidance states that FDA will place a device in Category A if one or more of the following criteria are met:

• No PMA approval, 510(k) clearance or de novo request has been granted for the proposed device or similar devices, and non-clinical and/or clinical data on the proposed device do not resolve initial questions of safety and effectiveness.

• The proposed device has different characteristics compared to a legally marketed device; and information related to the marketed devices does not resolve initial questions of safety and effectiveness for the proposed device. Available non-clinical and/or clinical data on the proposed device also do not resolve these questions.

• The proposed device is being studied for a new indication or new intended use for which information from the proposed or similar device related to the previous indication does not resolve initial questions of safety and effectiveness. Available non-clinical and/or clinical data on the proposed device relative to the new indication or intended use also do not resolve these questions.

Category B devices are those for which one or more of the following criteria are met:

• No PMA approval, 510(k) clearance or de novo request has been granted for the proposed device or similar devices; however, available clinical data (e.g., feasibility study data) and/or non-clinical data for the proposed device or a similar device resolve the initial questions of safety and effectiveness.

• The proposed device has similar characteristics compared to a legally marketed device, and information related to the marketed device resolves the initial questions of safety and effectiveness for the proposed device. Additional non-clinical and/or clinical data on the proposed device may have been used in conjunction with the leveraged information to resolve these questions.

• The proposed device is being studied for a new indication or new intended use; however, information from the proposed or similar device related to the previously indication resolves the initial questions of safety and effectiveness. Additional non-clinical and/or clinical data on the proposed device may have been used in conjunction with the leveraged information to resolve these questions. 

The descriptions of the category A and B devices will allow FDA to take into consideration developments regarding the device that occurred subsequent to the initial categorization, and to change categories if needed.  The sponsor of a device should include a request to change the category as an IDE supplement.  FDA will include a categorization decision in either the IDE approval letter to the sponsor or a letter to the sponsor in response to a request for category change.  

By Kurt R. Karst – 

It was just last week when one orphan drug exclusivity labeling carve-out case (presumptively) came to an end when the U.S. Court of Appeals for the District of Columbia Circuit ruled for FDA in the context of a generic version of  FUSILEV (levoleucovorin) for Injection (see our previous post here).  Little did we know, however, that just a few days prior to that June 3, 2016 D.C. Circuit decision AstraZeneca Pharmaceuticals LP (“AstraZeneca”) submitted a Citizen Petition (Docket No. FDA-2016-P-1485) to FDA (dated May 31, 2016) raising yet another orphan drug exclusivity labeling carve-out issue.  The petition immediately reminded us of that famous quote from Don Michael Corleone in The Godfather: Part 3 – “Just when I thought I was out, they pull me back in" – where the “I” is “FDA” and the “they” is “AstraZeneca.”

AstraZeneca’s petition was posted on regulations.gov earlier this week and concerns FDA approval of ANDAs and 505(b)(2) applications for generic and “follow-on” versions of the company’s blockbuster drug CRESTOR (rosuvastatin calcium) Tablets, 5 mg, 10 mg, 20 mg, and 40 mg, which FDA approved on August 12, 2003 under NDA 021366.  The petition stems from FDA’s May 27, 2016 approval of Supplement 033 to CRESTOR NDA 021366 adding a new indication: “for treatment of pediatric patients 7 to 17 years of age with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, total C, nonHDL-C and ApoB as an adjunct to diet, either alone or with other lipid-lowering treatments.”  AstraZeneca will presumably be granted a period of orphan drug exclusivity for this use until May 2023 based on an earlier orphan drug designation for the drug for pediatric HoFH. 

According to AstraZeneca:

First, carving out AstraZeneca’s protected pediatric HoFH labeling from the labeling of a product marketed under an ANDA or section 505(b)(2) NDA would present substantial safety and efficacy risks.  Although FDA may in some instances approve ANDAs that omit protected pediatric labeling, FDA has made clear that a carve out is inappropriate when, as here, the protected pediatric labeling is “necessary for the safe use of the drug.”  Crestor® is labeled for treatment of HoFH in adult and pediatric patients, and for treatment of heterozygous familial hypercholesterolemia (“HeFH”), a related but far less severe condition.  In many instances, the recommended dosage and course of treatment differ between adult HoFH and pediatric HoFH patients, and likewise between HeFH and HoFH patients.  Given these differences, there are substantial risks that doctors would over- or under-treat pediatric HoFH patients if generic or other rosuvastatin calcium omitted AstraZeneca’s protected pediatric HoFH labeling.

Second, irrespective of whether a carve out would present a safety risk, FDA lacks legal authority to carve out pediatric labeling protected by orphan drug exclusivity.  Together, the Hatch-Waxman Act’s same-labeling requirement and FDA’s pediatric-labeling regulations impose a categorical rule: pediatric labeling information subject to orphan drug exclusivity may not be omitted from generic-drug labeling.  The Best Pharmaceuticals for Children Act, 21 U.S.C. § 505A(o), permits the carve out of labeling protected only by patent and Hatch-Waxman exclusivity—and therefore provides no basis for carving out labeling protected by orphan drug exclusivity.  FDA also possesses several other “general” carve-out authorities, see 21 C.F.R. §§ 314.94(a)(8)(iv), 314.127(a)(7), but those authorities are inapposite in light of FDA’s subsequently adopted pediatric-labeling rules and Congress’s enactment of section 505A(o).  Indeed, prior to the passage of section 505A(o), FDA concluded that it lacked authority to carve out protected pediatric labeling in circumstances nearly identical to those presented here.  FDA and the United States District Court for the District of Maryland concluded in the Otsuka litigation that FDA has authority to carve out pediatric labeling protected by orphan drug exclusivity.  However, that conclusion is incorrect for the reasons given above and in Part II.B of this Citizen Petition.

As noted above, AstraZeneca’s petition once again raises our old friend FDC Act § 505A(o).  That provision, titled “Prompt approval of drugs under section 355(j) when pediatric information is added to labeling,” and also known as the “Anti-Glucophage  Provision” (or Section 11 of the Best Pharmaceuticals for Children Act) states:

(1) General rule – A drug for which an application has been submitted or approved under section 355(j) of this title shall not be considered ineligible for approval under that section or misbranded under section 352 of this title on the basis that the labeling of the drug omits a pediatric indication or any other aspect of labeling pertaining to pediatric use when the omitted indication or other aspect is protected by patent or by exclusivity under clause (iii) or (iv) of section 355(j)(5)(F) of this title.

(2) Labeling – Notwithstanding clauses (iii) and (iv) of section 355(j)(5)(F) of this title [(concerning 3-year new clinical investigation exclusivity)], the Secretary may require that the labeling of a drug approved under section 355(j) of this title that omits a pediatric indication or other aspect of labeling as described in paragraph (1) include—

(A) a statement that, because of marketing exclusivity for a manufacturer—

(i) the drug is not labeled for pediatric use; or

(ii) in the case of a drug for which there is an additional pediatric use not referred to in paragraph (1), the drug is not labeled for the pediatric use under paragraph (1); and

(B) a statement of any appropriate pediatric contraindications, warnings, or precautions that the Secretary considers necessary.

FDC Act § 505A(o) was front and center in an April 2015 FDA Letter Decision concerning approval of ANDAs for generic versions Otsuka Pharmaceutical Co.’s (“Otsuka’s”) ABILIFY (aripiprazole) with labeling that omitted information concerning pediatric patients and protected by orphan drug exclusivity.  And, as noted above, that FDA Letter Decision led to litigation and a May 2015 decision in favor of FDA (which supported a labeling carve-out by generics) by the U.S. District Court for the District of Maryland (see our previous posts here and here).

In the petition, AstraZeneca first asserts that the carve-out situation presented as a result of the recent approval of Supplement 033 for pediatric HoFH meets a three-part policy FDA laid out in the Agency’s April 2015 ABILIFY Letter Decision:

FDA has adopted a safety and efficacy policy (the “Policy”) that squarely applies to AstraZeneca’s protected pediatric HoFH labeling.  Under the Policy, a generic drug is “misbranded” and “will not [be] approve[d]” where

1. the reference-listed drug “is approved in adults and pediatric patients for the same indication”;
2. “the pediatric information is protected by exclusivity and is significantly different from the information regarding use in adults for the same indication”; and
3. “a carve-out of [the] pediatric information while the adult information is retained in the ANDA labeling may result in a potential safety risk to pediatric patients.”

Astra Zeneca argues that each criterion above is met in the case of CRESTOR.  “Unlike Abilify, Crestor® meets all three of the Policy’s criteria and is therefore entitled to de facto exclusivity for the duration of AstraZeneca’s seven-year period of orphan drug exclusivity,” says AstraZeneca.

And regardless of whether or not the “Policy” applies here, says AstraZeneca, FDA may not carve out orphan drug exclusivity-protected pediatric HoFH information from ANDA and 505(b)(2) labeling because the Agency lacks the authority to do so, despite what the District of Maryland ruled in Otsuka, which is “incorrect and should be overturned.”

[N]one of FDA’s carve-out authorities applies to pediatric labeling protected by orphan drug exclusivity, regardless of a factual inquiry into whether the omitted labeling raises a safety issue. . . .

[First, ] FDA’s pediatric-labeling regulations mandate that dosing, specific indications, and safety data pertaining to pediatric uses “must appear in all prescription drug labeling.”  21 C.F.R. §§ 201.57(a), (a)(6)–(7), (a)(13), (c)(2)(i)(B), (c)(3)(i)(H) . . . .   These FDA pediatric-labeling regulations create a barrier to approval of a generic drug when (i) the reference-listed drug is approved for one or more pediatric indications and (ii) at least one of those pediatric indications is protected by patent, Hatch-Waxman, or some other form of exclusivity. . . .

[Second,] [b]ecause section 505A(o) does not address other forms of exclusivity—including exclusivity afforded by the Orphan Drug Act, 21 U.S.C. § 360cc(a)—the barrier to generic-drug approvals presented in the Glucophage precedent remains with respect to orphan drug exclusivity.

[Third,] [FDA’s] general carve-out regulations [(i.e., 21 C.F.R. §§ 314.94(a)(8)(iv), 314.127(a)(7))]  do not fill the void left by section 505A(o) for at least five reasons [detailed later in the petition].

AstraZeneca, which pushed FDA to quickly approve Supplement 033, wants FDA to act promptly on the company’s petition.  Why?  July 8, 2016 is the date that pediatric exclusivity applicable to U.S. Patent No. RE 37,314 listed in the Orange Book for CRESTOR expires, and when FDA is expected to approve multiple and currently tentatively approved ANDAs for generic CRESTOR.  FDA already approved one ANDA – Watson Laboratories, Inc.’s (“Watson’s”) ANDA 079167; approved on April 29, 2016 (see here and here) – for generic CRESTOR.  According to AstraZeneca, however, that ANDA approval was authorized because the company “granted Watson a patent license and a selective waiver of all periods of exclusivity applicable to FDA’s May 27, 2016, approval of the pediatric HoFH indication and labeling with respect to Watson’s marketing of its generic rosuvastatin product.” 

Watson is apparently one of several “first applicants” eligible for 180-day exclusivity, which would have been triggered on May 2, 2016 when the company commercially marketed its generic CRESTOR.  FDA notes in the approval letter for ANDA 079167 that Watson may have forfeited eligibility for 180-day exclusivity for failure to obtain timely tentative approval, but that “[a]t least one first applicant remains eligible for 180-day generic drug exclusivity for Rosuvastatin Calcium Tablets, 5 mg, 10 mg, 20 mg, and 40 mg,” thus setting up a Nateglinide-like situation (see our previous post here).

If FDA does approve ANDAs for generic CRESTOR on July 8, 2016, then it seems likely that litigation will ensue – probably not in the U.S. District Court for the District of Maryland given that court’s Otsuka decision – and FDA’s carve-out authority under FDC Act § 505A(o) will once again be tested.

By Jenifer R. Stach & Ricardo Carvajal –

Carrying through on what had been designated as a high priority item, FDA rolled out its sodium reduction initiative with several actions, all on the same day.  On June 1, 2016, FDA published a Federal Register notice to announce the availability of draft guidance, held a same-day webinar (see slides here), issued a response letter denying a 2005 citizen petition submitted by the Center for Science in the Public Interest (CSPI), and updated the FDA Voice blog with a post by CFSAN Director Susan Mayne, Ph.D.

The draft guidance, “Voluntary Sodium Reduction Goals: Target Mean and Upper Bound Concentrations for Sodium in Commercially Processed, Packaged, and Prepared Foods” provides recommendations to reduce the estimated average U.S. sodium intake of 3,400 mg/day to 2,300 mg/day over the next ten years.  FDA expects that the goal to reduce average sodium intake will benefit the U.S. population in reducing hypertension, a major risk factor in cardiovascular disease and stroke.  However, questions have been raised about what the optimal level of sodium intake might be, and whether low sodium intake exposes most people to increased risk of death and cardiovascular events while only benefiting the small minority of the population with hypertension and a high sodium intake.     

The draft guidance acknowledges that sodium reduction is a complicated endeavor, given the many functions of sodium-containing ingredients in food.  To achieve the short-term and long-term sodium intake goals of 3,000 mg/day and 2,300 mg/day, FDA proposes to set short-term 2-year targets and long-term 10-year targets for sodium content in sixteen major categories of commercially processed, packaged, and prepared foods (see page 4 of the guidance and page 2 of the slides).  These sixteen major categories include:  1) Dairy-Cheese, 2) Fats, Oils, and Dressings, 3) Fruits, Vegetables, and Legumes, 4) Nuts and Seeds, 5) Soups, 6) Sauces, Gravies, Dips, Condiments, and Seasonings, 7) Cereals, 8) Bakery Products, 9) Meat and Poultry, 10) Fish and Other Seafood, 11) Snacks, 12) Sandwiches, 13) Mixed Ingredient Dishes, 14) Salads, 15) Other Combination Foods, and 16) Baby/Toddler Foods.  Within these sixteen categories, FDA has further provided 150 sub-categories (see Appendix 1 to the draft guidance).  In the webinar, Dr. Mayne stated that FDA created the categories to avoid a “one size fits all approach.”  Categories are weighted according to the leading selling products in each category.

In a nod to concerns that sodium reduction could lead to increased levels of other nutrients, the overview section of the draft guidance states that “[c]hange should not negatively affect the nutritional quality of the foods by modifying other nutrient levels (e.g., added sugars or saturated fat) to less-healthy levels (e.g., taking into account all Dietary Guidelines recommendations and FDA policies).”  FDA intends to monitor these levels as part of an ongoing effort to monitor sodium intake levels.

While FDA acknowledged that consumer education is important, the agency has concluded that education is not enough to reduce sodium consumption.  FDA is operating under the premise that “[a]pproximately 75 percent of total sodium intake comes from processed and commercially prepared (e.g., restaurant) foods,” so FDA is relying on industry to take voluntary action with respect to reduced sodium levels in those foods.  The guidance specifically encourages large food manufacturers (whose products make up a significant proportion of national sales in one or more categories) and national and regional restaurant chains to pay particular attention to the recommendations. 

FDA also acknowledges ongoing efforts to reduce sodium in foods by the New York City Department of Health and Mental Hygiene in partnership with 70 local and state health departments, initiatives by the United Kingdom’s Food Safety Authority, and the joint FDA and FSIS request for comment on sodium reduction in 2011 (see our blog post here). 

As announced in the draft guidance, the Federal Register notice, and webinar slides, FDA is seeking comment on:

• FDA’s proposed food categories
• Methods for determining sodium content and developing recommended targets
• Challenges of implementation for short-term and long-term goals

FDA is providing separate comment periods for the short-term and long-term sodium content targets.  With respect to the short-term 2-year targets, FDA is providing a 90-day comment period, with comments due on August 31, 2016.  For the long-term 10-year target, FDA is providing a 150-day comment period with comments due on October 31, 2016.  FDA intends to hold a series of discussions with stakeholders, with the first discussion to be held as a webinar at the end of June. 

In its letter denying CSPI’s citizen petition, FDA described its approach to sodium reduction as “the most effective and appropriate approach at this time based on the scientific and technical information currently available to us about the feasibility sodium reducction across the entire breadth of the complex and heterogeneous U.S. food supply.”  FDA explicitly declined CSPI’s request to revoke the GRAS status of salt, and thereby subject salt to regulation as a food additive.  As we noted in a prior posting, CSPI sued FDA to compel action on its citizen petition.  The denial of the petition and the rollout of FDA’s sodium reduction initiative effectively bring that litigation to a close.  Two days after the rollout, CSPI filed a notice of dismissal.

By Kurt R. Karst & Douglas B. Farquhar –

On June 3, 2016, a three-judge panel (Judges Thomas B. Griffith, Brett M. Kavanaugh, and  Robert L. Wilkins) of the U.S. Court of Appeals for the District of Columbia Circuit ruled for FDA and Intervenor-Appellee Sandoz, Inc. (“Sandoz”) (represented by Hyman, Phelps & McNamara, P.C.) and upheld FDA’s approval of Sandoz’s generic levoleucovorin drug product. The Court issued an Opinion and Order affirming a May 27, 2015 summary judgment Decision from Judge Royce C. Lamberth of the U.S. District Court for the District of Columbia. The rulings came in a lawsuit lodged by Spectrum Pharmaceuticals, Inc. (“Spectrum”) challenging FDA’s February 24, 2015 denial of a related Citizen Petition (Docket No. FDA-2014-P-1649) and March 9, 2015 approval of Sandoz’s ANDA 203563 for a generic version of Spectrum’s FUSILEV (levoleucovorin) for Injection with a labeling “carve-out” (Sandoz’s label omits certain information about an indication protected by orphan drug exclusivity).  The win for FDA (and Sandoz) further extends the Agency’s winning streak on generic drug labeling carve-out challenges.

As we previously reported (here and here), Spectrum initially filed a Complaint and a Motion for Temporary Restraining Order and/or Preliminary Injunction alleging that FDA’s approval of ANDA 203563 in certain vial sizes was unlawful. Spectrum claimed that Sandoz’s approval for the unprotected methotrexate use and with labeling omitting the orphan drug exclusivity-protected colorectal cancer use violated the company’s orphan drug exclusivity.  Spectrum’s Motion for Temporary Restraining Order was denied in an April 29, 2015 Minute Order, and a Hearing on Spectrum’s Motion for Preliminary Injunction was set for May 18, 2015.  The parties subsequently filed Cross-Motions for Summary Judgment. 

In his May 27, 2015 Memorandum Opinion, Judge Lamberth granted FDA’s and Sandoz’s Motions for Summary Judgment and denied Spectrum’s Motions for Preliminary Injunction and Summary Judgment, holding that FDA’s approval of Sandoz ANDA 203563 was valid.  In doing so, Judge Lamberth held that: (1) FDA’s Approval of Sandoz ANDA 203563 did not violate the Orphan Drug Act or Spectrum’s orphan drug exclusivity because physicians may prescribe Sandoz’s generic version of FUSILEV for the protected colorectal cancer use; (2) FDA’s approval of ANDA 203563 in a large vial size for the methotrexate indication was not arbitrary and capricious even though Spectrum argued it was inconsistent with an earlier FDA position on the permissible uses of larger vial sizes; and (3) FDA’s approval of Sandoz ANDA 203563 with labeling omitting information on FUSILEV’s protected colorectal cancer use was a permissible labeling carve-out, despite Spectrum’s argument that it resulted in a generic drug that is less safe than FUSILEV for the remaining conditions of use.  Judge Lamberth ruled that FDA, under the FDC Act and FDA regulations, should not have granted expedited review to Sandoz’s ANDA without notifying Spectrum in advance, but held that the lack of notice had no effect because Spectrum’s arguments had already been fully considered by the Agency.

On appeal, and reviewing the case de novo, the D.C. Circuit panel affirmed Judge Lamberth’s decision.  With respect to Spectrum’s primary argument – i.e., that FDA violated Spectrum’s orphan drug exclusivity for colorectal cancer when the Agency approved Sandoz ANDA 203563 in a large vial size for FUSILEV’s methotrexate indication, because Sandoz’s product could nevertheless be used in colorectal cancer patients – the Court found permissible FDA’s interpretation of the statute – i.e., that orphan drug exclusivity protects only a labeled use and that a generic drug that is not labeled with that use cannot violate another company’s orphan drug exclusivity.  According to the panel:

First, FDA’s reading of the statute closely hews to the text.  As the Fourth Circuit reasoned in Sigma-Tau Pharmaceuticals, Inc. v. Schwetz, 288 F.3d 141 (4th Cir. 2002), the words “for such disease or condition” suggest Congress intended to make section 360cc “disease-specific, not drug-specific,” and the rest of the statutory language focuses on protecting approved indications, not intended off-label uses.  The statute creates limits on the approval of an “application,” which by implication directs FDA to evaluate what is written on the application.  An application will necessarily include only stated indications, not intended off-label uses. 

Second, FDA’s interpretation conforms to the statutory purposes of the Orphan Drug Act. Spectrum raises a number of policy arguments, urging primarily that the agency’s approach would undermine the Orphan Drug Act’s incentives for drug innovation.  But . . . innovation was not Congress’s only concern when it created the drug approval process.  Congress also sought to promote affordable drugs.  FDA’s interpretation accommodates both interests by allowing generic producers to enter the market for certain purposes while, at the same time, protecting a company’s right to market its pioneer drugs for exclusive uses. . . . 

To the extent FDA has discretion in choosing how best to implement the Orphan Drug Act, it is up to the agency to strike the balance between the congressional policy goals of drug affordability and innovation.  We will not impose a choice on FDA that Congress did not require.   Spectrum’s policy concerns cannot supplant FDA’s reasonable resolution of these issues, especially because we already rejected similar arguments that allowing labeling carve-outs at all under the Food, Drug, and Cosmetic Act undermines the exclusivity rights of producers of pioneer drugs.  See Bristol-Myers, 91 F.3d at 1499-1501.  There is nothing in the Orphan Drug Act that changes our view.  [(Some internal citations omitted; emphasis in original.)]

Spectrum further argued that even if the Orphan Drug Act doesn’t require FDA to take into account the intended off-label use of a generic drug, FDA’s orphan drug regulations do.  For example, FDA’s regulation at 21 C.F.R. § 314.3(b)(14) defines the term “same drug” to mean, in part, “a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug” (emphasis added).  This argument also missed the mark, found the Court:

We agree with FDA and conclude that during the approval process, the agency can look solely to Sandoz’s labeling claims to determine the intended use of its drug.  FDA’s approach here is consistent with how the agency has interpreted “intended use” outside of the ANDA approval context to mean “the objective intent of the persons legally responsible for the labeling of drugs.”  21 C.F.R. § 201.128.  Under that regulation, intent “is determined by such persons’ expressions” or “may be shown by the circumstances surrounding the distribution” of the drugs. Id. (emphasis added).  For example, intent may be shown by “labeling claims” or other statements by drug manufacturers.  Id.  To be sure, FDA recognizes that there may be situations in which it will look beyond just the manufacturer’s statements, but nothing in its regulations requires FDA to do so.  FDA’s decision to look to Sandoz’s labeling claims as an objective measure of Sandoz’s intent is reasonable and consistent with FDA’s regulations.

The Court was also unpersuaded by Spectrum’s remaining two arguments. 

With respect to Spectrum’s argument that FDA’s approval of Sandoz ANDA 203563 in a large vial size entailed an unjustified policy change in light of an earlier general draft guidance document on allowable excess volume and labeled vial size in injectable drug products, the Court found that “there was no departure that would demand explanation here.”  “The guidance document at issue,” said the Court, “offers a general approach for pharmaceutical drugs, and such broad guidance must give way to more specific risk analysis by the agency.” 

Finally, Spectrum’s argument that FDA was required to give the company notice and an opportunity to be heard before expediting review of Sandoz ANDA 203563 in response to a drug shortage also fell flat with the Court, disagreeing with Judge Lamberth on this issue.  The Orphan Drug Act (FDC Act § 527(b)(1)) provides that FDA can approve another application for a drug protected by orphan drug exclusivity if FDA finds, “after providing the holder notice an opportunity for the submission of views,” that the company with orphan drug exclusivity “cannot assure the availability of sufficient quantities of the drug to meet the needs [of patients] with the disease or condition for which the drug was designated.”  FDA’s regulation at 21 C.F.R. § 316.36 implements this provision and largely tracks the statute.  But as the Court correctly states, these provisions don’t apply in the case where an ANDA is to be approved for a use not protected by orphan drug exclusivity:

The Orphan Drug Act creates a notice obligation only when FDA abrogates a pioneer drug’s period of market exclusivity. . . .  The clear purpose of the notice obligation is to protect the rights of producers of pioneer drugs in the event FDA decides a drug shortage requires it to eliminate those rights.  In contrast, the statute says nothing at all about notice requirements when FDA expedites its review of an ANDA or simply evaluates a drug shortage without more. . . .  Because FDA did not cut short Spectrum’s period of market exclusivity, Spectrum was not entitled to notice and an opportunity to be heard before the agency approved Sandoz’s ANDA.

Hopefully the Circuit Court’s panel decision marks the end of the matter, though we’ll be waiting intently to see if a petition for rehearing/rehearing en banc is filed in the coming weeks. 

By Jenifer R. Stach & Alan M. Kirschenbaum –

In our blog post last Fall reporting on an a new price increase penalty imposed on generic drugs under the Medicaid Drug Rebate Program, we predicted more drug price legislation to come. The next statutory response to rapidly increasing pharmaceutical prices has emerged from Vermont in the form of a transparency requirement. On June 3, 2016, Vermont Governor Peter Shumlin signed into law S. 216, which requires pharmaceutical manufacturers to submit justifications for price increases for certain drugs. (See pp. 2250-51.)

Under the law, each year the Green Mountain Care Board, in collaboration with the Department of Vermont Health Access (DVHA), will identify 15 drugs on which the state spends significant health care dollars, and “for which the wholesale acquisition cost [WAC] has increased by 50 percent or more over the past five years or by 15 percent or more over the past 12 months.” The Board will provide this list to the Vermont Attorney General (AG), which will require the manufacturer of each drug on the list to provide a justification that the AG determines to be “understandable and appropriate”. The list, and the respective WAC increases, will also be posted on the Board’s web site.

The manufacturer’s justification must include all relevant information and documentation to support the WAC increase, which may include:

• all factors that have contributed to the WAC increase;
• the percentage of the total WAC increase attributable to each factor; and
• an explanation of the role of each factor in contributing to the WAC increase.

Before December 1 of each year, the DVHA and the AG must submit a report to the Vermont General Assembly based on the information received from manufacturers, and the AG must also post the report on its web site. However, the law prohibits the disclosure of the reported information in a manner that identifies an individual drug or manufacturer.

If a manufacturer fails to provide “the information required” by the statute, the AG may bring an action in civil court for injunctive relief and impose a civil fine of $10,000 for each violation – i.e., each failure to provide required information.

This law leaves many questions unanswered. Most importantly, what criteria will the AG use to determine whether a WAC increase is “understandable and appropriate,” and what are the consequences if an increase is not? While it is clear that the AG can seek penalties for a failure to report information, are penalties contemplated against manufacturers that do submit information but the AG does not deem it “understandable and appropriate” support for a WAC increase? It would appear the answer to the latter question is “no”, because the law provides that “nothing in this section shall be construed to restrict the legal ability of a manufacturer to change prices to the extent permitted under Federal law.” With respect to procedure, no process or timeline is established for the annual submissions, other than the December 1 deadline for the submission of the AG/DVHA report Congress.

We expect that the DVHA and/or the AG will be issuing guidance to implement this law. We will be updating our readers on relevant issuances.

Hyman, Phelps & McNamara, P.C., the nation’s largest boutique food and drug regulatory law firm, seeks a junior to mid-level associate with substantive experience in medical devices and other areas of food and drug law and regulation to assist with a growing practice.  Strong verbal and writing skills are required.  Compensation is competitive and commensurate with experience.  HP&M is an equal opportunity employer.

Please send your curriculum vitae, transcript, and a writing sample to Anne K. Walsh (awalsh@hpm.com).  Candidates must be members of the DC Bar or eligible to waive in.

  In recent years, the level of scrutiny on foreign pharmaceutical manufacturing facilities in countries like China and India has skyrocketed—along with the demand and dependence of western countries on the supply of goods coming from those facilities. With the international pharmaceutical supply chain imperiled like never before, what can drug manufacturers do to protect themselves?

This free webinar, presented by Dechert LLP and Hyman, Phelps & McNamara P.C., will discuss recent pharmaceutical supply chain developments and what steps companies need to take to prevent and remediate compliance issues in the context of:

• The uptick in investigations in China and India.
• The potential impact of adverse regulatory actions against nonconforming facilities.
• Threats Posed by Bribery and Corruption.
• Anti-corruption compliance issues from U.S. and Asian perspectives.
• “War stories” from recent investigations.

When

Wednesday, June 22, 2016
12:00 p.m. – 1:00 p.m. ET

Where

This presentation will be simulcast via Webex as a webinar.  Please click here to register. 

Speakers

Douglas B. Farquhar
Director
Hyman, Phelps & McNamara PC
Washington, D.C.

Mark I. Schwartz
Of Counsel
Hyman, Phelps & McNamara PC
Washington, D.C.

Jeremy B. Zucker
Partner
Dechert LLP
Washington, D.C.

Lewis Ho
Partner
Dechert LLP
Hong Kong

Kareena Teh
Partner
Dechert LLP
Hong Kong

Application for accreditation of this program for Continuing Legal Education (CLE) in California, Massachusetts, New Jersey, and New York is currently pending.

For questions, please contact Reiko Tate (reiko.tate@dechert.com).

By David C. Gibbons & Jeffrey N. Wasserstein –

The most recent assault on FDA’s regulation of off-label promotion came from Congress. In a recent letter to the Secretary of the Department of Health and Human Services (HHS), the House Committee on Energy and Commerce told HHS that it wants to see change. Letter from the Honorable Fred Upton and the Honorable Joseph R. Pitts, Ranking Members of the House Committee on Energy and Commerce, to the Honorable Sylvia Burwell, Secretary of HHS (May 26, 2016) [hereinafter “HEC Letter”].  The Committee wrote to express its “concerns” about the position HHS has taken on FDA regulation of “proactive dissemination of truthful and non-misleading information that is outside the scope of a [medical] product’s FDA-approved labeling.” Id. at 1.  Grounded in the proposed changes to the way off-label promotion would be regulated under the 21st Century Cures Act, the Committee challenged the Administration’s view that the 21st Century Cures legislation “could undermine regulatory standards by allowing unproven uses of therapies to be marketed to health care payors as though such uses had been proven safe and effective.”  Statement of Administration Policy: H.R. 6 – 21st Century Cures Act (July 8, 2015) (here).

Based on the premise that “scientifically accurate” but off-label information is “critical to optimizing patient care,” the Committee stated that a strict prohibition on manufacturers from proactively providing such information is generally “no longer sound public policy” and does not survive constitutional scrutiny. HEC Letter at 1.  The Committee pointed to the numerous cases where courts have found First Amendment protection for truthful and non-misleading speech by pharmaceutical manufacturers, beginning with Sorrell v. IMS Health, 564 U.S. 552 (2011), and continuing with United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), Amarin Pharma, Inc. v. FDA, No. 15 Civ. 3588 (S.D.N.Y. Mar. 8, 2016), Pacira Pharms., Inc. v. FDA, No. 15 Civ. 7055 (S.D.N.Y. Dec. 15, 2015), and United States v. Vascular Sols., Inc., No. 5:14-CR-00926 (W.D. Tex. Feb 26, 2016).  After reviewing the key cases in this area, the Committee stated, “[a]s FDA’s authorizing committee, we are increasingly perplexed by the agency’s unwillingness or inability to publicly clarify its current thinking on these issues in a coherent manner.”  HEC Letter at 2.  The Committee noted that policy on whether and how pharmaceutical and medical device companies are permitted to speak about off-label uses of its products was being made, not by FDA rulemaking or subregulatory guidance, but rather through settlement agreements involving cases like those noted above, which the Committee described as “ad hoc . . . lacking any semblance of consistency and cohesiveness.” Id.

In the HEC Letter, the Committee expressed its belief that HHS and the current Administration are blocking the path to clear policy on off-label promotion. The Committee stated that “it is our understanding that HHS has not allowed FDA to issue its completed draft guidance addressing the scope of permissible ‘scientific exchange’” and further described the Administration as being “reflexively opposed” to policy changes “despite their legal footing continuing to crumble.” Id. at 2, 4.

In a display of its eagerness both to move forward and to establish law in this area, the Committee provided a Discussion Draft of a proposed Amendment to the Federal Food, Drug, and Cosmetic Act (FD&C Act) that would allow pharmaceutical and medical device companies greater freedom to disseminate information about their products that is outside of their products’ labeling. To this end, the Amendment proposes four important changes:

First, the Amendment would narrow the definition of “labeling” to include written, printed, or graphic material that accompanies pharmaceutical products only when such material is required to accompany the products under the FD&C Act of the Public Health Service Act. Discussion Draft of Proposed Amendments to the FD&C Act with respect to communication about drugs and devices, and for other purposes, 114th Cong., at 2 (Jan. 30, 2015) (attached as an addendum to the HEC Letter) [hereinafter “Discussion Draft”].  The FD&C Act currently defines labeling as “all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.”  FD&C Act § 201(m).  The term “accompanying” has been interpreted broadly by the U.S. Supreme Court, which held that “[o]ne article or thing is accompanied by another when it supplements or explains it . . . No physical attachment one to the other is necessary. It is the textual relationship that is significant.” Kordel v. United States, 335 U.S. 345, 350 (1948).  Confining labeling to include only those materials that are required to accompany medical products would exempt a substantial proportion of materials prepared by or on behalf of a medical products company from the regulatory requirements associated with labeling.

Second, the Amendment would explicitly codify a provision stating that advertising, scientific exchange, and investor communications are not labeling. FDA regulations state that advertisements in both print and broadcast media are subject to the requirements of the FD&C Act.  21 C.F.R. § 202.1(l)(1).  The regulations go on to state that “printed, audio, or visual matter descriptive of a drug and references published . . . for use by medical practitioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor are hereby determined to be labeling . . . .” Id. § 202.1(l)(2).  Thus, FDA has taken the position that most drug advertisements are labeling and regulated as such, in accordance with the provisions of the FD&C Act and FDA regulations.  As noted above, the effect of this change would be to exempt a substantial proportion of materials prepared by or on behalf of a medical products company from regulatory requirements associated with labeling, and thus allow manufacturers greater freedom in advertising their products.

Third, the Amendment would limit the definition of intended use of a medical product to include only “the objective intent of the manufacturer and sponsor . . . or persons acting on the manufacturer’s or sponsor’s behalf, as demonstrated by statements contained in labeling, advertising, or analogous oral statements” but not in accordance with the “actual or constructive knowledge of the manufacturer or sponsor” that the medical product will be used off-label. Discussion Draft at 4.  The ability of FDA to allege that a manufacturer has placed a misbranded medical product into interstate commerce, based on the intended use of such product inferred from “the circumstances surrounding the distribution” of the product would be eliminated by the Amendment.  Thus, the Amendment curbs both FDA enforcement actions against manufacturers for off-label promotion that otherwise meets the truthful and non-misleading standard as well as civil lawsuits under the federal False Claims Act based on a misbranding theory.

Finally, the Amendment would permit a broad array of scientific exchange. The Amendment expressly provides that scientific exchange would not constitute labeling, advertising, or evidence of a new intended use of a medical product.  The Amendment describes scientific exchange as including:

• [D]issemination of scientific findings in scientific or lay media;
• [P]ublication of results of scientific studies;
• [L]etters to the editor . . .;
• [C]ommunications at scientific or medical conferences or meetings;
• [D]issemination of medical or scientific publications, reference texts, or clinical practice guidelines;
• [C]ommunication, both proactive and reactive, of information regarding a manufacturer’s [R&D] efforts;
• [C]ommunication, both proactive and reactive, of scientific, medical, or technical information or findings, including communication of such information by personnel in scientific, medical, or clinical development departments of manufacturers; and
• [C]ommunication, both proactive and reactive, of health care economic and health outcomes information . . . . Id. at 7-8.

The dissemination of such information would be permitted so long as it is supported by “evidence generated in accordance with the scientific method;” includes a “conspicuous and prominent statement” that the use of the product is off-label; and does not include a statement that the product has been demonstrated to be safe and effective for such use. Id. at 6.  This non-exhaustive list of activities that would constitute scientific exchange essentially would provide a safe harbor for certain types of off-label information disseminated by manufacturers. Id. at 6-7.

While it is too early to predict the success of the Amendment proposed by the Committee, it is clear that many forces are aligned to provide greater freedom to pharmaceutical and medical device manufacturers in the dissemination of truthful and non-misleading off-label information about their products.

By Kurt R. Karst –      

It’s been just over a year – May 28, 2015 – since Judge Randolph D. Moss of the U.S. District Court for the District of Columbia handed down his 40-page Opinion in a lawsuit lodged by Amarin Pharmaceuticals Ireland Limited (“Amarin”) against FDA challenging the Agency’s February 21, 2014 Exclusivity Determination that Amarin’s VASCEPA (icosapent ethyl) Capsules, 1 gram, which FDA approved on July 26, 2012 under NDA 202057, is not eligible for 5-year New Chemical Entity (“NCE”) exclusivity. Our year-long patient waiting came to an end on May 31, 2016 when FDA finally issued a new Exclusivity Determination concluding that VASCEPA is eligible for (i.e., granted) 5-year NCE exclusivity.  The 16-page Exclusivity Determination, announced by Amarin, is the latest – and perhaps the last – chapter in an exclusivity saga that started years ago.  And it comes on the heels of the so-called “NCE-1” date when an ANDA for a generic version of a drug product granted NCE exclusivity and containing a Paragraph IV certification can be submitted to FDA: July 26, 2016.

As readers of this blog know, in May 2015, Judge Moss ruled for Amarin, granting the company’s Motion for Summary Judgment and denying FDA’s Motion for Summary Judgment. In setting aside FDA’s exclusivity decision, Judge Moss wrote:

[FDA’s] ultimate conclusion that Vascepa, a drug “no active ingredient of which . . . has been approved” in a previous NDA, was not entitled to exclusivity, is contrary to the statute’s plain meaning. Rather than explaining this discrepancy, the administrative decision only adds to the problem by emphasizing the divergence between the Agency’s regulatory inquiry and the statutory requirement.  Whether the problems with the FDA’s decision are characterized as failures under Chevron step one, step two, or the APA’s requirement of reasoned decision-making, the Agency’s decision must be set aside.

Judge Moss remanded the matter to FDA for further proceedings consistent with his Opinion.

We won’t repeat all of the facts and circumstances – and the twists and turns – that led up to FDA’s May 31, 2016 Exclusivity Determination. You can refer to our previous posts for that – see here and here.  But in a nutshell, FDA’s rationale for denying NCE exclusivity was that eicosapentaenoic acid (“EPA”), “the single active moiety in Vascepa, was also an active moiety contained in another, previously approved drug, Lovaza (omega-3-acid ethyl esters) Capsules (Lovaza),” that  FDA approved on November 10, 2004 under NDA 021654.  Specifically, in denying NCE exclusivity for VASCEPA, FDA rejected the “one-to-one” framework and relationship between active ingredient and active moiety traditionally applied when deciphering the active moiety in a drug product.  Instead, for naturally derived mixtures, such as LOVAZA, FDA applied a “one-to-many” approach.  According to FDA, “[i]n cases where at least part of the mixture is well characterized and some components of the mixture that are consistently present and active are identifiable or have been identified,  . . . [t]he approach that is the most consistent with the relevant definitions, facts, and policies present in this case is one in which the entire mixture is the single active ingredient, but that active ingredient may contain more than one component active moiety.”  Judge Moss flatly rejected this “one-to-many” approach and FDA’s rationale for it as inconsistent with the statute.  

Going back to the drawing board with Judge Moss’ decision in hand, FDA says that the Agency “reevaluated whether the ‘one-to-many’ or the ‘one-to-one’ framework should be applied to Lovaza to determine whether EPA is an active moiety previously approved in Lovaza,” and thus, whether or not VASCEPA contains an NCE and should be granted 5-year exclusivity.  Upon reevaluation, and given “[m]ultiple factors unique to this matter,” FDA landed on adopting the “one-to-one” framework in this case, and ultimately concludes that EPA was not previously approved. FDA lays out those factors in the May 31, 2016 Exclusivity Determination:

First and foremost, the Agency took into consideration the Court’s Opinion, and, in particular, the Court’s finding that, in light of FDA’s previous decision that the entire mixture is the active ingredient of Lovaza, the application of FDA's exclusivity regulations to Lovaza under the “one-to-many” framework was inconsistent with the statutory language.

Second, the Agency considered its prior active ingredient determination for Lovaza and the reasons underlying it. At the time of approval, FDA determined that the active ingredient of Lovaza was the entire mixture. Also at the time of approval, FDA explicitly rejected the suggestion from Lovaza’s sponsor that Lovaza’s established name should consist of the names “EPAee” and “DHAee,” determining instead that the name “omea-3-acid ethyl esters” would be suitable because it “was designed to correspond to the mixture.”

In addition, in its Lovaza Strength Citizen Petition Response, FDA reaffirmed its conclusion that Lovaza's active ingredient is the entire fish oil mixture.

Third, FDA reviewed previous Agency 5-year NCE exclusivity decisions in the context of naturally derived mixtures and notes again that at least some of those decisions are consistent with the “one-to-one” framework. As the Agency acknowledged in its initial Vascepa exclusivity determination, “the few relevant prior Agency statements and prior actions where FDA considered 5-year NCE exclusivity matters in the context of naturally derived mixtures have not necessarily resulted in consistent outcomes.”  Some of those decisions, however, suggest that the Agency could consider the entire mixture to be both the active ingredient and the active moiety for Lovaza, as it did in the exclusivity determinations for the lung surfactants InfaSurf and Curosurf and for products containing pancrelipase and hyaluronidase.

Fourth, the Agency considered the lack of guidance describing how FDA makes exclusivity determinations for naturally derived mixtures. Prior to the issuance of the Vascepa exclusivity determination, there was no explicitly defined framework for identifying active moieties in the context of naturally derived mixtures for purposes of 5-year NCE exclusivity, nor could one easily be gleaned from the applicable statute, regulations, and precedent.  As discussed above, the statute and regulations do not expressly address 5-year NCE exclusivity in the context of naturally derived mixtures.  In fact, the prior Agency statements and actions regarding this matter were difficult to reconcile. Although guidance is not required before FDA can act, FDA believes the lack of guidance and diversity of practice also counsels in favor of applying the “one-to-one” framework on remand.

Lastly, the Agency considered whether any of the reasons it had provided for declining to adopt the “one-to-one” framework when it previously considered the active moiety for Lovaza bars adopting the “one-to-one” framework for Lovaza now. . . . [J]ust as the Court recognized that FDA is free to determine whether any particular naturally derived mixture is better understood as containing one or multiple active ingredients, so too the Agency believes it has regulatory and scientific discretion to determine whether any particular naturally derived mixture can be described as containing one or multiple active moieties.  Accordingly, as explained in this letter, the Agency has determined, in order to bring the Agency’s decision in harmony with the Court’s Opinion, that the active moiety of Lovaza, a partially characterized mixture, is the entire mixture.

FDA takes great pains to emphasize that the Agency’s May 31, 2016 Exclusivity Determination applies only in the case of LOVAZA/VASCEPA, noting that the ruling is made “under the narrow circumstances of this case” and given the “unique” factors of the matter. Despite FDA’s best efforts, however, creative lawyers will find ways to use Judge Moss’ decision to their benefit when arguing for (or perhaps against) a future FDA exclusivity determination.  

By Riëtte van Laack –

On May 27, 2016, FDA published the final rule, required under FSMA, regarding “the Mitigation Strategies to Protect Food against Intentional Adulteration.” 

Food defense has been on the agenda ever since the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (commonly referred to as “the Bioterrorism Act”), became law in 2002. The Bioterrorism Act and FDA implementing regulations introduced requirements for food facility registration and provide the agency with food shipment and other records. However, there were no specific requirements or regulations to protect against intentional adulteration. FSMA changed that as it mandates that FDA issue regulations that require registered food facilities to develop a food defense plan to prevent intentional adulteration of food that may result in large-scale public harm.

The final rule specifically exempts several categories of facilities:

• Facilities that have less than 10 million dollars in annual sales, during a three-year period preceding the calendar year;
• Facilities that hold foods, except liquid storage tanks;
• Facilities that (re-)pack or (re-)label foods where the container that directly contacts the food remains intact;
• Farms;
• Animal food facilities;
• Alcoholic beverages under certain conditions, and
• Certain on-farm processing of low-risk foods.

All registered facilities that are not exempted must develop a food defense plan that includes a vulnerability assessment, actionable process steps, mitigation strategies, monitoring, corrective actions, verification and recordkeeping. They must follow risk-based steps to protect against the potential for wide-scale harm to public health from an intentional act, including an act from “an inside attacker.” A “qualified individual,” a term added in the final rule, must implement the mitigation strategy after conducting a vulnerability assessment for every step in the food production process. The food defense plan must be analyzed at least every three years. All records must be retained at the facility for two years.

The final rule is significantly different from the proposed rule published in 2013. The changes, made in response to the more than 200 comments, are “designed to provide either more information, where stakeholders requested it, or greater flexibility for food facilities in determining how they will assess their facilities, implement mitigation strategies, and ensure that the mitigation strategies are working as intended.”

For example, in the proposed rule, FDA identified four specific areas of vulnerability (bulk liquid receiving and loading; liquid storage and handling; secondary ingredient handling, and, mixing and similar activities) as processes that required focused mitigation strategies. The final rule no longer specifies areas of vulnerability but requires that a company perform a vulnerability assessment based on the evaluation of: 1) The potential public health impact of the addition of contaminant; 2) The degree of physical access to the product; and 3) The ability of an attacker to successfully contaminate the product.

The final regulation also exempts more facilities, e.g., dairy farms and “qualified facilities,” and gives all companies more time to comply. FDA had proposed an effective date of 60 days after the publication of the rule and one (1) year after the effective data for compliance. The final rule still provides for an effective data of 60 days after the publication, i.e., July 28, 2016. However, companies get significantly more time to come in compliance. Facilities other than small companies now get three (3) years to come into compliance. Small companies, i.e., companies employing fewer than 500 employees, get an extra year (i.e., four (4) years from the effective date).

FDA recognizes that the requirement for a food defense plan is separate and apart from food safety and a new concept for industry. Its “implementation of this rule will involve a broad, collaborative effort to foster awareness and compliance through guidance, education, and technical assistance.”

In addition to the final rule, FDA published a fact sheet and explanatory diagrams to assist companies in determining whether the rule applies to them, as well as an overview of the requirements. In addition, FDA plans to provide updates to its food defense page, which it has developed as a resource for a voluntary food defense program.

FDA has scheduled a webinar regarding the new regulation for June 21, 2016.

By Allyson B. Mullen & Jeffrey N. Gibbs –

Oh Medical Device Amendments how we love thee. This Saturday marks your 40th birthday.  In light of this momentous occasion, we wanted to wish you a very happy birthday with a blog post all your own. 

In 1976, Gerald Ford was President, the U.S. celebrated its 200th birthday, the average price for a gallon of gas was 59 cents, and you and the $2 bill were born. We are so glad that you’re more popular than the $2 bill! 

You were born with the cutest little definition:

“an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:

• recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
• intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
• intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”

Your parents thought this definition would simplify life for everyone. Sometimes, though, you can’t always get what you want.  No one ever could have dreamed of all the controversies your “primary intended purposes” and “chemical action” phrases would spark years later. 

And, to be honest, some of your other provisions have been a bit cryptic. We’ve spent many confounding years working on mysteries without any clues.  Expecting you to make perfect sense was to dream the impossible dream.  You’ve always surprised us with your complexity.  You started off as an adorable little law.  As we examined you more closely, we saw how multi-dimensional you were, bigger on the inside than the outside. 

You were never a quiet, sleepy child. You got down to work right away.  Baby, you were born to run. 

At first, things didn’t go so smoothly. When you were seven, you were even called FDA’s Neglected Child.  But nobody can call you that now.  Now, the Law is not mocked. 

You grew up quickly, and started confusing your older sibling, the drug industry, with your crazy new regulatory pathway, the 510(k) process. Who would have thought that out of all of your carefully crafted text, one tiny provision would have led to the most utilized regulatory pathway for medical devices and one of the most important provisions in the entire law?  But just like a little Hobbit overthrew a mighty sorcerer, this one seemingly insignificant paragraph upended the whole device regulatory regime.  Did anyone think about this when they wrote the Law?  We don’t know.  We weren’t in the room where it happened.

Even though you’re entering your fifth decade, we love that you are still trying to figure out who you are. We’d give you advice but children won’t listen.  Is a product a device if it is not treated like one? 

Really, what is a device? 40 years and still no one knows exactly!  Do you encompass laboratory developed tests, clinical decision support software, a product that contains a little chemical action (but not too much), some other cool new device we haven’t even thought of yet?  And that’s without mentioning your half-sibling, “enforcement discretion.”  Maybe.  As you wish.

Sometimes, we do wish you’d just find yourself and settle down. But recently, it seems every 5 years you go through another growth spurt.  You never can just let it be.  In fact, it looks like you’re due for another big change next year. 

Even now, you’re full of surprises. After banning just one device in 40 years, you proposed two bans just this year.  Suddenly, it’s banned on the run. 

One thing is for sure; you’re never boring. We can’t wait to see what the next 40 years brings.

Happy Birthday!

Love,

HPM’s Device Group

PS: Since we couldn’t sing you a happy birthday song, we’ve sprinkled some references to music in this note.