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.

By Jenifer R. Stach –

The Federal Trade Commission announced that it will host a workshop, “Putting Disclosures to the Test” at the Constitution Center, 400 7th St SW, Washington, DC 20024 on September 15, 2016. 

The FTC stated that “[e]ffective disclosures are critical in helping consumers make informed decisions in the marketplace.”  The FTC highlighted three areas where it believes disclosures are critical in consumer protection:           

• disclosures in advertising designed to prevent ads from being deceptive;
• privacy-related disclosures, including privacy policies and other mechanisms to inform consumers that they are being tracked;
• disclosures in specific industries designed to prevent deceptive claims, including jewelry, environmental claims, and fuel economy advertisements.

The workshop is free, and open to the public.  The FTC is soliciting presentation proposals as well as public comments.  Presentation proposals may be submitted to disclosuretesting@ftc.gov.  Public comments may be submitted to the FTC on its website here until November 2, 2016.

The American Conference Institute (“ACI”) is holding its fourth annual FDA Boot Camp – Medical Devices Edition on Thursday, July 21 to Friday, July 22, 2016 at the InterContinental Chicago Magnificent Mile, Chicago, IL. This year’s program has been revamped to provide both a “basic training” in FDA regulatory law, as well as “advanced training” sessions tailored to the application of this knowledge to real-life situations. Highlights from this year’s program include a “Ripped from the Headlines” panel, containing updates on key developments in the FDA regulatory bar, and an in-depth Post- Conference Master Class, delving into the hot-button topics of in vitro diagnostics, laboratory developed tests, companion diagnostics, and combination products. Hyman, Phelps & McNamara, P.C.’s Jeffrey N. Gibbs will be speaking on “Low to Moderate-Risk Devices – Clarification of the 510(k) Clearance and Dissecting the De Novo Classification.”

You can register for the program here.  FDA Law Blog is a conference media partner, and blog readers can receive 15% off the tuition fee by using discount code P15-999-FDA16 when registering for the conference.  A new price tier for the conference will go into effect later this week.

By Riëtte van Laack –

On Friday the 20th of May, FDA announced the availability of the final regulations for nutrition labeling and serving sizes (in prepublication format).  The final regulations will be published in the Federal Register on May 27, 2016.  That date will be used in setting the effective date of July 26, 2016, and the compliance date of July 26, 2018 (or July 26, 2019 for businesses with less than 10 million dollars in annual food sales).  In addition to the final regulations, FDA published a fact sheet, a slide show, changes to the nutrition facts panel,  a statement by the Commissioner, and a Q&A.

Nutrition Facts Rule

In the prepublication format, the final regulation regarding Nutrition Facts and Supplements Facts label is 943 pages. This is not surprising in light of the large number of comments, but it appears that FDA has made relatively few changes to the proposed rule.  Here are some highlights

• Format of the Nutrition Facts box (most of the format changes do not apply to the Supplement Facts box)

The differences between the original label and the new label are significant and illustrated by a comparison between the original and new label.

The two major differences between the proposed rule and the final rule are that the daily value column remains on the right (FDA had proposed to move it to the left), and the requirement to declare total sugar as “total sugars” (not as “sugars”), and “added sugars” by the statement “includes x g added sugars.”  The latter change is intended clarify that added sugars are a subcomponent of total sugars.

• Changes in Required Nutrients

Despite numerous objections, FDA finalized the final rule to require the listing of added sugars and to redefine dietary fiber.  Likely less controversial are the changes in mandatory vitamins and minerals; Vitamin A and vitamin C will no longer be mandatory, whereas vitamin D and potassium will be mandatory.

Added sugars:  As proposed, the final regulation requires declaration of added sugars in grams (includes x g of added sugars) and declaration of a percent of Daily Value for added sugars (not for total sugars). 

What constitutes added sugars and how this might affect labeling of certain products has generated a lot of questions (e.g., would juice from concentrate need to label all sugars as added sugars).  FDA clarified its intent in the final regulation.  Sugars from fruit or vegetable juice concentrates are “added sugars” only to the extent that they add sugars in excess of what would be expected from the same volume of 100 percent fruit or vegetable juice of the same type.  Recognizing that there is no nutritional difference between sugars in 100% juice prepared from concentrate and in 100% juice not from concentrate, the final regulation specifies that fruit or vegetable juice concentrates used towards the total juice percentage label declaration or for Brix standardization are not considered “added sugars” for purpose of the nutrition labeling.  Similarly, neither fruit juice concentrates which are used to formulate the fruit component of jellies, jams, or preserves in accordance with the standards of identity, nor the fruit component of fruit spreads, are “added sugars” for purposes of nutrition labeling. 

FDA also removed from the definition of added sugars, the language that stated that naturally occurring sugars that are isolated from a whole food and concentrated so that sugar is the primary component are added sugars. Consequently, dairy ingredients containing lactose, except lactose as defined in 21 C.F.R. § 168.122, no longer fall within the definition of added sugars.

It is evident that careful analysis will be required to determine whether and how added sugars must be declared, and in what amount.  Further, careful record keeping will be required. 

Dietary Fiber:  As we previously discussed, FDA’s proposal concerning the definition of dietary fiber raised some concern.  FDA proposed to narrowly define dietary fiber to include “non-digestible soluble and insoluble carbohydrates (with 3 or more monomeric units), and lignin that are intrinsic and intact in plants,” and isolated and synthetic fiber determined by FDA to have a beneficial physiological effect.  At the time of the proposal, FDA had determined that [beta]-glucan soluble fiber and barley beta fiber the only isolated fibers that qualified.  The final rule includes additional fibers, i.e., psyllium husk, cellulose, guar gum, pectin, locust bean gum, and hydroxypropylmethylcellulose.  FDA intends to publish a separate notice to seek comment on the available scientific data on other isolated or synthetic non-digestible carbohydrates (e.g., inulin, bamboo fiber, soy fiber, pea fiber) to assist the agency in the review of the scientific evidence.  FDA also plans to issue guidance regarding the requirement to show a beneficial physiological effect of isolated and synthetic fibers that are not already included in the regulation or considered in the notice.

Folate/Folic Acid:  FDA had proposed to no longer consider folate and folic acid synonyms, and require the vitamin to be identified as folate for foods and as folic acid for dietary supplements.  In response to comments, FDA reconsidered this approach.  Now, for both foods and dietary supplements, the vitamin will be identified as “folate.”  The rule further details how to label/identify the presence of synthetic folic acid (e.g., for dietary supplements); if the source of the folate is a synthetic source, such information must be declared in parentheses (e.g., folate 400 mcg DFE (240 mcg folic acid)).

Vitamins and Minerals:  For nutrition labeling of conventional foods, the mandatory vitamins and minerals will be vitamin D, iron, calcium, and potassium.  The amount and percent DV for these nutrients must be declared.  For other minerals and vitamins, the declaration of the amount is generally is voluntary.

• Record Keeping Requirements

Whereas previously, FDA could verify nutrition labeling by analysis of the food, verification of compliance with the revised regulation cannot be done without review of records.   Businesses are required to make and keep records for verification of the mandatory declaration of added sugars, dietary fiber, vitamin E, folic acid, and folate.  The rule does not specify what records must be kept.

• Other Issues

The above is only a sample of the many aspects of the final rule.  The preamble to the Nutrition Labeling regulation addresses numerous other issues such as the reference values for choline, the voluntary declaration of fluoride, changes in reference values, and changes in nutrition labeling for foods for children (certain nutrients that previously could not be listed, now must be listed).  The final rule will impact virtually every conventional food product. 

As acknowledged by FDA, the revisions to the labeling regulations impact other regulations, including nutrient content claim and food additive regulations (e.g., the food additive regulation for vitamin D bases the use of vitamin D on a product containing a certain percentage of the reference daily intake for calcium).  FDA has signaled that it intends to address that impact in due course.

Serving Sizes of Foods

At 170 pages in the prepublication format, the final rule regarding serving sizes and reference amounts customarily consumed (RACC) is significantly shorter than the nutrition labeling rule.  . As discussed in the proposed rule, the proposed changes were based on evaluation of new consumption data and research, petitions.  FDA had proposed several changes, including revisions of RACCs (reduction for yogurt, increase in RACC for ice cream), new RACCs (different RACC for carbonated beverages than for milk), and a revised definition of single serving size container. 

There are a number differences between the proposed and final rule.  Possibly, the most significant difference is FDA’s decision to lower the upper limit of dual column labeling from 400 percent to 300 percent of the RACC.  FDA had proposed that products that contain at least 200 percent but no more than 400 percent of the RACC be labeled with “dual column” nutrition information to indicate the amount of calories and nutrients both “per serving” and “per package”/“per unit.”  In response to comments, the final rule requires such dual column labeling for products that contain at least 200 percent and but no more than 300 percent of the RACC.  FDA concluded that “[p]roviding an upper limit at 300 percent of the RACC would ensure that dual-column labeling captures 90 percent of the consumption habits for about 91 percent of food products and limit the possibility that dual column labeling will be required for package sizes that are not likely to be consumed in a single eating occasion.”  The dual column must list the quantitative amounts and percent DVs for the entire container, in addition to listing the quantitative amounts and percent DVs for the serving size derived from the RACC.  Examples of products affected are a 24-ounce bottle of soda (new RACC is 12 oz) or a pint of ice cream (new RACC is 2/3 cup).

Under the final rule, containing less than 200 percent of the RACC must be labeled as a single-serving container.  For products that are packaged and sold individually that contain more than 150 percent but less than 200 percent of the applicable reference amount, the Nutrition Facts label may also voluntarily provide, to the left of the column that provides nutrition information per container (i.e., per serving), an additional column that lists the quantitative amounts and percent Daily Values per common household measure that most closely approximates the RACC.

In response to comments, various proposed RACCs were revised, e.g., FDA has proposed to increase the RACC for ice-cream from 1/2 cup to 1 cup but, after redefining the category to include both bulk products and novelties, set the RACC for this category at 2/3 cup.

Combined, the two final rules are extensive and are bound to affect virtually every conventional food product (and many dietary supplements) on the market.  In both rules, FDA mentions that it will issue guidance to clarify a variety of issues, such as what to include in a petition regarding a synthetic fiber, and what is the RACC for a bagel thin.  In addition, the Agency indicated there will be other updates in the future, e.g., RACCs for children food products.

By David C. Gibbons & John R. Fleder –

The Second Circuit has issued an interesting new opinion that suggests liability under the federal False Claims Act (FCA) cannot attach to at least certain types of off-label promotion. While many of the interesting sections of the court’s discussion appeared only in dicta, and was not the central holding of the case, the decision does provide insight into the Second Circuit’s thinking concerning a question that both we and our readers have been wrangling with since U.S. v. Caronia, 703 F.3d 149 (2d Cir. 2012), was decided.

That is, can the government’s theory of FCA liability be predicated solely on a manufacturer’s off-label promotion of its product? The answer seems to be no, according to the Second Circuit in United States ex rel. Polansky v. Pfizer, No. 14-4774 (2d Cir. May 17, 2016) (“Polansky IV”), a case heard by a panel that included Judge Debra Ann Livingston, who also presided over Caronia.

The FCA imposes liability upon any person who, among other things:

(A) knowingly presents [to the federal government], or causes to be presented, a false or fraudulent claim for payment or approval; [or]

(B) knowingly makes, uses, or causes to be made or used, a false record or statement material to a false or fraudulent claim . . . . [31 U.S.C. § 3729(a)(1)(A)-(B).]

A Look Back At Franklin

Some courts have broadly construed the FCA to include statements made by pharmaceutical manufacturers to prescribers that are material to the payment of claims for the manufacturer’s products by Medicare or Medicaid. See, e.g., United States ex rel. Franklin v. Parke-Davis, 147 F. Supp. 2d 39, 53 (D. Mass. 2001). In Franklin, NEURONTIN (gabapentin), a drug approved by FDA for epilepsy was also prescribed for a variety of off-label uses, including pain management, epilepsy, bipolar disorder, and attention deficit disorder. Id. at 45. The relator, a former medical science liaison with Parke-Davis, alleged that the company “engaged in an extensive and far-reaching campaign” to promote the product for off-label uses and “to coach doctors on how to conceal the off-label nature of the prescription” so that such uses could be reimbursed under patients’ healthcare insurance, including government programs. Id. at 45-46.

Ruling on a Motion to Dismiss, the court, in Franklin, had to resolve whether the alleged off‑label marketing scheme could cause a false claim to be presented. On this issue, the court denied Parke-Davis’ Motion stating that “the alleged FCA violation arises . . . from the submission of Medicaid claims for uncovered off‑label uses induced by [Parke-Davis’] fraudulent conduct.” Id. at 52. Parke‑Davis argued that its conduct could not have met the causation element of the FCA because the independent actions of prescribers and pharmacists “were an intervening force that [broke] the chain of legal causation.” Id. The court countered that this would have been true if the intervening efforts of the prescribers had been unforeseeable. However, the court stated, “the participation of doctors and pharmacists in the submission of false Medicaid claims was not only foreseeable; it was an intended consequence of the alleged scheme of fraud.” Id. at 52-53. Thus, the court denied (in part) Parke-Davis’ Motion to Dismiss. Id. at 44.

Contrasting View of FCA Liability under Polansky

The case brought against Pfizer by Dr. Jesse Polansky examined the paradigm presented in Franklin. Polansky alleged that Pfizer, Inc. (“Pfizer” or the “Company”) violated the FCA by off‑label marketing its cholesterol‑lowering drug, LIPITOR^®, for patients with cholesterol levels outside of the National Cholesterol Education Program Guidelines (Guidelines). Polansky IV at 3.

Polansky alleged that Pfizer acted unlawfully under the following theory: Pfizer marketed LIPITOR for patients whose cholesterol levels were below the cutoff for receiving LIPITOR under the Guidelines; the Guidelines are “incorporated into and made mandatory” by the approved prescribing information (PI); Pfizer “induced” prescribers to use the drug in such patients; and federal and state healthcare programs paid for such off‑label uses. Id. at 2.

The lower court dismissed the complaint, holding that the Guidelines “themselves expressly disclaimed prescriptive force.” Id. at 13. The lower court had held that “Pfizer had not engaged in off-label marketing as a matter of law” and, therefore, could not have violated the FCA. Id. at 11.

The Second Circuit, affirming on the same ground, stated: “[the Guidelines’] general guidance need not hold for individual patients and should not override a physician’s clinical judgment about appropriate treatment of a particular patient.” Id. at 13-14 (internal quotation marks omitted). Since the Guidelines were recommendations and not mandatory within the labeling, the Second Circuit concluded that even if LIPITOR were promoted outside the Guidelines, such conduct did not constitute off‑label promotion. Id. at 13.

The most interesting part of this case, however, is the dicta expressing doubt whether off‑label promotion of pharmaceuticals is ever properly a basis for FCA liability. Here, the Second Circuit, in sharp contrast to the court in Franklin, stated:

[I]t is unclear just whom Pfizer could have caused to submit a ‘false or fraudulent’ claim: The physician is permitted to issue off‐label prescriptions; the patient follows the physician’s advice, and likely does not know whether the use is off‐label; and the script does not inform the pharmacy at which the prescription will be filled whether the use is on‐label or off. We do not decide the case on this ground, but we are dubious of Polansky’s assumption that any one of these participants in the relevant transactions would have knowingly, impliedly certified that any prescription for Lipitor was for an on‐label use. Id. at 16.

The district court had earlier reasoned that, because it is commonly understood that physicians may prescribe drugs for uses outside those approved by FDA and appearing in the product’s PI, “the entities to which reimbursement claims are made could hardly be understood to have operated on the assumption that the physician writing the prescription was certifying implicitly that he was prescribing LIPITOR in a manner consistent with the Guidelines.” Mem. and Order, United States ex rel. Polansky v. Pfizer, No. 04-cv-0704, 1 (E.D.N.Y. May 22, 2009) (“Polansky I”) at 12.

The Second Circuit’s opinion liberally discusses and applies its earlier ruling in Caronia, particularly with regard to how doctors are legally allowed to prescribe an FDA-approved drug for a use that has not been approved by FDA. However, the Polansky court stated that “pharmaceutical manufacturers are generally prohibited from promoting off-label uses of their products if the off-label marketing is false or misleading, or if it evidences that a drug is intended for such off-label use and is therefore ‘misbranded.’” Polansky IV at 5. The Court relied on the last part of that discussion by pointing to 21 C.F.R. § 201.128, an FDA regulation that defines a product’s “intended use.” Interestingly, FDA has proposed to strike the provision in this regulation that places the onus of providing adequate directions for the use of a medical product on the manufacturer when the manufacturer is merely on notice that its product is being used outside its FDA-approved uses. FDA, Clarification of When Products Made or Derived From Tobacco Are Regulated as Drugs, Devices, or Combination Products; Amendments to Regulations Regarding “Intended Uses,” 80 Fed. Reg. 57756, 57757, 57764 (Sep. 25, 2015). See our previous post on this proposed rule here.

The Court also agreed with the lower court that “there is an important distinction between marketing a drug for a purpose obviously not contemplated by the label (such as, with respect to Lipitor, ‘to promote hair growth or cure cancer’) and marketing a drug for its FDA-approved purpose to a patient population that is neither specified nor excluded in the label.” Polansky IV at 17-18. We are unclear as to the meaning of the distinction that the court drew here and we will have to see if other courts follow it. In fact, we are skeptical that any court will be able to resolve the serious constitutional issues raised by FDA’s policies with regard to off-label marketing by applying the distinction made by the Second Circuit.

For Polansky, whose legal battles in this matter against Pfizer have now lasted six times as many years as he was employed by the Company, the Second Circuit’s decision may be the practical end of his long dispute with Pfizer.

We note that the court’s ruling reached a result that is certainly favorable to pharmaceutical and medical device manufacturers facing FCA claims predicated on a theory of off-label promotion. Nevertheless, the court stated somewhat ominously at the end of its decision that where the promoted use is one where “it would be obvious to anyone” that it is not FDA-approved, FCA claims may survive a motion to dismiss. Polansky IV at 18. This language could mean that, at least in the Second Circuit, some off-label promotion by manufacturers may well expose them to FCA liability.

By Kurt R. Karst –   

A recent letter decision from FDA to the Patent and Trademark Office (“PTO”) concerning the availability of a Patent Term Extension (“PTE”) for U.S. Patent No. RE 41,571 (“the ‘571 patent), a method-of-use patent listed in the Orange Book covering Purdue Pharma L.P.’s (“Purdue’s”) BUTRANS (buprenorphine) Transdermal System (NDA 021306; approved on June 30, 2010) might mean that we are one step closer to another PTE court battle.  In a March 28, 2016 letter, FDA rejects Purdue’s characterization of the active ingredient in BUTRANS as buprenorphine levulinate, instead of buprenorphine base, as explained in Purdue’s February 28, 2014 supplemental PTE submission. 

As we previously reported, Purdue submitted a PTE application in August 2010 (Docket No. FDA-2012-E-0152) requesting a PTE for the ‘571 patent.  The PTE application was submitted only a few months after the U.S. Court of Appeals for the Federal Circuit ruled on May 10, 2010 in PhotoCure v. Kappos, 603 F.3d 1372 (Fed. Cir. 2010) and Ortho-McNeil Pharm., Inc. v. Lupin Pharms., Inc., 603 F.3d 1377 (Fed. Cir. 2010).  Those decisions concern the proper interpretation of 35 U.S.C. § 156(a)(5)(A), which states that the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred.”  The Federal Circuit ruled that that an “active ingredient” interpretation instead of an “active moiety” interpretation of the PTE statute – and the term “product” in particular – should be applied for PTE purposes (see our previous post here).  In dicta in the PhotoCure decision, however, the Federal Circuit suggested that the PTO might look at additional factors in considering whether or not a patent covering a product is eligible for a PTE. 

Although buprenorphine is not new – FDA has approved several applications for drug products containing buprenorphine, including BUPRENEX (NDA 018401), SUBUTEX (NDA 020732) – Purdue latched on to the PhotoCure dicta and made its case for a PTE for the ‘571 patent:

In contrast to [previous FDA approvals], the active ingredient for Butrans™ is buprenorphine base, which has never before been approved by the FDA. Moreover, buprenorphine base was required to undergo full FDA review, and has pharmacological properties that set it apart from buprenorphine hydrochloride.  Accordingly, the ‘571 patent that covers Butrans™ remains eligible for a patent term extension under 35 U.S.C. § 156.  See Photocure ASA v. Kappos, 603 F.3d 1372 (Fed. Cir. 2010) (allowing a § 156 extension even where similar active ingredient was previously approved by the FDA, since later approved active ingredient covered by extension application had different biological properties and underwent separate regulatory approval); Ortho-McNeil Pharm. v. Lupin Pharm., 603 F.3d 1377 (Fed. Cir. 2010) (allowing § 156 extension for enantiomer even though the racemate had already been approved by the FDA).

In other words, notwithstanding FDA’s previous buprenorphine NDA approvals, Purdue took the position that the ‘571 patent covering BUTRANS is eligible for a PTE because the drug product contains a different active ingredient (i.e., buprenorphine base) and has different properties that warranted separate patenting and separate FDA NDA approval (i.e., a different regulatory review period).

In June 2012, FDA sent a letter to the PTO stating that the Agency’s records “indicate that BUTRANS does not represent the first permitted commercial marketing or use of the product, as defined under 35 U.S.C. § 156(f)(1).”  And in a separate PTE matter, the PTO rejected arguments similar to those raised by Purdue with respect to dicta in the PhotoCure decision (see our previous post here).

Given these events, Purdue took a different tack.  In a February 28, 2014 supplemental PTE submission, the company argued that BUTRANS does not contain buprenorphine base, but rather buprenorphine levulinate.  If that were the case, then the ‘571 patent would be eligible for a PTE, because FDA has not previously approved an application under FDC Act § 505 for a drug product containing buprenorphine levulinate, or a salt or ester of buprenorphine levulinate.  However, FDA’s March 28, 2016 letter to the PTO rejects this approach: 

Purdue’s position is extraordinary.  Essentially it argues that the submissions that it made to obtain approval of this NDA, which asserted and presented evidence that the active ingredient of the drug was buprenorphine, were false.  Moreover, Purdue’s position would mean that the drug product that it has been marketing is misbranded because its labeling fails to bear the proportion and quantity of what Purdue now claims to be the active ingredient, buprenorphine levulinate. . . . 

Purdue has not submitted sufficient evidence to demonstrate that buprenorphine levulinate, a salt form of buprenorphine, is formed in the adhesive matrix of the Butrans Transdermal Delivery System (TDS). . . .  [Purdue’s nuclear magnetic resonance] experiments show, at best, that there is an interaction between buprenorphine and levulinic acid in chloroform, which is likely to occur for any given organic acid and organic base if present in a solvent environment like chloroform under soluble conditions.  For example, any combination of the ingredients in Butrans could hypothetically produce interactions leading to other undefined substances in the matrix.  While theoretically salts can be formed in situ, there is no evidence of this actually occurring in the TDS adhesive matrix.

With FDA’s position in hand, we expect that the PTO will, in due course, issue a determination that the ‘571 patent is ineligible for a PTE.  Once that decision becomes final, Purdue could abandon further efforts to obtain a PTE, or fight on in court.

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.

By Kurt R. Karst –      

An FDA decision to revoke designation of a drug (or a biological product) as an orphan drug is a rare event.  (Though it’s not as rare as revocation of orphan drug exclusivity, which has happened only once – see our previous post here).  Until recently, we were aware of only three orphan drug designation revocations in the 30-plus year history of the Orphan Drug Act.  That number more than doubled in April 2016 when FDA revoked four orphan drug designations for various drugs for the treatment of hypertension in pediatric patients.

FDA’s orphan drug regulations (21 C.F.R. § 316.29(a)) provide three independent bases under which orphan drug designation can be revoked – if FDA finds that:

(1)  The request for designation contained an untrue statement of material fact; or

(2)  The request for designation omitted material information required by [21 C.F.R. Part 316]; or

(3)  FDA subsequently finds that the drug in fact had not been eligible for orphan drug designation at the time of submission of the request therefor.

Prior to April 2016, we were aware of only three orphan drug designation revocations.  In each of these three cases (shown below), orphan drug designation was revoked because FDA determined that the drug “had not been eligible for orphan drug designation at the time of submission of the request.”  (We also note that in 2011, FDA denied a citizen petition seeking the revocation of orphan drug designation for MAKENA (hydroxyprogesterone caproate) Injection, 250 mg/mL (then known as GESTIVA).)  Specifically, FDA previously rescinded orphan drug designation for:

1. Papaverine – On February 6, 1992, OOPD designated Pharmedic Co.’s papaverine topical gel for the “treatment of sexual dysfunction in spinal cord injured patients.”  FDA revoked the designation on September 16, 1993 after additional information showed that the potential target population of the drug could be significantly larger than originally stated.
2. Methylnaltrexone – On June 17, 1996, FDA designated the University of Chicago’s methylnaltrexone for the “treatment of chronic opioid-induced constipation unresponsive to conventional therapy.”  FDA revoked the designation on January 9, 1998 after new information indicated that the drug could be used in a significantly larger patient population.
3. Pancreatic Enzymes – On January 23, 2002, FDA designated Altus Biologics Inc.’s TheraCLEC-Total, a microbially-derived pancreatic enzyme product containing amylase, lipase, and protease, as an orphan drug for the “treatment of exocrine pancreatic insufficiency.”  FDA revoked the designation on June 28, 2007 based on information showing that the drug could be used in a significantly larger patient population – specifically HIV/AIDS patients who suffer from fat malabsorbtion (see our previous post here).

The four new instances of orphan drug designation revocations that recently appeared on FDA’s Orphan Drug Designations and Approvals database are:

• Valsartan Oral Solution – Designated as an orphan drug on October 28, 2015 for the “treatment of hypertension in pediatric patients 0 through 16 years of age” (Carmel Biosciences)
• Lisinopril Oral Solution – Designated as an orphan drug on January 27, 2015 for the “treatment of primary hypertension with complications and secondary hypertension in pediatric patients (ages 0 through 16 years of age” (BioRamo, LLC)
• Lisinopril Oral Solution – Designated as an orphan drug on October 14, 2015 for the “treatment of hypertension in pediatric patients 0 through 16 years of age” (Silvergate Pharmaceuticals, Inc.)
• Enalapril Maleate (Powder for Oral Solution) – Designated as an orphan drug on January 30, 2013 for the “treatment of hypertension in pediatric patients” (Silvergate Pharmaceuticals, Inc.)

The four new revocations share several similarities.  There are the obvious similarities of indication and timeframe of designation.  But also note that in each instance FDA’s Orphan Drug Designations and Approvals database identifies the dosage form of the designated drug.  That’s unusual and likely indicates that orphan drug designation was granted based on a plausible hypothesis of clinical superiority (perhaps “greater safety” or “major contribution to patient care”) because FDA had previously approved the same drug (i.e., active moiety) for the same rare disease. 

As to FDA’s basis for revoking orphan drug designation for the four drugs above, we suspect that FDA stumbled upon some information that the Agency believed supported withdrawal and then determined that each drug “had not been eligible for orphan drug designation at the time of submission of the request” because the United States prevalence of pediatric hypertension exceeded the 200,000 person cut-off. 

By Kurt R. Karst –      

The first iteration of the Generic Drug User Fee Amendments (“GDUFA”) – “GDUFA I” – is now well into Year 4 of the 5-year program, and anticipation is growing as to what the second iteration of the program – “GDUFA II” – might hold for the generic drug industry. According to the various (and not terribly transparent or informative!) minutes from the GDUFA Reauthorization Stakeholder Meetings and the GDUFA Reauthorization Negotiation Sessions, we can expect many small changes and refinements to GDUFA, but probably not a lot of big changes.  Many (if not most) of the changes may be captured in what will be the GDUFA II Performance Goals and Procedures letter accompanying the GDUFA II legislation.  Most folks probably would not be surprised to learn that we have a GDUFA II wish list: a list of some of the things we hope to see included in the next iteration of the user fee program.  Most of the items we’re hoping for are small changes.  For example, we would like to see user fee relief for small businesses, prompt posting of all final and tentative ANDA approval letters (along with a return to the “date of submission” listed in the letter – see here) (after all, one of the tenets of GDUFA is transparency) . . . and a deadline for FDA to rule on a citizen petition requesting that the Agency designate a drug as a Reference Listed Drug (“RLD”).  That last item may seem a bit out of left field to most folks, but it’s important to ANDA (and to 505(b)(2) NDA) applicants.

FDA stated the Agency’s policy for designating RLDs back in 1992 in the preamble to the Agency’s final regulations implementing certain provisions of the 1984 Hatch-Waxman Amendments. There (57 Fed. Reg. 17,950, 17,958 (Apr. 28, 1992)), FDA stated:

FDA will designate all reference listed drugs. Generally, the reference listed drug will be the NDA drug product for a single source drug product.  For multiple source NDA drug products or multiple source drug products without an NDA, the reference listed drug generally will be the market leader as determined by FDA on the basis of commercial data.  FDA recognizes that, for multiple source products, a product not designated as the listed drug and not shown bioequivalent to the listed drug may be shielded from direct generic competition.  If an applicant believes that there are sound reasons for designating another drug as a reference listed drug, it should consult FDA. Once FDA designates that reference listed drug, that drug will continue to be the reference standard even if the drug is later replaced as the market leader.  

FDA’s policy is further described in the recently revised preface to the Orange Book:

By designating a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent, FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart. Such variations could result if generic drugs were compared to different drugs.

However, in some instances when a listed drug is not designated as the reference listed drug and/or not shown to be bioequivalent to the reference listed drug, such listed drug may be shielded from generic competition. An applicant wishing to market a generic version of a listed drug that is not designated as the reference listed drug may petition the Agency through the citizen petition procedure (see 21 CFR 10.25(a) and CFR 10.30).  If the citizen petition is approved, the listed drug will be designated as an additional reference listed drug, in which case an ANDA citing the designated reference listed drug may be submitted.

Over the years, FDA has received and responded to scores of citizen petitions requesting that the Agency assign RLD status to various NDA and ANDA approved drug products. FDA only very rarely denies a citizen petition requesting RLD designation (see our previous post here).  Given the rarity of denials, and what we think should be a relatively perfunctory process, it’s surprising to us that FDA takes soooo long to issue a decision on an RLD designation citizen petition request.  Just take a gander at our FDA Citizen Petition Tracker for all of the pending petitions identified as “”Citizen Petition – RLD Designation” under “Petition Type.”  Some have been pending for years with nothing more than the boilerplate interim response required within 180 days after FDA receives a petition.

And worse yet, an applicant is stuck in limbo until FDA grants the petition and designates the identified drug as an RLD. That’s right – an ANDA (and probably a 505(b)(2) NDA as well) would be shot down upon submission unless the drug product identified in the application as the basis of submission is not identified in the Orange Book with a “+” showing RLD status.  (See our previous post on the difference between what we’ve termed the “big RLD” and the “little rld.”)  In fact, draft FDA guidance (“ANDA Submissions — Content and Format of Abbreviated New Drug Applications”) says as much:

When an applicant wants FDA to designate a second RLD, the request is made through a citizen petition submitted to FDA’s Division of Dockets Management in accordance with §§ 10.20 and 245 10.30. An applicant may submit the application only after the citizen petition has been granted. [(Page 7; emphasis added)]

Moreover, we’ve been told that the Division of Filing Review (“DFR”) in the Office of Generic Drugs would issue a Refuse-to-Receive (“RTR”) letter to an applicant if the incoming ANDA identifies a drug product that is not designated as a RLD as the basis of submission of the application. Although DFR would likely first give the ANDA applicant an opportunity to change the basis of submission to a product that is identified as an RLD before issuing an RTR letter, in most instances that’s not an option for an ANDA applicant.

Other types of citizen petitions are subject to a statutory deadline. There’s the 150-day deadline for so-called “Section 505(q) Citizen Petitions,” a 270-day deadline for FDA to respond to so-called “Section 505(w) Discontinuation Citizen Petitions,” and a 90-day deadline for FDA to respond to an ANDA Suitability Petition.  FDA’s been pretty good about meeting the newer statutory deadlines for 505(w) and 505(w) petitions (see our previous posts here and here),  but FDA’s 30-plus year history of responding to ANDA Suitability Petitions in a timely manner is pretty dismal (you can read our analysis of that track record here).  In any case, if RLD Designation petitions were subject to a statutory deadline, or, better yet, a performance goal under GDUFA II – perhaps 90% of petitions reviewed and acted on within 60 or 90 days of receipt – we would probably see better results.  And ANDA applicants would be in a better position to plan and seek approval.

By McKenzie E. Cato* & Allyson B. Mullen –

On May 16, FDA issued its final guidance document on postmarket surveillance of medical devices, “Postmarket Surveillance Under Section 522 of the Federal Food, Drug, and Cosmetic Act,” approximately five years after issuing the draft guidance. The stated purpose of this guidance is to assist manufacturers in fulfilling section 522 obligations by providing recommendations on the format, content, and review of postmarket surveillance plan submissions.  The final guidance outlines the section 522 postmarket surveillance process from initial identification of an issue through creation of a surveillance plan and submission of interim and final reports.

FDA’s postmarket surveillance program has been, and continues to be, a work in progress. About a year after issuing the draft guidance, FDA published a white paper titled “Strengthening Our National System for Medical Device Postmarket Surveillance” (see our previous post on FDA’s action plan here). One outcome from this action plan was the creation of a multi-stakeholder Planning Board via the Brookings Institution in 2014.  The Board issued a 75-page report documenting its recommendations and a 5-year implementation plan for a National Medical Device Postmarket Surveillance System in February 2015 (see our post on this report here).

The Brookings report pointed out that a “key challenge” in conducting section 522 studies is a lack of incentives for clinicians and patients to participate due to the “reporting burdens and other requirements on top of their usual practice.” The report identified registry-based surveillance as a possible solution to this problem.  The final guidance incorporated this suggestion and added “Comprehensive, Linked, Registry-Based Surveillance” to its list of postmarket surveillance study designs.  The final guidance explains that this design “leverages national registry infrastructure” and “is characterized by shared responsibilities of multiple stakeholders.”

The most notable changes from the draft guidance are the addition of procedures for increased status monitoring, review, and communication between manufacturers and the Agency. First, FDA has created a system of “decision letters” for evaluating a proposed surveillance plan.  After evaluating whether a proposed plan “is administratively complete and whether the plan will result in the collection of useful data,” FDA may issue one of the following letters:

• Not Acceptable Letter: The submission is found to be administratively incomplete.
• Approval Letter: FDA approves of the proposed plan as submitted.
• Minor Deficiency Letter: There are minor deficiencies that must be addressed before the plan is approved.
• Major Deficiency Letter: There are serious deficiencies relating to whether the plan will result in the collection of useful data that will answer surveillance questions.
• Disapproval Letter: FDA disapproves of the plan as submitted because FDA has determined that it is not likely to result in the collection of useful data that will address the postmarket surveillance questions in the 522 order.

Requests from a manufacturer to revise an approved surveillance plan would be subject to the same decision letter process. In contrast, the draft guidance merely stated that FDA would issue an approval order, an approvable letter requesting revisions, or a letter disapproving the proposed plan.  The final guidance includes a new “Section 522 Administrative Checklist” in an appendix.  In the last few years, FDA has implemented several new administrative reviews for submissions, such as the 510(k) “Refuse to Accept Policy” checklist and the pre-submission guidance (finalized in 2014), which includes a “Q-Sub Acceptance Checklist.”  This new Section 522 Administrative Checklist will hopefully be helpful to companies in avoiding “Not Acceptable” letters.

Additionally, the draft guidance included a list of categories that FDA may use in determining postmarket surveillance plan status: Plan Pending, Plan Overdue, Study Pending, Progress Adequate, Progress Inadequate, Completed, Terminated, and Other.  The final guidance added several new categories to this list:  Noncompliant, Revised/Replaced, and Consolidated.  According to a September 2015 GAO report, of the postmarket surveillance studies ordered by FDA from May 1, 2008, through February 24, 2015, 88% are inactive. About one-third of the studies classified as “inactive” were studies that were consolidated with other related study orders.  The additional status categories in the final guidance, particularly the addition of a “Consolidated” category, appears to be an attempt to better track the outcome of the vast majority of postmarket surveillance studies which become inactive.

The final guidance does not incorporate any significant changes to the recommended content and format of interim and final reports. However, one comment by AdvaMed on the draft guidance criticized the vagueness of the language used by FDA in describing the criteria the Agency uses to evaluate interim and final reports (e.g., “the completeness of the report”).   FDA has added some additional language to clarify these criteria.  For example, in regards to the “completeness” of an interim report, the final guidance explains that FDA will review “progress towards achieving primary and secondary endpoints and performance goals, or sufficient individual endpoint data to infer progress in the case of composite endpoints.”  The final guidance also adds that if an interim report includes insufficient data or raises new safety or effectiveness concerns, FDA may take certain regulatory actions, including requesting labeling changes, issuing safety communications, or even taking compliance and/or enforcement action.

FDA has greatly expanded the list of postmarket surveillance information that may be posted publicly on FDA’s 522 webpage. In addition to general information about postmarket surveillance studies (e.g., application number, applicant name, device name, status) and reporting information (e.g., interim and final report schedule, receipt dates, status category), which were listed in the draft guidance, the final guidance states that the following additional information may be posted on the 522 webpage:

• General surveillance plan parameters: Design description, data source, comparison group, analysis type, patient population
• Detailed surveillance plan parameters, where applicable: Design description, sample size (patients and sites), patient population description, data collection, follow-up visits and length of follow-up
• Interim report results: Interim summary data and/or FDA analyses “when appropriate to protect the public health,” including number of patients enrolled, number of sites enrolled, and interim safety/effectiveness findings
• Final report results, where applicable: Actual number of patients enrolled, actual number of sites enrolled, patient follow-up date, final safety/effectiveness findings, study/surveillance strengths and weaknesses

General and detailed study parameters and report results are already posted on FDA’s section 522 website, so it is unclear whether the final guidance was updated to reflect existing policy or whether FDA plans to post even more specific information about postmarket surveillance plans moving forward.

Since the draft guidance was issued in August 2011, the Food and Drug Administration Safety and Innovation Act (FDASIA) amended section 522 to provide that FDA may issue a postmarket surveillance order at the time of device approval or clearance or any time thereafter. FDASIA also specified that a manufacturer must commence postmarket surveillance within 15 months after the order is issued.  The final guidance has been edited to reflect these timing considerations.  The guidance notes that failure to commence surveillance within the 15-month period is a prohibited act which renders the device misbranded. 

Finally, the final guidance expands on the section about repercussions for failure to comply with a section 522 order. Unless an exemption is granted, manufacturers must comply with the order, even if the manufacturer has stopped marketing the device subject to the order.  The guidance states that FDA will review requests to terminate or modify a postmarket surveillance plan on a case-by-case basis, but notes that FDA is less likely to grant such requests for devices that are implanted long-term.  

Companies should note that 522 orders are appealable. The final guidance reiterates section 822.22 of the regulations, indicating that if a manufacturer disagrees with FDA about the content of a surveillance plan or a proposed plan is disapproved, the manufacturer has several procedural options.  A manufacturer may request a meeting with the Office Director of OSB, appeal FDA’s decision in accordance with 21 C.F.R. § 10.75, request an informal hearing under 21 C.F.R. Part 16, or request review by the Medical Devices Dispute Resolution Panel of the Medical Devices Advisory Committee.  While not used frequently (according to FDA’s website only 4 were issued last year), manufacturers are often required to expend a great deal of time and resources to comply.  We hope that the final guidance provides those manufacturers faced with a 522 order greater clarity as to the process and details for compliance. 

*Summer Associate

By Anne K. Walsh & John R. Fleder –

DOJ Deputy Attorney General Sally Q. Yates spoke last week before the New York City Bar Association White Collar Crime Institute to provide an update on the DOJ policy she announced in September 2015, about which we reported here and here. The focus of her speech was to describe the changes, “both within the Department and outside the Department,” that have been implemented as a result of the eponymous policy, which Ms. Yates refers to as the Individual Accountability Policy.

Companies under DOJ scrutiny continue to provide facts about individuals to the government. Indeed, Ms. Yates reported that no company has decided not to cooperate with DOJ’s requests for information, despite some critics’ predictions of cooperation fallout from the new policy.  Ms. Yates opined that a decision to forego the benefits accorded cooperation and to “roll the dice” would be a “particularly risky calculus, especially for a publicly traded company.”  Indeed, according to her, companies not only continue to cooperate, but are making “real and tangible efforts” to identify facts about individual conduct.  She described how some companies even provide prosecutors with “Yates Binders,” another eponymous term used to describe compilations of relevant emails of individuals being interviewed by the government.  For companies unsure how to satisfy the government, Ms. Yates offered that companies should turn over information to DOJ “as they receive it,” recognizing that companies may not have all the facts lined up early in the investigation.  And she also encouraged company counsel to ask the prosecutors questions regarding the scope and how to proceed, noting that these question are case-specific and that it is not possible to identify hard and fast rules.

Ms. Yates emphasized that the policy does not require a company to make a “legal conclusion” about whether any employee is civilly or criminally responsible for the conduct. She stated that DOJ just wants the facts, and that DOJ will make its own judgment about whether an action results in civil or criminal exposure.  Although this sounds like an opportunity for a company to avoid having to “serve up” an individual to DOJ, corporate counsel will almost always have to link the conduct to a legal conclusion to the extent the facts expose the company to civil or criminal liability.

Moreover, the policy continues to pose very troublesome questions for corporations and their counsel. How do they disclose all the “facts” to the government without waiving privilege?  What “warnings” should be given to employees being interviewed by outside counsel when counsel knows that there is a reasonable chance that the company may need to disclose the facts uncovered in the interviews of those employees?

Expressing no doubt that the new policy has shaken up the rules of the road, Ms. Yates assured that “equilibrium will return” and that a “new normal will exist.” She defined the new normal to hold wrongdoers accountable based on facts and evidence, not on position or title, power or wealth. As Ms. Yates herself acknowledged, however, the policy is not even a year old; it remains to be seen if there are true benefits of this shift in approach.

The FDA Law Blog is pleased to announce the release of the FDA Deskbook, prepared by the attorneys at Hyman, Phelps & McNamara, P.C., the same authors who provide the expertise and analysis contained in this blog.  The FDA Deskbook is a complete resource on compliance and enforcement issues affecting FDA-regulated industry.  Readers of this blog are entitled to a 25% discount using this link.

By Riëtte van Laack –

FDA announced the availability of the Final Guidance for Medical Foods: “Frequently Asked Questions About Medical Foods; Second Edition.”

As we previously reported, in August 2013, FDA issued a draft guidance, updating the 2007 guidance for medical foods. In the 2013 draft guidance FDA made numerous statements that we believe were not in accordance with the law. Among other things, FDA specifically excluded foods for certain diseases, such as diabetes, from the medical food definition. The draft guidance generated many comments.

In the notice of availability published in the Federal Register, FDA asserts that it modified “the guidance where appropriate” and “made editorial changes to improve clarity.” Review of the Guidance shows that, overall, FDA largely ignored the comments and continues to narrowly interpret the definition of medical foods. This is disappointing but hardly surprising development.  

Possibly the most surprising change is FDA’s new rationale for exclusion of foods for diabetics from the medical food definition. In the 2013 draft guidance, FDA acknowledged that diabetes is associated with nutrient requirements but those requirements could be met by modification of the diet alone. Therefore, such products failed one of FDA’s regulatory requirements for medical foods. In the final guidance, FDA now asserts that there are no special nutrition requirements for patients with diabetes. Therefore, foods for diabetics fail one of the statutory requirements.

Since this is guidance and FDA does not need to explain its actions, we can only speculate as to FDA’s reasons for its persistence in misinterpreting the law.