By Anne K. Walsh –

In what may be a game-changer for drug companies, a court in the District of Columbia has been asked to set forth parameters for a pharmaceutical company that markets its products in a way that the government may consider to be off-label promotion.  Par Pharmaceuticals recently challenged (here and here) FDA’s authority in the off-label promotion arena on First Amendment and Administrative Procedure Act grounds.  Specifically, Par’s action challenges the government’s theories that drugs promoted for unapproved uses are either unapproved “new drugs” based on the statutory definition contained in the Federal Food, Drug, and Cosmetic Act, or “misbranded” drugs, because the drug failed to bear adequate directions for use, sometimes called the “backdoor” new drug charge.   

Par very clearly and accurately describes in its court documents the problems associated with these legal theories, so they are not necessary to reiterate here.  In addition to those challenges, what is unique about Par’s challenge is that it also seeks a declaratory judgment from the court that FDA cannot prosecute Par for making on-label statements about a drug’s approved uses.  Although this seems intuitively logical, Par’s case highlights the overbreadth of FDA’s “intended use” regulations and its authority to regulate speech. 

According to Par, the U.S. Attorney’s Office in the District of New Jersey subpoenaed documents relating to Par’s sales and marketing of its drug, Megace® ES.  Megace® ES is approved only for AIDS patients, to treat anorexia, cachexia or unexplained weight loss (also known as wasting) frequently associated with AIDS patients.  It is more frequently prescribed by physicians, however, for non-AIDS patients who experience wasting, such as cancer and geriatric patients.  Indeed the majority of its sales are to off-label populations.  

In the Complaint, Par details how it purposefully tailored its marketing strategy knowing that the drug was only approved for use by AIDS patients.  Par evaluated the market and decided to talk to doctors in oncology and long-term care settings, not to promote off-label for these patients, but to discuss the on-label treatment of AIDS patients who doctors serve in these settings.  Par determined that these doctors “reasonably may encounter patients suffering from AIDS-related wasting, and thus may have occasion to prescribe Megace® ES for its on-label use.”  Complaint, ¶ 50.  In discussions with Par, the government indicated that Par should have confirmed that there are a “sufficient” number of on-label patients being treated in those settings before Par called on them.  Id. ¶ 71.  Of course as Par correctly notes, there is no guidance provided by the government that defines what is a “sufficient number” to allow Par to have no fear of promoting on-label in those settings.

There are several factors that support a favorable ruling to Par in this action assuming the Court reaches the merits of the dispute.  First, there is practice-based evidence and scientific support of the drug’s efficacy in treating these off-label populations.  Second, there are several authoritative treatment guidelines recommending the off-label use of the drug, including from government agencies like CMS, a sister agency of FDA.  Third, the government determined that the off-label uses are “medically accepted” and reimburses for them from its federal healthcare programs.  Finally, the use of Megace® ES is virtually the standard of care for treating wasting, in AIDS, non-AIDS, geriatric, and oncology patients.  Indeed, this was one of the reasons why it was impossible for Par to develop an appropriate placebo-controlled clinical trial (typically necessary for FDA approval) – as doctors refused to use something other than Megace® ES on their patients.  

This action by Par is just another development in what industry hopes is a restriction on FDA’s authority to prohibit truthful, non-misleading speech.  In the last few months, we have seen the Supreme Court’s decision in IMS Health v. Sorrell, the Citizen Petition filed by the Medical Information Working Group asking FDA for clearer off-label regulations, and supplemental briefs filed in the pending Second Circuit appeal in United States v. Caronia (reported on here).  Because a victory by Par could result in a ruling that certain marketing conduct cannot be prosecuted, many in the industry eagerly await the outcome here.

By Kurt R. Karst –    

Like any good thriller movie that coaxes you into a feeling of finality – right before the surprise twist makes you jump out of your seat – the saga over a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering The Medicines Company’s (“MDCO’s”) ANGIOMAX (bivalirudin) has been a legal thriller for the ages with many surprise twists.  Now there’s a new one . . . . 

As FDA Law Blog readers know, MDCO’s PTE battle has touched all three branches of government throughout the years.  Most recently, Section 37 of the Leahy-Smith America Invents Act (“AIA”) (Pub. Law No. 112-029), titled “Calculation of 60-Day Period for Application of Patent Term Extension” and referred to by some as “The Dog Ate My Homework Act” or the “Medco fix,” amended the PTE statute at 35 U.S.C. § 156(d), and was intended to legislatively resolve MDCO’s PTE battle. 

The inclusion of Section 37 in the AIA was contentious to say the least.  During the Senate’s consideration of the AIA, U.S. Senators Jeff Sessions (R-AL), Tom Coburn (R-OK) and Joe Manchin (D-WV) proposed an amendment to strike Section 37 from the AIA, and sent out a “Dear Colleague” letter urging support for their amendment.  But the amendment failed by a narrow 51-47 vote and Section 37 became law. 

Shortly after the enactment of the AIA, MDCO sent a letter to the U.S. Court of Appeals for the Federal Circuit notifying the Court of the enactment of Section 37 and asserting that it resolves the merits of the ongoing ‘404 patent PTE litigation with APP Pharmaceuticals, LLC (“APP”) (see our previous posts here, here, and here).  APP vigorously disagreed, however, that Section 37 resolved the case, and has argued that Section 37 cannot constitutionally be applied and that Section 37 does not take effect for one year after AIA enactment.  The Federal Circuit ordered MDCO and APP to simultaneously file supplemental briefs addressing the effect of Section 37 of the AIA on the disposition of the case.  Those briefs were filed earlier this week.  Oral argument is scheduled for November 15, 2011.

Now Sens. Sessions and Coburn have reignited their opposition to Section 37.  Earlier this week, they proposed an amendment – SA 812 – to the 2012 Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act (H.R. 2112), intended to effectively nullify Section 37.  SA 812 would add Section 114 to the appropriations bill and states:

Sec. 114. No funds appropriated, or otherwise made available, under this Act may be used by the Director of the United States Patent and Trademark Office to carry out section 37 of the Leahy-Smith America Invents Act (35 U.S.C. 156 note), including the flush sentence added to section 156(d)(1) of title 35, United States Code, by such section 37.

The Sessions/Coburn amendment has received support from the Generic Pharmaceutical Association and Citizens Against Government Waste (“CAGW”).  CAGW sent out a letter to the Senate on October 19th urging support for SA 812.  Other groups may be waiting in the wings to voice their support for the amendment. 

As noted above, the previous amendment failed by a narrow 51-47 vote; however, many of the "nay" votes last time may have been cast to prevent a disruption in the AIA's enactment.  Now separated from patent reform, the vote could change.

We know you’re on the edge of your seats.  Stay tuned for more thrills.

By Kurt R. Karst –   

On October 19, 2011, FDA issued a proposed rule to amend the Agency’s December 29, 1992 (57 Fed. Reg. 62,076) orphan drug regulations.  The proposal is not a whole-scale overhaul of FDA’s orphan drug regulations, but rather a group of amendments “intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since those regulations were issued” and that are based on the Office of Orphan Products Development’s (“OOPD’s”) review of more than 3,350 orphan drug designation requests since December 1992.  FDA’s proposal is the latest development on the orphan drug front.  As we reported last week, the National Organization for Rare Disorders (“NORD”) released a landmark report (authored by Chairman of the NORD Board of Directors and Hyman, Phelps & McNamara, P.C. Director, Frank J. Sasinowski) on the flexibility in FDA’s review of potential treatments for patients with rare diseases.

FDA’s proposed rule addresses 13 specific issues (some of which we touched on earlier this week when we reported on an OOPD Standard Operating Procedures and Policies):

(1)  Demonstration of an appropriate “orphan subset” of persons with a particular disease or condition that otherwise affects 200,000 or more persons in the United States, for the purpose of designating a drug for use in that subset (21 C.F.R. § 316.20(b)(6));

(2)  Eligibility for orphan-drug designation of a drug that is otherwise the same drug for the same orphan indication as a previously approved drug (21 C.F.R. §§ 316.3(b)(3), 316.20(a), and 316.20(b)(5));

(3)  Eligibility for multiple orphan-drug exclusive approvals when a designated orphan drug is separately approved for use in different subsets of the rare disease or condition (21 C.F.R. § 316.31);

(4)  Requirement for demonstrating clinical superiority for the purpose of orphan-drug exclusive approval (21 C.F.R. § 316.3(b)(3)(iii));

(5)  Requirement for submitting the name of the drug in an orphan-drug designation request (21 C.F.R. § 316.20(b)(2));

(6)  Required drug description and scientific rationale in a designation request (21 C.F.R. § 316.20(b)(4));

(7)  Required information in a designation request relating to the sponsor's interest in the drug (21 C.F.R. § 316.20(b)(9));

(8)  Timing of a request for orphan-drug designation (21 C.F.R. § 316.23(a));

(9)  Responding to a deficiency letter from FDA on an orphan-drug designation request (21 C.F.R. § 316.24(a));

(10)  FDA publication of information regarding designated orphan drugs (21 C.F.R. § 316.28);

(11)  FDA recognition of orphan drug exclusive approval (21 C.F.R. § 316.34(c));

(12)  Miscellaneous terminology changes (21 C.F.R. Part 316); and

(13)  OOPD address change (21 C.F.R. § 316.4).    

Below we note some of the proposed changes and clarifications that we think merit special attention.

Demonstration of an “Orphan Subset” of a Disease or Condition.  One element of an orphan drug designation request is to explain the relevant “medically plausible subset” (“MPS”) of individuals (if any) affected by a particular disease or condition that is eligible for a therapy (21 C.F.R. § 316.20(b)(6)).  FDA’s orphan drug regulations do not clearly define the term “medically plausible subset.”  In fact, in the preamble to the 1992 regulations, FDA stated that it “declines to provide examples of medical plausibility or to further develop the definition of [an MPS].  Application of the concept is a matter of judgment based on the specific facts of each case.” 

Recognizing that the term “medically plausible” “has been misinterpreted to mean any medically recognizable or any clinically distinguishable subset of persons with a particular disease or condition,” and that “[i]nappropriate application of the concept of a [MPS] could result in the creation of subsets of non-rare diseases or conditions that are artificially narrow,” FDA proposes to remove the term “medically plausible” in 21 C.F.R. § 316.20(b)(6) “and instead provide a description of how an appropriate subset [(i.e., an ‘orphan subset’)] may be identified for the purpose of orphan-drug designation.”  Specifically, 21 C.F.R. § 316.20(b)(6) is proposed to state:

Where a drug is under development for only a subset of persons with a particular disease or condition that otherwise affects 200,000 or more people, a demonstration that, due to one or more properties of the drug, the remaining persons with such disease or condition would not be appropriate candidates for use of the drug

FDA goes on in the preamble to note that “[w]hen a sponsor has established that the selected population constitutes a non-arbitrary subset, e.g., by describing the scientific or medical basis for limiting the potential use of the drug to that population and demonstrating that such scientific or medical basis is reasonable, the target population is an acceptable orphan subset of persons with the particular disease or condition for the drug of interest.”  FDA also provides some useful examples of what the Agency says are appropriate and inappropriate orphan subsets, and recommends that sponsors ask themselves a few of questions to test whether a subset of patients within a larger disease or condition grouping that has a United States prevalence of 200,000 or more persons can be considered an appropriate orphan subset for purposes of orphan drug designation:

• Is the intended subset artificially restricted in any way with respect to the use of the drug to treat the disease or condition?
• Given that the drug may potentially benefit this particular subset of persons, is there a reasonable scientific or medical basis for believing that the drug would also potentially benefit the remaining population with the non-rare disease or condition or a larger subset of that population?  If not, why not?

Eligibility for Orphan Drug Designation of a Drug That Was Previously Approved for the Orphan Indication.  FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug” (emphasis added).  Over the years, there has been confusion as to how FDA/OOPD interprets the term “orphan drug” in this regulation.  The term is specifically defined at 21 C.F.R. § 316.3(b)(10) to mean “a drug intended for use in a rare disease or condition as defined in section 526 of the act.”  But does this mean that an “orphan drug” is any previously approved drug for a rare disease or condition, regardless of whether or not it was designated and approved as an orphan drug?

FDA states in the proposed rule that “[i]n the absence of a clinical superiority hypothesis, the Agency does not interpret the orphan-drug regulations to permit orphan designation of a drug that is otherwise the same as a drug that is already approved for the orphan use, either where the approved drug received orphan-drug exclusive approval (even after such drug's exclusivity period has run out) or where the approved drug was not previously designated as an orphan drug and thus did not receive orphan exclusive approval” (emphasis added).  Accordingly, FDA proposes to amend certain regulations to delete the word “orphan” in the phrase “approved orphan drug” in order to “clarify that these provisions would be applicable to a drug that is otherwise the same drug as any previously approved drug for the same orphan disease or condition, regardless of whether such drug was designated as an orphan drug” (emphasis in original).

Eligibility for Multiple Orphan-Drug Exclusive Approvals.  For years now, we understand that FDA has adopted a “pie approach” to orphan drug designation, under which a single orphan drug designation can result in multiple periods of orphan drug exclusivity.  That is, an approval for each slice of the pie (i.e., the designation) can result in separate 7-year periods of exclusivity.  As FDA explains in the preamble to the proposed rule:

The scope of orphan exclusive approval for a designated drug is limited to the approved indication or use, even if the underlying orphan designation is broader.  If the sponsor who originally obtained orphan exclusive approval of the drug for only a subset of the orphan disease or condition for which the drug was designated subsequently obtains approval of the drug for one or more additional subsets of that orphan disease or condition, FDA will recognize orphan-drug exclusive approval, as appropriate, for those additional subsets from the date of such additional marketing approval(s).  Before obtaining such additional marketing approval(s), the sponsor in this instance would not need to have obtained additional orphan designation for the additional subset(s) of the orphan disease or condition.

This interpretation is proposed to be included in 21 C.F.R. § 316.31(b).  FDA also notes in the preamble what this interpretation means with respect to clinical superiority and subsetting, stating that:

After approval of the drug for one or more subsets of the orphan disease or condition, a subsequent sponsor may, without submitting a plausible hypothesis of clinical superiority, seek designation of the drug for the subset(s) of the orphan disease or condition for which the drug has not yet been approved.  FDA may designate the drug for use in the remaining subset(s) without requiring a postulation of clinical superiority.  To obtain such a designation, however, the sponsor must demonstrate that, at the time of its designation request, the entire population with the orphan disease or condition, not just the remaining subset(s) of the population, is under the prevalence limit, unless the sponsor can demonstrate that the remaining subset(s) is an orphan subset in accordance with § 316.20(b)(6).

Demonstration of Clinical Superiority.  FDA’s proposal is intended to clarify that merely because FDA/OOPD has granted orphan drug designation based on a plausible hypothesis of clinical superiority does not mean that clinical superiority has been demonstrated and the orphan drug can be approved or approved with a period of 7-year exclusivity.  FDA states in the preamble to the proposed rule that:

It is possible . . . that a sponsor that has obtained designation of its drug on the basis of a hypothesis that the drug will be clinically superior will be unable, upon submission of the marketing application, to demonstrate that the drug is clinically superior to the previously approved drug.  In that case, if the already approved drug has remaining exclusive approval, the subsequent drug would not itself be eligible for approval, because it is the same drug as the drug with exclusive approval.  If the approved drug does not have exclusive approval, the subsequent drug may be approved, but would not itself be eligible for orphan-drug exclusive approval.

FDA also states with respect to the “major contribution to patient care” (the so-called “MC-to-PC”) basis for clinical superiority (see our previous post here) that:

a drug that is otherwise the same drug as a previously approved drug, and for which a clear showing of greater effectiveness or greater safety has not been made, may still be considered clinically superior within the meaning of § 316.3(b)(3)(iii) if it makes a major contribution to patient care.  FDA believes that such clinical superiority is meaningful only when the subsequent drug provides safety or effectiveness comparable to the approved drug.  For example, to claim that a drug makes a major contribution to patient care through a new formulation or a different route of administration, the sponsor must also address whether the change renders the drug less safe or less effective than the approved drug.  (Emphasis added)

Timing of Request for Orphan-Drug Designation.  FDA’s proposal would amend 21 C.F.R. § 316.23(a) to clarify the timing of an orphan drug designation request.  According to FDA, “[i]t is not clear in the current regulatory language that one sponsor’s marketing application would not prevent a different sponsor from submitting a request for orphan designation for the same drug for the same orphan use and that this subsequent sponsor would not have to submit a plausible hypothesis of clinical superiority.” 

The proposed revisions to 21 C.F.R. § 316.23(a) would not only clarify that a sponsor may not submit an orphan drug designation request after the submission of a marketing application for the drug for the rare disease or condition, but also that “submission by a sponsor of a marketing application for the drug for the orphan indication does not prevent another sponsor from submitting a request for orphan designation of the same drug for the same orphan use.”  However, “[o]nce any sponsor’s marketing application for the orphan indication has been approved, with or without orphan exclusive approval, another sponsor may not obtain orphan-drug designation for the same drug and the same orphan indication or use for which the approval was granted absent a plausible hypothesis of clinical superiority.”

Responding to a Deficiency Letter From FDA on an Orphan Drug Designation Request.  Noting that “FDA regulations are currently silent on when sponsors must respond to a deficiency letter from FDA on an orphan-drug designation request,” and that while some sponsors respond promptly to deficiency letters, other sponsors “may take several years or more to respond without sending any interim communication to FDA,” the Agency proposes to amend 21 C.F.R. § 316.24 to require that sponsors respond to a deficiency letter within 1 year after issuance, unless the sponsor requests (in writing) an extension of time to respond within the 1-year period.  “Such a request would specify both the reason(s) for the requested extension and the length of time of the requested extension,” says FDA.  According to FDA, a “repeat request” for an extension may be granted if the sponsor submits a new extension request before expiration of the deadline as originally extended, and if such request states both the reason(s) for the request and the requested length of time of the extension.

In the event a sponsor fails to respond to a deficiency letter, fails to request an extension
of time within a year, or if FDA denies an extension request, the Agency says that it may consider the designation request voluntarily withdrawn.  FDA notes in the proposal that the Agency “will grant all reasonable requests for an extension”; however, FDA goes on to state that:

some deficiencies may be less suitable to extension requests than others.  For example, FDA generally expects that deficiencies involving an inaccurate or incomplete prevalence estimate will be readily addressed within 1 year.  Other types of deficiencies, however, may take longer to address.  For example, deficiencies involving the scientific or medical rationale supporting a designation request for only a subset of persons with a particular disease or condition may require sponsors to conduct research and develop additional data, which may take several years or more.  For the latter types of deficiencies, FDA generally anticipates granting extension requests to allow sponsors to develop necessary supporting data and information.

Electronic or written comments on the proposed rule (Docket No. FDA-2011-N-0583) are due by January 17, 2012.

By Jennifer D. Newberger –

On October 14, 2011, Representative Brian Bilbray (R-CA) introduced H.R. 3203, the “Novel Device Regulatory Relief Act of 2011.”  This bill intends to amend section 513(f) of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to expedite the process for requesting de novo classification of a device.  The de novo review process is a compromise between the 510(k) clearance process and the more rigorous premarket application (“PMA”) approval process, generally reserved for higher risk devices.  It was added to the FDC Act to address novel devices that lack a predicate device but pose only a low to moderate risk, making them ill-suited to the PMA process.

Unfortunately, the current statutory requirements for the de novo process make it difficult and burdensome for both industry and FDA.  The statute currently requires that, before submitting a petition for de novo classification to classify a device into class I or II, the manufacturer must submit a 510(k) notification to FDA and await a determination that the device is not substantially equivalent (“NSE”) and therefore classified into class III, even if the manufacturer knows there is no appropriate predicate. 

Representative Bilbray’s proposal would eliminate this often unnecessary step by allowing a request “without regard to whether such person has received written notice of classification into class III . . . .”  In other words, if a manufacturer knows there is no appropriate predicate for a proposed moderate- to low-risk device, the manufacturer could skip the 510(k) process and submit a de novo petition first.  Of course, it would probably be desirable for the manufacturer to have an understanding with FDA that a de novo petition is the best approach.  Thus, there will be a need for advance discussions.  Nonetheless, this simple change would give FDA more flexibility.

This provision should be non-controversial, and acceptable to both industry and FDA.  As discussed in our previous blog post, FDA recently issued a Draft Guidance revising the de novo classification process in an attempt to make the process more efficient.  Given the current statutory language, however, FDA was constrained to continue to require a 510(k) filing.  Representative Bilbray’s language would do away with this requirement, potentially making the de novo process more appealing to both FDA and industry.

By Cassandra A. Soltis –

Earlier this year, we reported on the Interagency Working Group’s (“IWG’s”) proposed voluntary principles for marketing food to children.  The IWG includes representatives from the Federal Trade Commission (“FTC”), the Centers for Disease Control and Prevention, the Food and Drug Administration, and the United States Department of Agriculture (“USDA”).  As a result of comments the IWG received from stakeholders, it now appears that the proposed voluntary principles will be significantly modified. 

In recent testimony before the House Energy and Commerce Committee’s Subcommittee on Health and Subcommittee on Commerce, Manufacturing, and Trade, the FTC’s David Vladeck, Director of the Bureau of Consumer Protection, stated that consumer and public health advocates “strongly supported the proposal as one that would significantly improve the nutritional profile of foods marketed to children.”  In contrast, the “common theme of industry . . . was that the proposal was simply unworkable and should be withdrawn.”  However, the Council of Better Business Bureau’s Children’s Food and Beverage Advertising Initiative ("CFBAI"), which currently has 17 member companies, did submit its own nutrition principles to the IWG for consideration. 

The “anticipated revisions” to the voluntary principles are apparently intended to “address industry’s concerns” and overlap somewhat with the CFBAI’s nutrition standards.  Some of the changes include revising the marketing activities that fall within the scope of children’s media to those “used most extensively to specifically target children ages 2 to 11,” which would exclude adolescents ages 12 to 17, except for certain in-school marketing activities.  In addition, the criteria for determining whether marketing is directed to children would be modified so that they “are flexible enough to be neither over-inclusive – covering marketing to a general or family audience – nor under-inclusive – leaving out marketing that is clearly targeted to children.”

So why the change of heart?  Perhaps the FTC is having flashbacks from its unsuccessful “Kidvid” rulemaking, in which the Commission’s efforts to ban certain television advertisements directed to children ultimately resulted in Congress passing a law withdrawing the FTC’s authority to regulate advertising to children as unfair.  (The FTC retains the authority to take action against deceptive advertising to children, however.)  In addition, Congress allowed the FTC’s funding to lapse, which caused the agency to temporarily shut down.  (An FTC article provides an excellent overview of the Kidvid matter.)

The proposed revisions described in Mr. Vladeck’s testimony “are recommendations contemplated by the Working Group and have not yet been formally approved by the member agencies.”  The Commission will vote on the IWG’s report, provide it to the Department of Health and Human Services and USDA for final approval, and then submit it to Congress as directed in the accompanying statement to the 2009 Omnibus Appropriations Act.

By Susan J. Matthees –

We recently learned that on August 30, 2011, Philadelphia petitioned FDA pursuant to FDC Act § 403A(b) to request that FDA exempt Philadelphia from federal menu labeling requirements.  As far as we know, this is the first petition for an exemption from federal menu labeling requirements. 

As you may recall, section 4205 of the Patient Protection and Affordable Care Act of 2010 implemented FDC Act §403(q)(5)(H), which requires certain restaurants and vending machines to disclose nutrition information.  The law also amended FDC Act § 403A to preempt any state or local menu labeling requirements not identical to federal menu labeling requirements, unless the state or local government successfully petitions FDA for an exemption.  The city of Philadelphia enacted its own menu labeling requirements in 2008, and in the petition asks FDA for an exemption from FDC Act § 403A so that the city can continue to use its current menu labeling requirements. 

According to the petition, Philadelphia’s labeling requirements are “in large part consistent” with federal requirements, but Philadelphia’s ordinance requires more nutrition information to be displayed directly on the menu than federal law.  Philadelphia’s ordinance requires the amount of calories, sodium, saturated fat, trans fat, and carbohydrates to be listed on the menu, whereas federal law requires only calories to be included on the menu.  Under federal law, information on sodium, saturated fat, trans fat, carbohydrates, and other nutrients must be included in written form and made available upon request.  Philadelphia argues that providing nutrition information on the menu is the “only effective means” of communicating nutrition information to consumers. 

Philadelphia believes that by providing information on calories only, the federal law does not adequately address the city’s “public health crisis.”  The city is particularly concerned about requiring disclosure of the amount of sodium in foods.  According to the petition, Philadelphia County has the highest prevalence of hypertension and cardiovascular disease among the counties that contain one of the 10 largest US cities.  Citing studies detailing harmful effects of excess sodium consumption, Philadelphia argues that disclosing the amount of sodium directly on menus is necessary to reduce sodium consumption and a “vital tool to combat the high rates of hypertension, heart disease, and stroke” in Philadelphia.  Although the city acknowledges mixed success for menu labeling (see our previous post here), the petition cites some studies that have shown that nutrition labeling has a positive impact on consumer’s choices as hope that Philadelphia’s menu labeling requirements will influence consumers to chose lower sodium foods. 

In a clever move, Philadelphia uses FDA’s own initiative to reduce sodium to argue for the city’s menu labeling ordinance.  As we reported last month, FDA and FSIS are seeking information on issues related to reduction of dietary sodium.  Philadelphia offers its menu labeling as an opportunity to study sodium disclosure as a means to reduce sodium consumption.  Because Philadelphia is the only community in the nation that requires sodium information to be included on menus, the city argues that it provides a unique opportunity to study how disclosing information on sodium impacts overall consumption, and therefore should be granted an exemption.

By William T. Koustas –

We have previously reported (here, here, here, and here) on the court struggle in the United States District Court for the District of Columbia (“the Court”) between FDA and Regenerative Sciences, Inc. (“Regenerative”).  Regenerative challenges FDA’s claim that the company’s stem cell procedure is subject to FDA jurisdiction and regulation under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and/or the Public Health Service Act (“PHSA”) as an unapproved drug and/or biologic.  Regenerative has developed a procedure in which stem cells are isolated from a patient’s bone marrow, undergo an expansion in a laboratory and are then returned to the patient’s site of injury to treat musculoskeletal and spinal injuries (“Regenexx Procedure”).  Perhaps most interesting is the Government’s new argument that the Regenexx Procedure is subject to regulation by FDA because it involves interstate commerce.   

After Regenerative’s February 2009 lawsuit against FDA was dismissed, the Government sued Regenerative in June 2010 after FDA issued a Form 483 concerning an inspection of Regenerative’s Colorado facility.  Our previous blog entries on this case have additional discussion on its procedural background.  In our last post on this case in January, we discussed the Government’s motions for summary judgment and to dismiss Regenerative’s counterclaims.  Several documents have been filed in this case since that time, including Regenerative’s brief opposing the Government’s motion to dismiss in April 2011, the Government’s reply brief in support of its motion for summary judgment in August 2011, and Regenerative’s surreply in opposition to the Government’s motion for summary judgment in August 2011.  The Government responded to a show cause order in September 2011, and Regenerative recently filed its own response to that order in October 2011.

In its motion to dismiss, the Government claims that it is not attempting to regulate the practice of medicine, but rather, FDA is regulating the manufacturing of a drug product.  The Government further argues that Regenerative’s claim that the statements regarding minimal manipulation in the preamble of FDA’s HCT/P should have been subject to notice-and-comment rulemaking is without merit since the statements were only in the rule’s preamble and not part of the rule itself.  A fuller discussion of FDA’s HCT/P rule as it pertains to this case can be found in our last blog post.  Regenerative’s filing opposing the Government’s motion to dismiss argues that FDA is indeed attempting to regulate the practice of medicine.  Regenerative asserts that the Government cannot define what is and what is not the practice of medicine when it does not have the jurisdiction to regulate the practice of medicine to begin with and points out that Colorado’s definition of the practice of medicine is much broader than the Government’s definition.  Regenerative also argues that the U.S. Supreme Court has thwarted a prior Government attempt to define the practice of medicine in Gonzales v. Oregon, 546 U.S. 243 (2005).  Regenerative argues that the preamble statements regarding minimal manipulation in FDA’s HCT/P rule are part of the substantive rule and should have been implemented through notice-and-comment rulemaking. 

In its reply brief in support of its motion for summary judgment, the Government reasserts its argument that the cultured stem cells used in the Regenexx Procedure are drugs as defined in the FDCA and therefore subject to FDA approval.  The Government further argues that, although Colorado’s definition of the practice of medicine is fairly broad, it does not address the ability of a physician to produce a drug product which is regulated by FDA.  The Government further reiterates its view that Regenerative’s legal challenges to the HCT/P rule, including whether the statement regarding minimal manipulation should have been subject to notice-and-comment rulemaking, are time barred as we described in our previous blog post. 

The Government also argues that, as a drug, Regenerative’s stem cells are within FDA’s jurisdiction as they affect interstate commerce despite the fact that the Regenexx Procedure is done entirely in Colorado.  First, the Government asserts that the stem cells fall within the scope of interstate commerce since Regenerative obtains “components” to manipulate the stem cells from outside of the state.  Second, and most amazingly, the Government argues that interstate commerce is substantially affected because individuals traveling to Colorado to have the Regenexx Procedure would “depress the market for out-of-state drugs that are approved by FDA.”  This interpretation of interstate commerce appears to be new ground for the FDA.  In fact, it appears to be a novel interpretation of the FDCA, as is evidenced by the Government’s failure to cite any judicial precedent for their argument.  If this interpretation were to be accepted by the Court, we have difficulty envisioning that FDA would admit that any food, drug, device, biologic, or cosmetic product is not subject to FDA’s jurisdiction. 

In its surreply brief opposing the Government’s motion for summary judgment, Regenerative continues to argue that its physicians are engaged in the practice of medicine as defined by Colorado law and therefore outside of the jurisdiction of FDA.  Regenerative’s brief further suggests that FDA does not have jurisdiction to regulate the Regenexx Procedure even if it were considered a drug because it does not substantially affect interstate commerce as the procedure is entirely done in Colorado and does not have a national market.  While the Government seeks to counter this argument by broadly interpreting interstate commerce to include depressing the interstate drug market, Regenerative argues that such a broad interpretation of interstate commerce would allow FDA to regulate a medical procedure based on its ability to depress the interstate drug market.  This, Regenerative asserts, would clearly lead to the FDA regulation of any and all medical procedures and the practice of medicine as a whole.

More recently, the Court issued an order to show cause for the Government to demonstrate why it should not read the definition of device in the FDCA as informing and restricting the definition of drug.  The Court notes that the FDCA defines device as “an article used in the diagnosis, cure, mitigation, treatment or prevention of disease, 21 U.S.C. § 321(h)(2), but which, presumably unlike a drug, ‘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 its primary intended purposes’ 21 U.S.C. § 321(h).”  Based on this definition, the Court asked the Government why it should “not interpret the meaning of the word ‘drug’ to include not only an article for use in diagnosis, etc., and intended to affect the structure and function of a patient, but also an article that ‘achieve[s] its primary intended purposes through chemical action’ and which is ‘dependent upon being metabolized for the achievement of its primary intended purposes.’” 

The Government’s memorandum in response to the order to show cause essentially argues that there is nothing in the FDCA, or its legislative history, that suggests the definition of drug be narrowed as contemplated in the show cause order.  The Government asserts that by the FDCA “….implicitly recognizing that drugs often work through chemical or metabolic action and specifying that devices may not work through [such action] is not the same as mandating that all drugs must be shown to work through chemical or metabolic action.”  The Government also claims that the definition of the term drug as described in the show cause order would be contrary to decades of legal precedent.  Regardless, the Government asserts that the Regenexx Procedure works through chemical action, thus making it a drug under the Court’s proposed narrower definition of drug. 

In its response memorandum, Regenerative argues that, contrary to the Government, its review of the legislative history of the definition of device demonstrates that Congress did in fact intend that it “inform and restrict” the definition of drug.  It asserts that the fact that Congress wrote a new definition of device to exempt medical devices from the definition of drug effectively restricts the definition of drug.  As such, Regenerative argues, Congress intended to “inform and restrict” the definition of drug through the definition of device.  Regenerative also pushed back on the Government’s assertion that the Regenexx Procedure works through chemical action thereby causing it to be a drug, noting that there are many medical treatments that consist of living cells that are not considered drugs (e.g., blood transplants, organ transplants, etc.). 

The Government is expected to file a brief to Regenerative’s response to the show cause order by October 24, 2011.

By Kurt R. Karst –      

A Standard Operating Procedures and Policies (“SOPP”) prepared and used by FDA’s Office of Orphan Products Development (“OOPD”) for the review of orphan drug designation requests was recently made public and provides some interesting (and helpful) insight into OOPD’s policies.  Of particular interest are several of the appendicies to the SOPP, including Appendix B (“Scientific Rationale Supporting a Request for Orphan Drug Designation”), Appendix C (“Medically Plausible or Orphan Subsets Supporting a Request for Orphan Drug Designation”), Appendix D (“Lymphoma as the Subject of a Request for Orphan Drug Designation”), and Appendix E (“Recombinant Products and Orphan Drug Designation”).  While we have seen the policies described in the SOPP implemented in product-specific sponsor correspondence (or know them through OOPD designation precedent), never before have we seen them discussed in a more general policy document like the SOPP.

Scientific Rationale Supporting a Request for Orphan Drug Designation – FDA’s orphan drug regulations at 21 C.F.R. § 316.20(b)(4) require that a designation request contain “[a] description of the drug and a discussion of the scientific rationale for the use of the drug for the rare disease or condition, including all data from nonclinical laboratory studies, clinical investigations, and other relevant data that are available to the sponsor, whether positive, negative, or inconclusive.”  FDA may refuse to grant designation on the basis that “[t]here is insufficient information about the drug, or the disease or condition for which it is intended, to establish a medically plausible basis for expecting the drug to be effective in the prevention, diagnosis, or treatment of that disease or condition” (21 C.F.R. § 316.25(a)(2)). 

In describing what constitutes an adequate scientific rationale for the use of the drug for the rare disease or condition when applying for orphan drug designation, the SOPP states that while “OOPD will accept data from clinical investigations as providing the strongest rationale for establishing a medically plausible basis for expecting the drug to be effective in the prevention, diagnosis, or treatment of the disease or condition,” animal data may also be acceptable.  According to OOPD:

[A]s evidence of a medically plausible basis for expecting the drug to be effective in the rare disease under consideration, OOPD requires sponsors seeking orphan drug designation to provide sufficient information about the drug from in vivo studies in a relevant animal model of the disease or from clinical studies in patients with the rare disease or condition treated with the drug.  Please note, the data must be generated from in vivo studies in a relevant animal model of the disease or from clinical studies in patients with the rare disease or condition in which the animals and/or patients are treated with the active moiety that is the subject of the orphan drug designation request.  In the absence of human data and when no animal model of the disease exists, OOPD may consider alternatives that include in vitro data, a description of the mechanism of action of the product, and the pathogenesis of the disease or condition. [(Emphasis in original)]

Medically Plausible or Orphan Subsets Supporting a Request for Orphan Drug Designation – One element of an orphan drug designation request is to explain the relevant “medically plausible subset” (“MPS”) of individuals (if any) affected by a particular disease or condition that is eligible for a therapy (21 C.F.R. § 316.20(b)(6)).  The orphan drug designation process has been designed to ensure that MPSs are groups of patients with special requirements or characteristics that distinguish them from the larger disease grouping.  Although a product may have a beneficial effect on the entire group of individuals with a particular disease or condition, to be designated as an orphan drug, the product must be able to treat a disease or condition that is distinguished in some aspect from the larger disease or condition.  FDA’s orphan drug regulations do not clearly define the term “medically plausible subset.”  In fact, in the preamble to the regulations, FDA states that it “declines to provide examples of medical plausibility or to further develop the definition of [an MPS].  Application of the concept is a matter of judgment based on the specific facts of each case” (57 Fed. Reg. 62,076, 62,081 (Dec. 29, 1992)). 

OOPD’s SOPP takes a stab at defining an MPS:

A "Medically Plausible or Orphan Subset" of a more common disease or condition is defined by some characteristic of the drug or biologic that would limit its use to this subset of the disease or condition and would make the drug or biologic ineffective or too toxic to use in the complement of the subset of the disease or condition.  Examples of such characteristics would include mechanism of action of the drug or biologic or toxicity profile of the drug or biologic.  It is the policy of the Office of Orphan Products Development to apply this definition when faced with a request for orphan drug designation that targets a rare subset of a common disease or condition.

Lymphoma as the Subject of a Request for Orphan Drug Designation – What constitutes the disease or condition when the subject of a request for orphan drug designation is lymphoma?  That’s the question OOPD’s SOPP answers in Appendix D.  “At the crux of the issue,” says OOPD “is the question of ‘What is the disease?’”  The answer to this question has apparently changed over time.

Historically, OOPD has answered this question in different ways as the times have changed: it began with ‘lymphoma’; then was ‘Hodgkin’s disease and non-Hodgkin’s lymphoma” and subsequently progressed to “Hodgkin’s disease, non-Hodgkin’s B-cell lymphoma, non-Hodgkin’s T-cell lymphoma or non-Hodgkin’s null-cell lymphoma.”  With each iteration of OOPD nosology, sponsors were required to meet the statutory prevalence criteria for the disease terms that were put into effect.

As of the effective date of the SOPP – November 9, 2010 – OOPD says that the Office was “at a juncture where further splitting in the disease entities is well recognized by the medical community, and the terms ‘B-cell lymphoma’ and ‘T-cell lymphoma’ are thought not to be ‘diseases’ but rather to be agglomerations of distinct disease entities.”  To cut to the chase, OOPD states that the Office “recognizes the current [World Health Organization] classification of lymphomas as stipulating the diseases of record.” 

Recombinant Products and Orphan Drug Designation – The final appendix to the SOPP delves into the murky area of orphan drug “sameness” and “clinical superiority.”  (Clinical superiority is at the heart of one pending citizen petition – Docket No. FDA-2011-P-0213.)  FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan-drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug.”  FDA’s orphan drug regulations define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways:

(a) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;
(b) greater safety in a substantial portion of the target population; or
(c) demonstration that the drug makes a major contribution to patient care.

With respect to the clinical superiority of recombinant products over tissue-derived products when determinations of orphan drug “sameness” are being considered, OOPD states in the SOPP that:

OOPD will adopt the policy that products of recombinant origin are inherently superior to those of human origin because they are safer regarding person-to-person transmission of infectious agents.  It is recognized that such safety may in fact be only theoretical safety, that is, OOPD would not require evidence of infectious disease transmission with a human-derived product in order to establish the superiority of a corresponding recombinant product.  Rather, it is acknowledged that current understanding may not include all potential agents of human disease; accordingly, this epistemological limitation may prevent the institution of processing procedures that render products free from agents not yet discovered.  This policy, that recombinant products are inherently superior, is a conservative judgment based on a lengthy history of medical iatrogenesis coincident to the use of human-derived products.  But it is acknowledged to be a judgment, and not founded on contemporary data.

The concept of “inherent clinical superiority” has also shown up in other places.  For example, in 1997, FDA determined that BENEFIX (coagulation factor IX) was clinically superior to MONONINE and ALPHANINE (both coagulation factor IX products) based on the fact that “BeneFix™ is inherently less likely to transmit human blood-born viruses and other infectious agents, and is also less likely to transmit animal-derived zoonotic agents.”  

In addition to the policies discussed above, the SOPP provides other helpful information, such as for purposes of documenting cancer prevalence “[t]he Surveillance, Epidemiology, and End Results program (SEER) database maintained by the National Cancer Institute has been adopted as OOPD’s standard source for cancer prevalence information.”  The SOPP also states OOPD’s “3 expert policy” for purposes of documenting disease/condition prevalence when medical literature does not yield prevalence information.  “In the event a search of the medical literature reveals no adequate sources of prevalence of a disease or condition,” says the SOPP, “the sponsor may enlist the statements of three independent experts in the disease in question.  These experts must provide an estimate of the prevalence of the disease or condition with a detailed reasoning or method by which they arrived at their aforementioned estimate.  All experts contacted must be identified by the sponsor if using this method.”

By Ricardo Carvajal –

FDA announced its first seizure of a food that was administratively detained pursuant to FDA’s expanded authority under the Food Safety Modernization Act ("FSMA").  FSMA amended the FDC Act to make it easier for FDA to exercise the administrative detention authority that was originally conferred on the agency by the Bioterrorism Act of 2002.  Previously, FDA would have needed credible evidence that a food presented a threat of serious adverse health consequences or death to humans or animals.  Now, FDA only needs a reason to believe that a food is adulterated or misbranded – a much lower threshold.  Administrative detention is not intended to be a stand-alone enforcement tool; rather, it gives FDA a way to temporarily stop the further distribution of a food in commerce while the agency works with the Department of Justice to institute a seizure action.

It is not surprising that the agency chose food warehoused under allegedly insanitary conditions as the first target on which to exercise its expanded authority.  The agency has a long history of enforcement actions against such foods.  However, prior to FSMA, the type of evidence cited by FDA in this case might not have been sufficient to support the exercise of administrative detention.  It will be interesting to see whether the agency chooses to exercise administrative detention in cases that present more novel circumstances.

By Kurt R. Karst –      

“That’s all I can stand, I can’t stands no more.”  Those were the words spouted by Popeye the Sailor at the climax of each cartoon episode after having been threatened with bad behavior from an antagonist like Bluto or the Sea Hag.  Immediately thereafter, Popeye would squeeze open a can of spinach – or perhaps suck the spinach through his pipe – infusing him with invigorating power and he would give his adversary a thrashing. 

Popeye’s words seem to capture well the frustration that led Stat-Trade, Inc. (“Stat-Trade”) to open up its own can of “spinach” and file a Complaint and a Motion for Preliminary Injunction in the U.S. District Court for the District of Columbia seeking to compel FDA to comply with the requirements of the Prescription Drug User Fee Act (“PDUFA”) in assessing and granting waivers for prescription drug user fees in relation to the company’s NDA No. 020353 for NAPRELAN (naproxen sodium) controlled release tablets, 375 mg, 500 mg, and 750 mg. 

Under PDUFA (FDC Act §§ 735-736), FDA collects three types of user fees for a drug product that is the subject of a “human drug application”: (1) a one-time application fee that must be paid in order for FDA to accept an application for filing; (2) an annual establishment fee for “each prescription drug establishment listed in [an] approved human drug application as an establishment that manufactures the prescription drug product named in the application;” and (3) an annual product fee for each drug listed in FDA’s Orange Book (i.e., the active section of the Orange Book and not the Discontinued Drug Product List) that is the subject of an approved human drug application.  Annual establishment and product fees have been set at $520,100 and $98,970, respectively, for Fiscal Year 2012.  Those fees went into effect on October 1, 2011 – see our previous post here.  Companies that fail to pay fees are placed on an arrears list at FDA, and may be subject to certain other penalties.  FDA policy says that the Agency will refuse to accept for filing submissions from applicants in arrears.

For those companies that are subject to user fees – and in particular annual product and establishment fees – FDC Act § 736(d) provides a few mechanisms to offer relief.  For example, a company can request FDA to waive or reduce user fees under the “barrier to innovation” mechanism or under the “fees-exceed-the-costs” mechanism.  Under the “barrier to innovation” mechanism (FDC Act § 736(d)(1)(B)), a waiver is granted if “the assessment of the fee would present a significant barrier to innovation because of limited resources available to [the application holder] or other circumstances.”  Under the “fees-exceed-the-costs” mechanism (FDC Act § 736(d)(1)(C)), a waiver or reduction is granted by FDA if “the fees to be paid by such person will exceed the anticipated present and future costs incurred by [FDA] in conducting the process for the review of human drug applications for such person.” 

In addition, there are several exceptions under PDUFA that could preclude the assessment of user fees.  For example, under FDC Act § 736(a)(3)(B), a drug is exempt from product fees if it “is the same product as another product approved under an [ANDA] filed under [FDC Act § 505(j)].”  In a 1994 guidance document, FDA explained that “[i]f the [ANDA] has been approved and not withdrawn, the first approved product [(i.e., the NDA drug product)] is excluded from fees even if the generic product is not presently marketed.”  More recently, however, in a Federal Register notice concerning proposed changes to PDUFA (under PDUFA V), FDA says that a proposed technical change to FDC Act § 736(a)(3)(B) “will clarify FDA’s longstanding policy to use the active portion of the Prescription Drug Product List in the [Orange Book] to identify fee-eligible prescription drug products,” and that “FDA will assess a product fee on a prescription drug product when there are no other products on the Prescription Drug Product List that are the same as that product.”

NAPRELAN, which was approved on January 5, 1996, was not subject to generic competition until 2002 and 2003 when FDA approved generic versions of the 375 mg and 500 mg strengths under ANDA No. 075416.  In 2008, however, a U.S. district court ruled in patent infringement litigation that the ANDA sponsor infringed a patent held by Elan.  The ANDA sponsor stopped distributing its generic NAPRELAN and the products were moved from the active to the discontinued section of the Orange Book.  (Recently, the ANDA sponsor settled the patent infringement litigation with Elan.  Under the settlement agreement, the generic will not be marketed until either patent expiration or if there is a final finding of patent invalidity or unenforceability.)

Once the generic NAPRELAN was no longer marketed and was moved to the discontinued section of the Orange Book, FDA began sending invoices to Stat-Trade for annual product and establishment user fees, and in particular, fee invoices for the 375 mg and 500 mg strengths, which are the same strengths approved under ANDA No. 075416.  Stat-Trade timely submitted waiver requests to FDA under the “barrier to innovation” and “fees-exceed-the-costs” mechanisms discussed above.

In August 2010, FDA denied Stat-Trade’s barrier to innovation waiver request and informed the company that the Agency “had not reviewed Stat-Trade’s fees-exceed-the-costs waiver request, and would not do so unless and until Stat-Trade notified FDA that it would not appeal the denial of its barrier-to-innovation waiver request.”  Stat-Trade appealed the barrier to innovation waiver denial and FDA has allegedly continued to refuse to review the company’s fees-exceed-the-costs waiver request. 

Meanwhile, Stat-Trade failed to pay the invoiced user fee amounts and was therefore placed on FDA’s arrears list and was assessed more than $200,000 in penalties, interest and administrative fees.  In July 2011, Stat-Trade arranged for the payment of $1.3 million to cover all of the company’s outstanding PDUFA user fees and related penalties, interest, and administrative fees for Fiscal Years 2009-2011, thereby removing the company from the arrears list.  Stat-Trade’s user fee payment, however, did not mean that the company was abandoning its fight with FDA.  Stat-Trade further corresponded with FDA setting forth arguments why certain user fees should not be applicable and the company’s waiver requests granted. 

Just a couple of weeks after having paid FDA $1.3 million in back fees and penalties, FDA sent Stat-Trade an invoice for Fiscal Year 2012 user fees, including product fees for the 375 mg and 500 mg strengths of NAPRELAN.  Payment was due by October 1, 2011.  Stat-Trade promptly petitioned FDA (Docket No. FDA-2011-P-0696) for a stay of action concerning the assessment of product and establishment fees for Fiscal Year 2012, the application of FDA’s arrears policy, and the imposition of interest, penalties, and administrative fees with respect to Fiscal Year 2012 user fees.  On September 30, 2011, FDA responded that the Agency had “begun reviewing” Stat-Trade’s petition and would “respond promptly.”  Stat-Trade filed its Complaint on October 7, 2001, after not receiving a prompt response from FDA. 

State-Trade’s Complaint says that FDA has “adopted a final policy that violates PDUFA because it allows FDA to assess and collect annual ‘product fees’ for certain prescription drug products that are exempt from such fees pursuant to [FDC Act § 736(a)(3)(B)],” and that FDA has “applied this unlawful policy against Stat-Trade by assessing product fees for two strengths of [NAPRELAN] that are ‘the same’ as approved generic copies and thus exempt from product fees under PDUFA.”  In addition, Stat-Trade alleges that FDA’s refusal to review or process Stat-Trade’s fees-exceed-the-costs waiver request for more than nineteen months is contrary to PDUFA and violates the Administrative Procedure Act (“APA”).

Although PDUFA has been around for quite a while, legal challenges to FDA’s interpretation of the statute have been rare.  In fact, we are aware of only a single case – Winston Labs, Inc. v. Sebelius, No. 1-09-cv-04572 (N.D. Ill. 2009) – concerning what constitutes an “affiliate” for purposes of the small business user fee waiver provision.  FDA ended up losing that case – see our previous posts here and here.  

By Riëtte van Laack –

On October 4, 2011, the Center for Food Safety (“CFS”) announced the filing of what it touts as “a groundbreaking new legal petition” with FDA, demanding that FDA issue regulations that require the labeling of all food produced using genetic engineering.  CFS filed the petition on behalf of the Just Label It campaign.  Co-petitioners include various food companies, organic trade organizations, and other biotechnology opponents.

According to Petitioners, the differences between genetically engineered (“GE”) and conventionally produced foods are material, and lack of labeling that discloses that a food is GE is misleading to consumers.  Petitioners ask that FDA issue regulations that define GE as “a process that alters an organism at the molecular or cellular level by means that are not possible under natural conditions or processes . . . exclud[ing] modification that consists exclusively of breeding, conjugation, fermentation, hybridization, in vitro fertilization, or tissue culture.”  The label of a GE food would be required to indicate which ingredients are genetically engineered and include a notice “GENETICALLY ENGINEERED” followed by a statement “UNITED STATED GOVERNMENT NOTICE: THIS PRODUCT WAS PRODUCED USING GENETIC ENGINEERING.” 

Under FDC Act sections 403(a)(1) and 201(n), a food is misbranded if its labeling is false or misleading in any particular, including by virtue of failing to disclose facts material with respect to the consequences which may result from use of the food under customary or usual conditions of use.  In 1992, FDA issued a policy which states in part that bioengineered foods as a class are not materially different from conventional foods, and thus there is no basis to require labeling that specifies their method of production (FDA prefers the term “bioengineered” to GE).  FDA adhered to this position in a draft guidance on voluntary labeling of bioengineered foods issued in 2001. FDA’s current approach is to consider whether such labeling is required on a case-by-case basis.  The Agency operates a voluntary consultation program for bioengineered foods under which the agency considers numerous characteristics in its evaluation of potential differences between bioengineered and conventional foods.

According to Petitioners, "[t]he agency severely constricted what it called 'material,' limiting it to the ability of a change to be tasted, smelled, or known through the other senses.”  Petitioners assert that “whether the FDA believes that GE foods are ‘of the same or equal quality’ as their conventional counterparts is irrelevant to the question of whether it is misleading to label GE foods the same as conventional foods.  The proper focus is whether consumers are deceived and whether their right to know is abridged.”

Petitioners cite FDA’s regulations mandating labeling of irradiated foods and identification of the food source of hydrolyzed protein as precedents for FDA’s authority to mandate labeling based on production processes, even if those processes do not measurably affect the sensory and performance characteristics of the food. Moreover, citing the U.S. Court of Appeal for the Sixth Circuit decision in IDFA v. Boggs, petitioners argue that a difference does not need to be measurable; FDA may require labeling merely because conventionally produced food have a demonstrable history of safe use and there is a lack of history of safe use for GE foods.  Petitioners also mention the patentability of GE foods as evidence that GE foods are novel and cannot be equivalent to (i.e., are materially different from) conventional foods.

In light of FDA’s stance on labeling of bioengineered foods, its current strategic priorities, and its limited resources, it appears unlikely that the Agency will initiate rulemaking to mandate such labeling in the near future.  Meanwhile, Just Label It advises consumers who want to avoid bioengineered foods to “[l]ook for the USDA Organic seal and buy organic – The National Organic Standards prohibit the use of genetic engineering.”

By Kurt R. Karst –      

The first U.S. Conference on Rare Diseases and Orphan Products started with a bang today with the release of a landmark report announcing its findings of flexibility in FDA’s review of potential treatments for patients with rare (“orphan”) diseases.  The conference, which is co-sponsored by the National Organization for Rare Disorders (“NORD”), under the auspices of the Drug Information Association, is taking place in Washington, D.C. from October 11th-13th.  (Collaborating organizations include EURORDIS (the European Rare Disease Organization), FDA, NIH, and the Duke Clinical Research Institute.)  Chairman of the NORD Board of Directors and Hyman, Phelps & McNamara, P.C. Director, Frank J. Sasinowski, authored the report and presented on it at the conference.  (A copy of Mr. Sasinowski’s conference presentation is available here.)

The NORD study was designed to examine how much flexibility (if any) FDA exercises in reviewing orphan drugs.  In other words, the study was intended to determine whether FDA requires that marketing applications for orphan drug provide the conventional or traditional effectiveness data that are ordinarily expected for most drugs for more prevalent diseases.  The report examines the quantum of effectiveness evidence that provided the basis for FDA’s approval of the 135 non-cancer orphan drug new chemical entities approved between the creation of the Orphan Drug Act in 1983 and June 30, 2010.  Of the 135 drug approvals studied, NORD concluded that 45 would have met traditional data requirements, 32 reflected “administrative flexibility” based on a previously documented FDA system, and 58 reflected flexibility applied on a case-by-case basis.

“This review of FDA actions concludes that two of every three orphan drugs approved show FDA’s historic flexibility in its review of effectiveness data on orphan drug therapies, ” Mr. Sasinowski said in a NORD press release.  “Therefore, FDA has demonstrated in its actions on orphan products that it recognizes the importance of therapies for persons with rare disorders.  It would be helpful for such flexibility and importance to be recognized in a formal FDA policy, and for FDA officials to incorporate and recognize that flexibility in a systematic way in their evaluations of each new therapy in development and under FDA review for Americans with any rare disease.”

In June 2010, FDA held a Part 15 hearing, titled “Considerations Regarding Food and Drug Administration Review and Regulation of Articles for the Treatment of Rare Diseases” (Docket No. FDA–2010–N–0218), at which Mr. Sasinowski, on behalf of NORD, testified and recommended that FDA “develop and issue a specific Statement of Policy on FDA’s role in regulating therapies for rare disorders, which includes an explanation and affirmation of the FDA’s historic position that FDA flexibly applies the standards of safety and effectiveness with respect to therapies for those with rare disorders.”  That hearing was followed by a NORD citizen petition requesting “that a documented policy be established regarding the review of potential treatments for people with rare diseases.”  (See our previous post here.)  

The NORD report follows both the issuance of the proposed PDUFA V Reauthorization Performance Goals and Procedures (Fiscal Years 2013 through 2017), which state that FDA “will develop and disseminate guidance and policy related to advancing and facilitating the development of drugs and biologics for rare diseases, including . . . . encouraging flexibility and scientific judgment, as appropriate, on the part of reviewers when evaluating investigational studies and marketing applications for drugs for rare diseases,” and an FDA Report to Congress from the Agency’s Rare Disease Group (“RDG”).  As we noted last month, in the report, the RDG “identified both strengths and constraints in the current paradigm for drug and device regulation.”  Among the key areas in need of additional efforts identified in the RDG report is for FDA to “[g]ain a thorough understanding of the regulatory history of orphan drug products to help identify effective development approaches, particularly for addressing the uncertainties of biomedical knowledge along the product development pathway, so that patterns can be adapted to future development programs.”  This includes performing “a detailed analysis of FDA’s 27-year history of orphan drug approvals to identify factors and methods that have led to successful drug development and approval or have impeded development and identify areas for improvement.”  The NORD report should certainly help out in this respect. 

By John A. Gilbert, Jr. & Karla L. Palmer –

On Wednesday, October 5, 2011, the DEA published a final rule clarifying when a DEA registrant’s voluntarily surrender of its registration is effective.  The final rule amends 21 C.F.R. §§ 1301.52(a) and 1301.62(a) to make it clear that a registrant surrenders its DEA registration simply by submitting a Form 104 (for controlled substances registrants) or a Form 104c (for listed chemical registrants), or by providing written notice (in any format) to “any employee” of DEA expressing a desire to surrender a registration.  A voluntary surrender is immediately effective upon a DEA employee’s receipt of  a signed Form 104 or written notice, and thus does not require any further action on the part of the administration with respect to the surrender.

DEA’s “clarification” of a voluntary surrender is an important reminder of the perils of signing a voluntary surrender form (DEA Form 104) without the advice of counsel when presented with the form during an investigation or inspection.  The rulemaking also makes clear that a registrant can use any written notice to surrender a registration.   

Prior to this regulatory clarification, registrants, and at least one federal court, were at best unclear whether the DEA was required to issue a formal decision concerning the surrender after a registrant executed a Form 104.  For example, in 2004, a federal court in Utah found that a registrant was able to revoke his Form 104 voluntary surrender.  See Page v. Bruce, 2004 WL 72447 (D. Utah 2004).  The plaintiff physician in that case signed the Form 104 at his office during a DEA investigation.  The plaintiff stated that the DEA investigators threatened to report him to the assistant U.S. attorney’s office, stated that it was a “one-time deal,” and gave the plaintiff registrant a 30-minute window to make a decision whether to give up his registration.  Plaintiff signed the Form 104.

After having significant and immediate remorse over signing the Form 104, the plaintiff contacted DEA two hours later to revoke his surrender.  The plaintiff noted that, prior to signing the form, he was not advised, and thus did not understand, that: (a) DEA could not otherwise revoke his registration without issuing an order to show cause setting forth specific grounds, and a hearing; (2) prior to any hearing the registrant would have an opportunity to file a response and consult an attorney; (3) prior to any revocation the DEA would have the burden of proof at a hearing showing that the registrant posed an imminent danger to the public health and safety; (4) the registrant would have the right to an attorney present at the hearing, and be able to present and cross-examine witnesses; (5) the registrant would be entitled to appeal any administrative or legal decision resulting from the hearing; and, (6) the registrant would be able to retain his DEA registration throughout the course of the hearing and appeals process.  Id. at *3.

Despite DEA’s argument that the voluntary surrender was final and binding upon signing the Form 104, the court found, “[i]t is the DEA Administrator’s authority to revoke a DEA registration, not the registrant’s authority to revoke its own registration.  The statute, regulations and form do not authorize the termination or revocation of the registrant’s DEA privileges based solely on signing of a Form 104.”  Id.  Furthermore, the language in the Form 104 and federal law required the DEA to affirmatively act on a surrender to render it final; a registrant’s signing of the Form 104 was “merely a step in the process.”  2004 SL 72477. *6-7 (D. Utah 2004).        

DEA states in the final rule that a Form 104 (or Form 104c) surrender, or any surrender in writing, is effectively immediately upon receipt by any DEA employee without further action by the administration.  Thus, if a registrant signs the Form 104 when presented by a DEA investigator or agent, the registrant must be aware that he waives immediately several legal rights, including the right to notice of DEA’s allegations, legal counsel, a hearing, and appeal, among others (as described above).  In addition, DEA’s final rule would generally prohibit a registrant from later revoking the surrender if he has a case of buyer’s remorse or second thoughts about whether signing a Form 104 was a prudent course of action. 

Especially in light of DEA’s recent rulemaking, we believe even more strongly that DEA registrants should not sign a voluntary surrender without seeking the advice of legal counsel and certainly not under pressure or duress.  First, given DEA’s clarification of  21 C.F.R. §1301.52, a Form 104 is now effective immediately on receipt by a DEA employee, thus it provides a registrant no opportunity to reconsider its actions.  Second, a Form 104 itself contains many admissions, including, but not limited to, admissions that the registrant was “fully advised of its rights,” that the document was “freely executed,” and, most importantly, that it is signed “in view of my alleged failure to comply with the Federal requirements pertaining to controlled substances, and as an indication of my good faith in desiring to remedy any incorrect or unlawful practices on my part.”  

Even if the ultimate decision is to surrender the registration, registrants should consider the option of using another form of written surrender, so that the registrant will be able to make the decision knowingly, after advice of counsel, and with a full appreciation of the law, facts, circumstances and consequences surrounding the decision.  Also, the registrant can avoid unnecessary written statements or inferences on violations of the law and regulations.

By Jeffrey K. Shapiro –

A medical device manufacturer in most cases is legally required to obtain 510(k) clearance or premarket application (“PMA”) approval from the Food and Drug Administration’s (“FDA”) prior to commercial distribution.  Premarket reviews are conducted under the auspices of the Office of Device Evaluation (ODE) or the Office of In Vitro Diagnostics (“OIVD”) in the Center for Devices and Radiological Health (“CDRH”).  Unfortunately, disputes between sponsors and FDA sometimes arise during the review process.  A dispute may concern which review process is appropriate, i.e., whether a 510(k) clearance or PMA approval is required.  Or, it may be a disagreement over the type or quantity of supporting bench, preclinical or clinical data that should be required, or whether the data are adequate to support clearance or approval.  There also may be disputes in other areas – for example, the appropriate labeling for a device.  Typically, these disputes will culminate in an unfavorable decision at the ODE or OIVD Division level, such as a “not substantially equivalent” decision on a 510(k) submission or denial of a PMA application.

At present, the time required to appeal an adverse decision is uncertain, and it can easily take six to 12 months, or more.  This delay in market entry burdens applicants with higher than expected costs and retards the introduction of new technology and competitive products.  The public health would benefit if disputes between sponsors and FDA could be resolved in a more predictable and commercially reasonable time frame.

In the discussion below, I will briefly describe the available appeal processes, the problems with them, and potential strategies for a successful appeal.  I will also propose that CDRH establish an Office of Appeals for Premarket Submissions ("OAPS") in the Office of the Center Director to bring greater predictability, consistency and timeliness to the resolution of premarket disputes between sponsors and ODE reviewers.

*          *          *

A disappointed applicant has a range of appeal procedures theoretically available to obtain reconsideration of FDA actions and decisions.  Although not all options are available in all cases, and not all are immediately available after an initial denial, the potential procedural options include:  filing a petition for administrative reconsideration, 21 C.F.R. § 10.33, filing a citizen petition, 21 C.F.R. § 10.30, filing a petition for a stay of administrative action, 21 C.F.R. § 10.35, requesting a formal evidentiary hearing, 21 C.F.R. Part 12, requesting a public hearing before a public board of inquiry, 21 C.F.R. Part 13, requesting a public hearing before a public advisory committee, 21 C.F.R. Part 14, requesting a public hearing before the FDA commissioner, 21 C.F.R. Part 15, requesting a regulatory hearing, 21 C.F.R. Part 16, and requesting review of a scientific controversy by the Medical Devices Dispute Resolution Panel (“MDDRP”), 21 C.F.R. § 10.75(b)(2). 

For present purposes, it is not worth recounting the detailed requirements for these nine procedures.  (For good summaries of the first eight procedures listed, and an assessment of their advantages and disadvantages, see CDRH’s guidance document, Medical Device Appeals and Complaints: Guidance on Dispute Resolution (1998).  For a discussion of the MDDRP, see Resolving Scientific Disputes Concerning The Regulation Of Medical Devices, A Guide To Use Of The Medical Devices Dispute Resolution Panel; Final Guidance for Industry and FDA (2001).)  Suffice it to say that an applicant seeking to invoke one of these appeal options must have deep pockets, plenty of time to wait, and a willingness to accept varying degrees of public exposure and/or public participation.  Not surprisingly, most of the time these procedures are not commercially feasible.  The proof that they are impractical is that they are invoked rarely or never.

Typically, there is only one procedure that is commercially viable – a request for internal supervisory review.  The boundaries of this process are set forth in a short regulation, 21 C.F.R. § 10.75.  Section 10.75(a) describes when an internal supervisory review may be requested:

(a) A decision of an FDA employee, other than the Commissioner, on a matter, is subject to review by the employee's supervisor under the following circumstances:

(1) At the request of the employee.
(2) On the initiative of the supervisor.
(3) At the request of an interested person outside the agency.
(4) As required by delegations of authority.

The reference to “the request of an interested person outside the agency” is the authority that allows a disappointed applicant to request a supervisory review.

Section 10.75(b)(1) explains how the review will proceed:

(b)(1) The review will be made by consultation between the employee and the supervisor or by review of the administrative file on the matter, or both. The review will ordinarily follow the established agency channels of supervision or review for that matter.

As noted, the supervisor may consult the employee and/or review the administrative file.  The brevity of this provision allows FDA flexibility in the procedures to be followed.  For example, although the foregoing provision does not mention any role for the “interested person,” in practice interested persons are typically granted a meeting with the supervisor, if requested.  In some cases, but not always, the employee (or employees) responsible for the decision are also present at the meeting.  The downside of a flexible procedure is that some applicants may not know how best to proceed, since the regulation does not provide much instruction.  Indeed, the handling of these reviews tends to be fairly ad hoc.  In these situations, the CDRH Ombudsman can be a helpful resource in explaining the process and/or participating as an observer.

Section 10.75(c) specifies when a Center Director or the Office of the Commissioner will personally review an appeal:

(c) An interested person outside the agency may request internal agency review of a decision through the established agency channels of supervision or review. Personal review of these matters by center directors or the office of the Commissioner will occur for any of the following purposes:

(1) To resolve an issue that cannot be resolved at lower levels within the agency (e.g., between two parts of a center or other component of the agency, between two centers or other components of the agency, or between the agency and an interested person outside the agency).
(2) To review policy matters requiring the attention of center or agency management.
(3) In unusual situations requiring an immediate review in the public interest.
(4) As required by delegations of authority.

Finally, section 10.75(d) provides that a supervisory review is confined to information already in the administrative record:

(d) Internal agency review of a decision must be based on the information in the administrative file. If an interested person presents new information not in the file, the matter will be returned to the appropriate lower level in the agency for reevaluation based on the new information.

This requirement means that an applicant needs to think carefully about whether the administrative file contains the information upon which the appeal will be based.  If not, steps need to be taken to be sure that such information is in the administrative file (with an opportunity for the initial decision makers to consider it) prior to an appeal.

Typically, a supervisory review should be requested in writing, with an explanation why the original decision is erroneous.  The request should briefly describe the review process and then clearly explain the erroneous decision.  Applicants often damage their chances by an overly complex and detailed account of the proceedings below.  The impression of complexity may actually lead supervisory management to defer to the judgment of the reviewers.  Management also has limited time to digest the facts; keeping it simple is therefore more likely to speed the process and make the case more persuasive.

It is also a mistake to cast aspersions on the reviewers, suggesting that they are biased or simply out to “get” the company, or that they are incompetent.  Rather, it is more persuasive to focus the presentation on the facts, and to avoid questioning the good faith, competence or motives of the reviewers.  Remember:  the official reviewing the appeal is the supervisor of the reviewers, and is already working with them daily on a wide variety of matters.  The supervisory official is not likely to be easily persuaded by an assertion that the reviewers are either evil or incompetent.  Unfortunately, many appeals are presented in just this fashion.  In a supervisory review, it is far more persuasive to present the dispute as an honest difference of opinion, but one in which the reviewers made the wrong decision.

In some cases, the issue may have a legal or regulatory aspect to it.  FDA is legally required to treat like products alike.  The most common legal issue that can arise is an allegation that this requirement is not being followed, and the applicant’s product is being sent down a more difficult regulatory pathway than similar products or is subject to more burdensome data requirements.  This type of dispute may be a candidate for review by the Office of Chief Counsel (“OCC”) rather than a supervisory appeal.  There is not a specific procedure required for OCC review.  The applicant writes to the OCC, explains the issue and perhaps requests a meeting to present the case.  If the OCC agrees on the merits, they may intervene with the reviewing division at OIVD or ODE.

If the aid of the OCC is sought, it is critical that the dispute be cast in legal terms.  The OCC provides legal advice, and will not overrule a scientific decision.  Furthermore, the issue must be ripe for OCC review.  Typically, the OCC will not intervene until there is an actual decision to review.  For example, if there were a dispute over an additional information (“AI”) request during a 510(k) review, the OCC would be unlikely to intervene.  Rather, the applicant would typically need to take the process through to at least a “not substantially equivalent” decision before seeking help from the OCC.
 
The supervisory review process is usually the best and most realistic choice for an appeal.  At present, however, the process has a number of shortcomings.  First, there are no deadlines for FDA to review an appeal, hold a meeting, or make a decision.  Typically, an appeal needs to be squeezed into upper management’s busy schedule.  Matters that are “on the clock” such as a 510(k) decision or a PMA application milestone generally will take precedence.  Thus, appeals can languish for months until a meeting is held, and then sit for more months before a decision is made.   My own experience is that a supervisory review process can easily take more than six months to be completed, frustrating the applicant who remains in limbo.  There is no way for the public to know what the average time is for supervisory reviews, because no performance metrics are ever published. 

Second, there is an inherent conflict of interest in the supervisory review.  The supervisor must work with the review team daily on a wide range of matters.  The supervisor cannot afford to alienate them, and will presumptively have confidence in them.  Furthermore, they can have communications about the appeal with the review team that the applicant will not know about.  While most supervisors (in my experience) are careful to conduct a review fairly and impartially, the organizational and psychological dynamics add to the difficulty of successfully overturning an erroneous decision.

A desirable reform would be to create an Office of Appeals for Premarket Submissions (“OAPS”).  The OAPS would be located organizationally in the CDRH Director’s Office, reporting to the CDRH Ombudsman.  (This proposal could be extended to include the other Centers, in which case the OAPS should be located in the Commissioner’s Office.)  The Ombudsman would have overall responsibility for the operation of the OAPS.  The OAPS would have a dedicated staff with multidisciplinary scientific and medical expertise regarding medical devices.  Ideally, the staff would come from review division and would therefore have varied experience in conducting premarket reviews.  The staff should also have access to a dedicated OCC counsel as needed.

Crucially, the OAPS would operate under published written procedures with established milestones and timelines.  Initially, it might be necessary to offer OAPS review as a voluntary pilot project, since section 10.75(a)(3) currently offers “interested persons” a right to invoke supervisory review.  Ultimately, however, if the OAPS were successful, it might be appropriate to amend section 10.75 to incorporate review by the OAPS.  There is no reason that statutory changes should be required, since the creation of the OAPS would simply be a different way to handle supervisory reviews already established by regulation, not statute.  Ideally, all appeals would be routed to the OAPS, with appeal from the OAPS to the CDRH Director’s Office or to the Commissioner.  This approach would free up the Directors of OIVD and ODE from having to spend time and resources on appeals from the divisions, and would eliminate the conflict of interest inherent in this type of supervisory review.

There would be other benefits.  First, the OAPS could regularize the review process, creating publicly known milestones and timelines.  This would be consistent with the current “transparency” initiatives underway at FDA.  Right now, the supervisory review process is largely ad hoc, and is a mystery to many applicants.  Second, the OAPS would eventually have an experienced team focused on processing appeals.  This development would lend itself to consistency and efficiency in handling appeals.  It might even be possible to develop a database with information about dispute resolution patterns.  Such information would allow for published appeal metrics, including a data based insight into the performance of the review divisions.  For example, if a particular reviewing group develops a record of generating unusually high (or low) numbers of appeals and/or reversals, that would be valuable for FDA management to know.  Finally, the OAPS would be a single office that could be held accountable for timely and fair dispute resolution.  Right now, no one at FDA is specifically and publicly accountable for ensuring either timeliness or fairness in dispute resolution (although the CDRH Ombudsman can help impose accountability internally to a certain extent).

In conclusion, FDA offers many procedural avenues for dispute resolution.  None of them is satisfactory, however, and reform is needed.  Some day, it would be a good idea for Congress to sweep out all of the underbrush and establish by statute a few, practical and well delineated appeal procedures.  In the meantime, a more expeditious approach would be to revise internal supervisory review to have the bulk of such appeals handled by a specialized office, the OAPS.  This reform would greatly benefit the public health by bringing fairness, consistency, and, above all, timeliness to the appeals process.

By Kurt R. Karst –      

We have learned that FDA’s Office of Orphan Products Development (“OOPD”) has a new Acting Director.  Debra Lewis, O.D., M.B.A., who is OOPD Deputy Director, and who has been serving as Acting Director since the Departure of Dr. Timothy Coté earlier this year, announced earlier this week that Gayatri Rao, M.D., J.D. will become OOPD Acting Director starting the week of October 10th.  Dr. Rao graduated from the University of Medicine and Dentistry of New Jersey Medical School and earned both her law degree and bioethics masters degree from the University of Pennsylvania.  She comes to OOPD from FDA’s Office of Chief Counsel, thereby “bringing a unique medical and legal/regulatory background to move the OOPD rare disease mission forward,” Dr. Lewis wrote in an e-mail announcement.