In a blog posting that cited the agency’s goal of educating while regulating, FDA released the Food Safety Plan Builder (FSPB) – a software program “designed to assist owners/operators of food facilities with the development of food safety plans that are specific to their facilities and meet the requirements of the Current Good Manufacturing Practice, Hazard Analysis, and Risk-Based Preventive Controls for Human Food regulation (21 CFR Part 117).”  The FSPB web page makes clear that use of the FSPB is voluntary and does not necessarily ensure compliant food safety procedures.  Nonetheless, the FSPB can be expected to find an audience, especially among smaller manufacturers that are subject to extended compliance dates and might not have yet invested substantial resources in developing a food safety plan.  Even larger manufacturers who have already developed their plans may be tempted to delve into the FSPB as a point of reference.

In conjunction with the software, FDA released 16 (!) training videos on YouTube that address various aspects of FSPB.  FDA also released a user guide with more detailed information.  Perhaps not surprising in light of the subject matter, the user guide includes a lengthy legal disclaimer putting users on notice that FDA makes no warranties of any kind and admits of no liability for any damages, and that “[r]esponsibility for the interpretation and use of the [FSPB] and of the accompanying documentation lies solely with users.”

On August 21, 2017, the Health Resources and Services Administration (“HRSA”), the federal agency responsible for overseeing the 340B Drug Discount Program, published in the Federal Register a Notice of Proposed Rulemaking (“NPRM”) that would delay until July 1, 2018 the implementation of the Final Rule establishing the methodology for calculating the 340B ceiling price (including the so-called penny pricing policy) and civil monetary penalties (“CMPs”) for knowing and intentional overcharges of 340B covered entities (see our original post regarding the Final Rule here).

Similar to the reason given for previous delays (see our posts here and here), HRSA indicated that this latest delay to mid-2018 will “allow for necessary time to more fully consider the substantial questions of fact, law, and policy raised by the rule.” 82 Fed. Reg. 39,554.  The impetus for HRSA’s delay to the effective date of the Final Rule expressly derives from both the “Regulatory Freeze Pending Review” memorandum issued by the Trump administration on January 20, 2017 as well as the Executive Order issued the same day entitled, “Minimizing the Economic Burden of the Patient Protection and Affordable Care Act [(‘ACA’)] Pending Repeal.”  See our post here that described the Regulatory Freeze memorandum.  The Regulatory Freeze memorandum provided time for the Trump administration to review and reconsider regulations implemented during the Obama administration.  The Executive Order directed Trump appointees, including the heads of the U.S. Department of Health and Human Services (“HHS”) and other executive offices to “utilize all authority and discretion available to delay the implementation of certain provisions or requirements of the [ACA].” Id.  The ACA required HHS to improve aspects of 340B program integrity with a statutory mandate to develop a system to enable HHS to verify the accuracy of ceiling prices calculated and reported by manufacturers, including the implementation of “precisely defined standards and methodology for the calculation of ceiling prices,” and to impose CMPs for manufacturer overcharges to covered entities.  42 U.S.C. § 256b(d)(1)(B)(i)(I), (vi).  The 340B Final Rule was HRSA’s long-overdue rulemaking aimed at implementing those ACA provisions.  Despite unsuccessful attempts by Congress to repeal and replace the ACA since that Executive Order was issued, the Executive Order appears, nevertheless, to continue to affect certain rulemaking implementing the ACA, including this 340B Final Rule.

Unlike the previous delays, this one raises the possibility that substantive changes may be made to the Final Rule. This NPRM states that, more than merely delaying implementation, HRSA “intends to engage in additional rulemaking on these issues” and will take additional time to consider a “more deliberate rulemaking process.”  As a further signal that regulatory changes may be forthcoming, HRSA stated that the agency did not want manufacturers to invest time and expense coming into compliance with a Final Rule “that is under further consideration and for which substantive questions have been raised . . . .” Id.  However, the NPRM contains no information on what substantive questions have been raised or what the new rulemaking would entail.

Public comments on the delay to the effective date of the Final Rule are also being solicited by HRSA in this NPRM. They are due to the agency on or before September 20, 2017.

We will continue to track and report on further developments regarding implementation of the Final Rule or other updates concerning the 340B Drug Pricing Program.

In June 2017, two consumer advocacy organizations, the Center for Science in the Public Interest and the National Consumer League (“Plaintiffs”), sued FDA challenging the Agency’s interim final rule extending the compliance date for menu labeling and request for comments (see our previous post here).  In response, FDA filed a Motion to Dismiss the Complaint because: 1) the Plaintiffs lack standing; and, in the alternative, 2) even if the Plaintiffs have standing, Plaintiffs’ claims are premature and not ripe for review.

FDA argues that the Plaintiffs are not directly affected by the menu labeling rule. As a third party, Plaintiffs must meet a higher burden than a party that is directly affected by the rule, i.e., the regulated industry. FDA provides several arguments to support its claim that the Plaintiffs lack standing. For example, Plaintiffs had asserted an injury to their mission of conducting innovative research and advocacy programs in health and nutrition, and providing consumers with current, useful information about their health and well-being. However, as FDA notes, the menu-labeling rule is not designed to provide consumer advocacy organizations with information. Instead the purpose of the menu labeling is “for consumers to receive [nutritional] information directly from restaurants.” Moreover, FDA’s extension of the compliance date does not affect Plaintiffs’ advocacy work. According to FDA, whatever injuries Plaintiffs claim, they are “unsupported, self-inflicted by Plaintiffs, or dependent on voluntary actions by third parties.”

Even if the Plaintiffs have standing, FDA argues, Plaintiffs claims are not ripe. The interim final rule was just that, an interim rule. It is not a final determination; the decision is “in flux.” In fact, FDA notes that it expressly asked for comments and expressed a willingness to modify the extension of the willingness. Plaintiffs, like any other party, have had an opportunity (which they used) to submit comments. The comment period closed on August 2, 2017, almost two months after Plaintiffs filed their complaint. The Agency asserts that it is actively considering the numerous comments (according to the latest count, more than 71,000 comments were submitted). Since FDA is reviewing the comments and considering future actions, it does not make sense for the Court to take any action, FDA argues, and any determination by the Court on the merits may be “overtaken by the ultimate decision” by FDA.

Since standing must be addressed before the merits, FDA does not address the merits of the Plaintiffs’ complaint.

We look forward to reading Plaintiffs’ response.

FDA seems to be getting bolder in penalizing industry when it prevents an FDA investigator from taking photographs during a routine FDA inspection.

On August 2, 2017, FDA issued a Warning Letter to Homeolab USA Inc. (part of the parent company, Homeocan Inc. located in Montreal, Québec) for, among other things, impeding the FDA inspection by preventing the investigator from photographing a piece of equipment. FDA claimed the alleged failure to permit photographs constitutes a violation of the Federal Food, Drug, and Cosmetic Act (FDC Act), citing section 501(j) of the FDC Act, which deems drugs adulterated when an owner or operator of a drug facility limits an FDA inspection. FDA relied on its Guidance, titled “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection”, which provides examples of behavior that FDA considers to constitute a limitation and explicitly states that “impeding or resisting photography by an FDA investigator may be considered a limitation if such photographs are determined by the investigator to be necessary to effectively conduct that particular inspection.” Based on this and other alleged violations, FDA asserts in the Warning Letter that drugs produced at the Homeolab USA facility are deemed adulterated because of the company’s refusal to allow photographs.

Also, because Homeolab USA’s parent company is located in Québec, FDA banned the company’s products from entering the United States by placing the company on Import Alert 66-40. The Import Alert means that FDA can detain, without physical examination, products imported to the United States, and can continue to detain these products until it is satisfied that the appearance of a violation has been removed, either by reinspection or submission of appropriate documentation to the responsible FDA Center.

FDA previously issued a citation relating to a photo refusal in a September 2016 Warning Letter to Nippon Fine Chemical Co., Ltd. (see our previous post here). This Warning Letter was of note because FDA effectively shut down a drug facility based solely on its conduct during an FDA inspection. FDA deemed the drugs produced at the facility adulterated based on the fact that the company limited an inspection and/or refused to permit the FDA inspection in three ways: 1) barring access to areas, 2) refusing to provide copies of documents, and 3) limiting photography. That Warning Letter cited no other observed GMP or safety concern related to the company’s products or procedures.

The recent increase in Warning Letters referencing limiting photography as a violative act shows that FDA, relying on its non-binding guidance, is employing an expansive approach in exercising its inspection powers. This is in spite of the fact that, as far as we know, there has been no case in which a court has held that a company’s refusal to allow FDA inspectors to take photographs constitutes a violation of the FDC Act (see previous posts here and here).

But we will be watching closely to see whether a court agrees that FDA’s inspection authority requires industry to permit investigators to take photographs during routine inspections, and will ensure that our faithful blog consumers are made aware of developments.

* Not admitted in the District of Columbia

Children of the 1970/80s can easily recall that famous “How many licks does it take to get to the center of a Tootsie Pop?” commercial. Well, there’s a Hatch-Waxman version of that question: “How many approvals does it take to get to the center of 3-year exclusivity?”  While the world has known for a couple of years the answer to the Tootsie Pop question, FDA only recently provided an answer to the Hatch-Waxman version of the question.  And as with other recent 3-year exclusivity issues, the answer has come up in the context of abuse-deterrent opioids (see our previous posts here, here, here, and here).  But before we give up the answer, some background is on order. . . .

On April 26, 2016, FDA approved Collegium Pharmaceuticals, Inc.’s (“Collegium’s”) NDA 208090 for XTAMPZA ER (oxycodone) Extended-release Capsules for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. XTAMPZA ER was approved as a 505(b)(2) NDA, relying on FDA’s finding of safety and effectiveness for  OXYCONTIN (oxycodone HCl) Controlled-release Tablets (NDA 022272).

XTAMPZA ER was approved just days after the expiration of a period of 3-year exclusivity applicable to OXYCONTIN. That exclusivity was granted based on FDA’s April 16, 2013 approval of NDA 022272/S014, and was coded in the Orange Book as “M-153” (which is defined as: “ADDITION OF INFORMATION REGARDING THE INTRANASAL ABUSE POTENTIAL OF OXYCONTIN”).  In a March 3, 2015 Memorandum, the CDER Exclusivity Board explained the Agency’s decision to grant a period of 3-year exclusivity with respect to the April 16, 2013 approval of NDA 022272/S014 (see our previous post here), as well as the scope of that exclusivity: “the scope of 3-year exclusivity in this instance is limited to the addition of information to the [OXYCONTIN] labeling regarding the reduction of abuse via the intranasal route.”

In support of it’s NDA for XTAMPZA ER, Collegium conducted a couple of its own clinical investigations: an efficacy trial and a human abuse liability study assessing deterrence of intranasal abuse (Study CP-OXYDET-21). FDA subsequently granted Collegium a period of 3-year exclusivity for XTAMPZA ER that expires on April 26, 2019 and that is coded in the Orange Book as “NP” (for “New Product” exclusivity).

In light of a then-pending NDA for Inspirion Delivery Sciences, LLC’s (“Inspirion’s”) ROXYBOND (oxycodone HCl) Tablets, 5 mg, 15 mg, and 30 mg (NDA 209777) for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate, the CDER Exclusivity Board once again earlier this year had to assess the scope of 3-year exclusivity – in this case for XTAMPZA ER – and whether that exclusivity served as an obstacle to the approval of ROXYBOND. In a 20-page Memorandum dated April 20, 2017, the CDER Exclusivity Board concluded that “Xtampza ER’s exclusivity based on study CP-OXYDET-21 covers the specific formulation of Xtampza ER associated with its inlranasal [abuse-deterrrent] properties,” and that “[b]ecause RoxyBond’s formulation associated with its intranasal AD properties is different from that of Xtampza ER, it does not share any exclusivity-protected conditions of approval of Xtampza ER” and the 3-year NP exclusivity applicable to XTAMPZA ER “should not block approval of RoxyBond” (emphasis added).  So, FDA approved NDA 209777 for ROXYBOND on April 20, 2017.  (By the by, Pharmaceutical Manufacturing Research Services, Inc. recently filed a Complaint in the U.S. District Court for the Eastern District of Pennsylvania challenging FDA’s ROXYBOND approval.)

That’s right! Although FDA previously articulated what we’ve dubbed a “route of abuse” approach to abuse-deterrent opioid 3-year exclusivity, that approach has evolved.  It’s been modified a bit to account for formulation differences and the type of abuse-deterrence technology used (e.g., physical/chemical barriers, agonist/antagonist combinations, aversion, delivery system, and others discussed in FDA guidance).  FDA explains the general exclusivity framework as follows:

[I]n assessing the scope of 3-year exclusivity for a single-entity drug product containing the same active moiety as a previously approved single-entity drug product, the Agency looks at the innovative change(s) represented by the later-approved drug product relative to the previously approved drug product. Exclusivity for the later-approved drug product cannot cover any condition of approval for which “new clinical investigations” were not “essential.”  If an earlier-approved drug product was approved for a particular condition of approval, new clinical investigations would not be considered “essential” to support the same condition of approval for a later-approved drug product containing the same active moiety.  Rather, the new clinical investigations would be considered essential only to support a condition of approval for the later-approved drug product that is different from the condition of approval of the earlier-approved drug product.  Because 3-year exclusivity generally covers only the differences from a previously approved product, as a practical matter a later-approved product is likely to have a narrower scope of exclusivity than the product approved previously.

The following example provided by FDA illustrates the above concepts:

• The scope of exclusivity based on new clinical investigations that establish for the first time that an active moiety previously approved only as a single-entity, IR drug product can be formulated as a safe and effective extended-release drug product could potentially block approval of subsequent 505(b)(2) NDA for a single-entity, extended-release drug product containing that active moiety.
• Any determination of the scope of exclusivity for a subsequent 505(b)(2) NDA for an extended-release drug product containing the same active moiety would generally follow the framework described above in which the innovative change(s) represented by this product would be assessed relative to the first approved extended-release product. If, for instance, the subsequent product uses different extended-release technology for which new clinical investigations were essential, the scope of exclusivity for this subsequent product would only cover this innovative change.

FDA’s evolution in thinking has caused the Agency to reassess the scope of previously granted exclusivity. According to FDA:

In light of the evolution of the Agency’s approach to assessing 3-year exclusivity for certain [abuse-deterrent] opioids . . . . [the CDER Exclusivity Board] reassessed the scope of OxyContin’s 3-year exclusivity related to S-14. Applying an approach to the scope of 3-year exclusivity for [abuse-deterrent] opioids . . . in which the scope is defined by two primary characteristics: (1) the abuse route (intranasal); and (2) the type of abuse deterrence applied (physiochemical properties), the Board recommended that the scope of OxyContin exclusivity be limited to the condition of approval supported by the intranasal [human abuse liability] study, i.e., “labeling describing the expected reduction of abuse of a single-entity oxycodone by the intranasal route of administration due to physiochemical properties.”

With that reassessment, FDA then defined the narrowing scope of each period of successive 3-year exclusivity for single-entity oxycodone:

The approval of supplement S-14 for OxyContin established for the first time that a single-entity oxycodone product could be formulated with physicochemical properties expected to reduce intranasal abuse, and the resulting scope of exclusivity reflects this innovation. Xtampza ER, like OxyContin, is also a single-entity oxycodone product with physicochemical properties expected to reduce intranasal abuse.  The [human abuse liability] study supporting approval of Xtampza ER with an intranasal [abuse-deterrent] claim, CP-OXYDET-21, was not essential to show that a single-entity oxycodone product could be formulated with physicochemical properties expected to reduce intranasal abuse.  Approval of OxyContin S-14 had already established that.  Rather, the study was essential to support that Xtampza ER’s particular formulation contributes to its intranasal [abuse-deterrent] properties. Specifically, Study CP-OXYDET-21 demonstrated that, as a result of Xtampza ER’s specific formulation, intranasal administration of crushed Xtampza ER resulted in a substantially lower response to Drug Liking, High, and Take Drug Again measures, compared to IR oxycodone.  The Board thus recommends that the scope of Xtampza ER’s 3-year exclusivity based on study CP-OXYDET-21 be limited to “labeling describing the expected reduction of abuse of Xtampza ER by the intranasal route of administration due to physicochemical properties.”

Because ROXYBOND uses a combination of excipients that imparts physical and chemical barriers that make it difficult to manupulate and abuse the drug product, and that formulation differs from XTAMPZA ER to achieve its intranasal abuse-deterrent properties, FDA concluded that the approval of ROXYBOND (NDA 209777) was not blocked by XTAMPZA ER’s 3-year exclusivity.

So, how many approvals does it take to get to the center of 3-year exclusivity? Well, the answer will depend on the starting point, but apparently it’s not too many approvals in the context of abuse-deterrent opioids.  Furthermore, because FDA now defines the scope of 3-year exclusivity for an abuse-deterrent drug to encompass not only the route of abuse, but also the type of abuse-deterrence technology used, we assume that there will be far fewer instances in which 3-year exclusivity could serve as a block to abuse-deterrent opioid 505(b)(2) NDA approval.

Just last month, we blogged about what we believe to be the first Consent Decree signed by the government and an Outsourcing Facility, shutting down operations under judicial order until certain rigorous conditions are met.  Now, comes the second.

Isomeric Pharmacy Solutions, LLC and three affiliated individuals (all Defendants in the matter) signed a Consent Decree that was entered in federal court in Utah (U.S. District Court for the Central Division of the District of Utah) on August 3.  The Outsourcing Facility was also the subject of a Warning Letter in December 2016 and a recall about four months ago.

The Complaint filed in the case alleges that the named individual Defendants were owners or the Chief Operating Officer for the Outsourcing Facility, and that the Outsourcing Facility distributed drugs that were supposed to be sterile but that had “visible black particles” in a preservative-free injectable drug.  The Complaint also alleged that Isomeric found “spore-forming bacteria” in media fills (which are designed to demonstrate that there are no breaches of sterility in the manufacturing process), and contamination of aseptic processing areas with bacteria and fungus.  While the Complaint alleges that Isomeric detected flaws in products relating to, for example, particle size, the Complaint does not allege that any microbial contamination was found in products.  The Complaint also alleges that Isomeric distributed unapproved new drugs.

Under the terms of the Consent Decree, the Defendants are prohibited from distributing drugs manufactured at any of their facilities until and unless they take hire a qualified consultant who determines they are operating in compliance with current FDA’s Good Manufacturing Practice requirements, and FDA certifies, in writing, that FDA agrees.

Outsourcing Facilities are relatively new, quasi-drug manufacturing entities established by legislation in November of 2013 (see our previous post here).  They are permitted to compound and distribute certain drugs under certain conditions, without FDA approvals, adequate directions for use , compliance with new serialization and other drug tracking requirements, and without patient-specific prescriptions from health care providers (so-called “office use” compounding).

As we mentioned back in July, courts continue to address a wide variety of procedural questions arising from the Biologics Price Competition and Innovation Act (“BPCIA”). The most recent is a decision from the Federal Circuit in an interlocutory appeal pending since July 2016 in the revised Amgen v. Hospira matter, Case 1:15-cv-00839 (D. Del.), No. 2016-2179 (Fed. Cir. 2017).  Like many of the recent BPCIA actions of late, this case raises questions about how a reference product sponsor can adequately assert its patent rights when the biosimilar sponsor doesn’t provide all of its manufacturing information.

Here, the Federal Circuit essentially told Amgen that it won’t mandate discovery to support a fishing expedition.  Alleging various failures to comply with the BPCIA, Amgen filed its initial patent infringement complaint against Hospira with respect to a biosimilar version of Epogen in the District Court of Delaware. In the course of this litigation, Amgen appealed to the Federal Circuit the District Court’s denial of its Motion to Compel Discovery of Hospira’s biosimilar manufacturing process and related cell-culture information.  In the alternative, Amgen requested a Writ of Mandamus order to compel discovery.  The Federal Circuit denied both of these requests as meritless.

Disposing of the Motion to Compel Discovery quickly, the Federal Circuit explained that it lacked jurisdiction over the Motion to Compel under the collateral order doctrine, as discovery rulings generally do not qualify for exception to the final judgement rule (requiring parties to wait until final judgment to appeal rulings). Amgen argued that waiting until final judgment renders the decision “effectively unreviewable,” but the Federal Circuit could not identify a clear-cut statutory purpose undermined by denying immediate appeal.

In the alternative, Amgen argued for mandamus under the All Writs Act ordering the District Court to compel discovery. The Federal Circuit explained that mandamus is a drastic remedy reserved for extraordinary cases with no other means to attain the requested relief; a party seeking this remedy must demonstrate “clear and indisputable” right to such relief.  Here, the Federal Circuit could not identify a “clear and indisputable” right to the cell-culture information.  The Court explained that the BCPIA, as interpreted by the Supreme Court in Sandoz v. Amgen, leaves two relevant avenues for Amgen to secure process information from Hospira: sue for infringement of the patents included on the patent list exchanged with Hospira or sue for infringement of a patent that could be identified on such a list of patents.  Because Amgen did not list any of or bring suit on any of its cell-culture patents, the cell-culture process is not relevant to any claim of infringement asserted by Amgen (or any of Hospira’s defenses or counterclaims).  Amgen even conceded as much.

The Federal Circuit emphasized that “[n]othing in Sandoz suggests that the BPCIA somehow supplants the preexisting rules of civil procedure.”  While a sponsor may access information through discovery and a sponsor may list or sue on a patent for which an applicant has not provided information – all without risking Rule 11 sanctions (targeting arguments that have no evidentiary support) – the usual rules governing discovery still apply in the BPCIA context.  While an outline of BPCIA-avenues for obtaining withheld information certainly helps provide clarity, the denial of this interlocutory appeal isn’t surprising.  Nothing in Sandoz or any other BPCIA decision indicates a shift in civil procedures rules, but it is always helpful to have that in writing.

For now, Amgen v. Hospira continues on . . . without cell-culture information.

The American Conference Institute’s (“ACI’s”) 5th annual “Paragraph IV Disputes Master Symposium” is coming up! The conference will take place from October 2-3, 2017 at the InterContinental Chicago Magnificent Mile in Chicago, Illinois.

ACI has put together an excellent program for conference attendees that include presentations from esteemed Judges and key representatives from the FDA and the PTO. In addition, attendees will get to hear from a virtual “who’s who” of Hatch-Waxman litigators and industry decision makers.  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst, will be speaking at a session titled “Brand and Generic Perspectives on the FDA Final MMA Rule: Assessing Its Impact on Hatch-Waxman Practice.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a 10% discount off the current price tier.  The discount code is: P10-999-FDAB18.  You can access the conference brochure and sign up for the event here.

We look forward to seeing you at the conference. 

On August 3, 2017, FDA announced the availability of a draft guidance regarding child resistant packaging statements on drug products labels and labeling. To be clear, this draft guidance addresses the inclusion of a voluntary statement in the labeling for drug products, prescription as well as over-the-counter, that the packaging is child-resistant. FDA’s guidance does not address or affect the requirement for child resistant packaging under the Poison Prevention Packaging Act and the Consumer Product Safety Commission’s (CPSC’s) implementing regulations.

FDA asserts that the draft guidance “is intended to help ensure that such labeling is clear, useful, informative, and, to the extent possible, consistent in content and format.” Among other things, FDA recommends against the use of abbreviations, and recommends the use of the term “supplied” as opposed to “available.” The guidance further discusses the placement and appropriate terminology companies should use when including the statement in prescribing information, patient information, on the carton and immediate container labeling, and in the drug facts box (used on OTC products).

FDA does not explain what inspired FDA to issue a draft guidance for this type of label claims. It also provides no information about the interest of industry to use this type of voluntary claims on their drug products.

Comments must be submitted by October 2, 2017.

In a Complaint filed in the U.S. District Court for the District of Columbia last week, United Therapeutics Corporation (“UTC”) alleges that FDA unlawfully denied granting the company a period of orphan drug exclusivity upon the Agency’s December 20, 2013 approval of NDA 203496 for ORENITRAM (treprostinil) Extended-release Tablets for the treatment of Pulmonary Arterial Hypertension (“PAH”) (WHO Group 1) to improve exercise capacity. “FDA has unlawfully denied Orenitram its statutorily mandated exclusivity,” says UTC, which is represented by Hyman, Phelps & McNamara, P.C.  “FDA claimed that in order to receive orphan drug exclusivity for the oral formulation of treprostinil for use in the treatment of PAH, UTC ‘must demonstrate that oral treprostinil is clinically superior to the other treprostinil formulations by means of greater efficacy, greater safety or a major contribution to patient care (MCTPC).’”

FDA’s heightened standard for demonstrating clinical superiority to obtain orphan drug exclusivity was at the heart of a September 2012 lawsuit Depomed Inc. (“Depomed”) filed against FDA concerning GRALISE (gabapentin) Tablets (NDA 022544) (see our previous post here).  Depomed prevailed in the lawsuit.  In a September 2014 Memorandum Opinion, Judge Ketanji Brown Jackson of the U.S. District Court for the District of Columbia decided the case on Chevron Step 1 grounds, finding that “the plain language of the Orphan Drug Act requires the FDA to recognize exclusivity for Gralise” (see our previous post here).  The court stated that the statute:

employs the familiar and readily diagrammable formula, ‘if x and y, then z.’ Congress has crafted its command to the Secretary of the FDA in a manner that sets forth two circumstances – a drug that has been designated for a rare disease or condition, and the FDA’s approval of a marketing application for that drug – that, if present, result in a particular consequence: a seven-year period of abstinence regarding marketing approval for other such drugs.

FDA decided not to appeal Judge Jackson’s decision. Instead, FDA published in the December 23, 2014 Federal Register a “clarification of policy” notice in which the Agency addresses the effects of the Depomed court decision (see our previous post here).  In that notice, FDA “double-downed” on the Agency’s pre-Depomed regulations.  In short, FDA says that Judge Jackson’s decision is limited to GRALISE, and that the Agency will continue to apply its clinical superiority regulatory paradigm insofar as orphan drug exclusivity is concerned.

“FDA continues to apply this extra-statutory requirement for proof of clinical superiority despite the fact that the same requirement was expressly rejected by Judge Jackson in Depomed,” says UTC in its Complaint. “Because FDA admitted that Orenitram was properly designated as an orphan drug for the treatment of PAH, the statute dictated that FDA grant Orenitram market exclusivity for seven years from the date of approval,” until December 20, 2020.

UTC alleges that FDA violated the Administrative Procedure Act, saying that FDA’s “denial of orphan drug exclusivity for Orenitram upon approval of the drug for its orphan-designated indication was arbitrary and capricious, an abuse of discretion, exceeds Defendants’ statutory authority, and is otherwise not in accordance with the law.” UTC seeks a declaration that the company “is entitled to seven years of orphan drug exclusivity for Orenitram for the treatment of PAH starting from December 20, 2013,” and, among other things, an order directing FDA “to recognize that UTC is entitled to all benefits of orphan drug exclusivity approval,” and “[i]njunctive relief effectuating UTC’s orphan drug exclusivity by enjoining Defendants from approving any other drug covered by UTC’s exclusivity for the treatment of PAH until December 20, 2020.”

This was FDA’s recent admonition to ChemRite CoPac, Inc. (ChemRite), in a Warning Letter issued on June 29, 2017. Apparently the manufacturer of several over-the-counter oral rinses and oral moisturizing drug products uses the same equipment to manufacture numerous non-pharmaceutical materials, including an industrial car care product.

The letter stated in part that: “[t]his car care product is paraffin-based and labeled as ‘Harmful or fatal if swallowed’ and ‘Keep out of reach of children.’ You also manufacture other toxic non-pharmaceutical industrial and automotive care products, such as leather treatments…Leather Care,…Leather Lotion and sealants…, using the same mixing tank and filling line you use for OTC oral drug products.”

“The ingredients in your non-pharmaceutical products are extremely difficult to remove from manufacturing equipment, and could contaminate the drug products that you manufacture on shared equipment, such as the various oral solutions discussed above. It is unacceptable as a matter of CGMP to continue manufacturing drugs using the same equipment that you use to manufacture toxic industrial-grade car care products.”

So, to summarize, FDA is alleging that ChemRite has violated the Federal Food, Drug, and Cosmetic Act (FDCA) because: (a) the facility manufacturers non-pharmaceuticals on the same manufacturing equipment as it is manufacturing OTC drug products; (b) the non-pharmaceuticals (industrial and automotive care products) are toxic; and (c) the ingredients in these toxic products are extremely difficult to remove from the dual use manufacturing equipment.

This leads to some inevitable questions, such as: whether FDA would allege a violation of the FDCA if only the first two conditions had occurred but not the third, or if only the first condition had occurred. In other words, does the FDA believe that the FDCA forbids the manufacture of non-pharmaceuticals on pharmaceutical equipment regardless of whether or not the non-pharmaceuticals manufactured are toxic to humans? If so, what is the regulatory basis for this claim?

One also has to wonder how FDA would respond if ChemRite provided the agency with data that showed in a validated way not only that their dual use manufacturing equipment could be thoroughly cleaned without leaving a residue, but that in fact the equipment had been thoroughly cleaned prior to each of the lots of drug product manufactured on this equipment, without leaving any residue from the non-pharmaceutical manufacturing.

We probably won’t have answers to these questions anytime soon, but rest assured that when we do we will report them to our readers.

FDA’s Center for Devices and Radiological Health (CDRH) recently announced in the Federal Register and the FDA Voice blog that it has scheduled the first-ever meeting of the Patient Engagement Advisory Committee (PEAC), which will provide recommendations to FDA regarding the regulation of medical devices and the use of devices by patients.

This initiative is the result of 2012 legislation, section 1137 of the Food and Drug Administration Safety and Innovation Act (FDASIA), and public input that FDA solicited in response to it (see prior blog post here and FDA report here). This provision added section 569C (“Patient Participation in Medical Product Discussion”) to the Federal Food, Drug, and Cosmetic Act (FDC Act). It states: “The Secretary shall develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions. . . .” FDC Act § 569C(a)(1).

The topic of the first PEAC meeting, which will occur on October 11-12, will be patient input regarding medical device clinical trials. In particular, CDRH is seeking to (1) better understand challenges for patients in medical device clinical trials, (2) better understand how patient input is being used to overcome these challenges, and (3) receive recommendations from the PEAC on top areas for FDA to consider for action. The nine members of the PEAC include patient advocacy experts, patient representatives, consumer representatives, and directors of patient advocacy organizations.

According to the FDA Voice blog post announcing this meeting, FDA chose the topic of medical device clinical trials for the inaugural PEAC meeting because “patients often have concerns about participating in clinical trials or drop out once they have enrolled in a trial.” This, says CDRH, has the effect of making it more difficult to reach reliable conclusions in device trials and it can delay public access to technological advances.

The PEAC is the latest effort in the Agency’s larger shift towards inserting the patient voice into regulatory decision-making arising out of its implementation of section 1137 of FDASIA. Just last month, FDA’s Office of Health and Constituent Affairs (OHCA) announced it would be working with the Clinical Trials Transformation Initiative (CTTI) to create a work group with patient advocacy organizations, modeled after the European Medicines Agency’s Patients’ and Consumers’ Working Party, to talk about patient engagement at FDA.

We have been following closely CDER/CBER’s Patient-Focused Drug Development (PFDD) Initiative, a commitment under the fifth authorization of the Prescription Drug User Fee Act (PDUFA V) (see prior blog posts here and here), including a very successful parallel externally-led PFDD meeting program (see prior post here). By comparison, CDRH has been slower to provide formal, more direct opportunities for patient engagement as part of medical device regulatory decision-making.

Last September, CDRH and CBER finalized a guidance document on the inclusion of patient preference information in premarket approval applications, humanitarian device exemption applications, and de novo requests (see blog post here). However, since that guidance was finalized, the option to include patient preference information in certain device submissions does not seem to have been widely embraced by industry. In contrast, the PEAC will allow for engagement with patients in a more structured environment, which will hopefully lead to broader influence on CDRH decision-making.

* Summer Associate

When you think about it, FDA’s general regulatory paradigm for regulating medical devices has enjoyed a tremendous run. The overarching statutory and regulatory foundation was started in 1976 and largely in place in its current form by 1997. (Think 510(k)/de novo/IDE/PMA requirements for the premarket phase and registration and listing/MDR/Part 806 and QSR procedures for the postmarket phase.) Yet, this structure has been sufficiently flexible to evolve administratively and to efficiently regulate a broad range of ever‑advancing device technology up through the present day. That is a run of more than 40 years, and counting – no small achievement.

The recent developments in digital health technologies has brought the first existential challenge to this regulatory paradigm. Of course, software has long been incorporated in medical devices and subject to traditional regulation (Software In A Medical Device, or SIMD). And early iterations of software as a medical device (SAMD) fared reasonably well under FDA’s 1989 draft policy for computer products and software. The 1989 draft policy was withdrawn in 2005. Nonetheless, for a period of years after that, FDA still managed to address SAMD reasonably well within existing regulatory structures.

There were stumbles. For instance, the Medical Device Data System (MDDS) regulation, issued in 2011, addressed software and hardware that transfers, stores, and displays medical device data. It was an example of fitting new software into the existing regulatory structure. It was supposed to be an innovative, “light touch” regulation, because it placed MDDS products in Class I, exempting them from all premarket review and subjecting them primarily to the QSR for quality control. By 2015, however, FDA had learned that QSR compliance was not particularly necessary for MDDS products; the agency therefore withdrew all active regulation as an exercise of enforcement discretion.

Still, the torrential development of digital health software has continued and indeed accelerated since 2011. We have seen the widespread advent of big data, machine learning, health care apps for both physicians and consumers/patients, health‑related wearables, and more. As a result, FDA has now publicly recognized that a new regulatory structure is needed. On July 27, 2017, FDA’s new Commissioner stated:

FDA’s traditional approach to medical devices is not well suited to these [digital health] products. We need to make sure our approach to innovative products with continual updates and upgrades is efficient and that it fosters, not impedes, innovation. Recognizing this, and understanding that the potential of digital health is nothing short of revolutionary, we must work toward establishing an appropriate approach that’s closely tailored to this new category of products. We need a regulatory framework that accommodates the distinctive nature of digital health technology, its clinical promise, the unique user interface, and industry’s compressed commercial cycle of new product introductions.

In line with this thinking, FDA has issued a “Digital Health Innovation Action Plan.” Many elements of this plan appear to be a round up of actions already taken. The interesting thing is that many FDA actions have involved getting out of the way, i.e., identifying categories of software that do not require regulatory oversight even though they could fit within the broad statutory definition of a medical device. For instance, the plan reminds everyone:

• We focused our oversight on mobile medical apps to only those that present higher risk to patients, while choosing not to enforce compliance for lower risk mobile apps;
• We confirmed our intention to not focus our oversight on technologies that receive, transmit, store or display data from medical devices;
• We chose not to focus our oversight on products that only promote general wellness. [Id. at 2.]

Notwithstanding FDA’s efforts, Congress has taken a step as well. The recent 21st Century Cures Act has a software provision (section 3060) that brought greater clarity by statutorily defining the categories of digital health software that FDA shall not regulate, including clinical decision support software (CDSS) for physicians. We summarized section 3060 here.

There remains the question about how to regulate SAMD that should be subject to FDA premarket oversight. A developer of SAMD needs to rapidly bring a product to market, obtain user/market feedback and iterate with modifications in order to discover functionality that truly adds value (and is worth paying for). As the Commissioner acknowledges, the traditional premarket review processes are too slow to support this process. At the same time, while it may be acceptable to rush slightly buggy but cool “beta” software to the consumer market, it is not acceptable in the medical arena if the beta software puts patients at risk.

FDA now proposes to balance the competing considerations with a Software Pre‑Cert pilot (a beta regulatory program, if you will). The pilot (including how to apply) is described in a Federal Register notice here. The crux is that the Software Pre‑Cert pilot will be used to develop “criteria [that] can be used to assess whether a company consistently and reliably engages in high-quality software design and testing (validation) and ongoing maintenance of its software product” (p. 5). Companies meeting these criteria could eventually “bring certain types of digital health products to market without FDA premarket review or after a streamlined, less-burdensome FDA premarket review.” A detailed FDA slide presentation is here.

This idea is interesting, because it will enable FDA to develop trust in the engineering robustness of the software up front, and perhaps focus more on clinical considerations in product review. That may be a viable way to shorten the review cycle, especially for software modifications.

Or it may not. In the world of digital health, it is difficult to predict what will and will not work. It is a time once again for “bold persistent experimentation.” So, while the remainder of the device industry is still evolving reasonably well within the old regulatory structure, FDA is developing a new regulatory paradigm for digital health. The Software Pre‑Cert pilot is a promising first step. It remains to be seen whether it succeeds well enough to move out of beta and into more general use.

On July 27, 2017, the Drug Information Association (DIA) journal, Therapeutic Innovation & Regulatory Science, published recommendations from the Clinical Trials Transformation Initiative (CTTI) Patient Groups & Clinical Trials (PGCT) Project team, of which HP&M Attorney James E. Valentine is a member, on the best practices for effective patient group engagement.  This publication supplements the PGCT Project’s official recommendations, originally released by the team in October 2015 (see prior blog post here), and describes the team’s research methods and key takeaways from the endeavor.

CTTI is a public-private partnership to develop and drive adoption of practices that will increase the quality and efficiency of clinical trials. CTTI comprises more than 80 organizations, including representatives from government agencies (e.g., FDA, CMS, NIH), industry representatives, patient advocacy groups, professional societies, investigator groups, academic institutions, and others.  More information on CTTI is available on their website, here. 

CTTI’s PGCT Project was initiated to find evidence-driven, actionable solutions to questions on how patient groups and sponsors can best work together to increase the chances of successful clinical trials and therapy development.  The Project team consists of engagement experts from patient advocacy organizations, industry, academia, and FDA.

The team conducted 45- to 60-minute telephone interviews of 32 senior-level leaders from patient groups, academia, and industry who could provide insights into the development of meaningful partnerships between industry and patients. The discussion questions for the interview were developed by the team in consultation with an independent qualitative research and professional moderator, and were partially informed by findings from a previously reported joint CTTI/DIA survey.

A report of the team’s findings from these interviews was presented during a January 2015 expert meeting of industry, academia, patient group, and government stakeholders.  The meeting attendees provided feedback on the team’s qualitative research results, and worked in subgroups to help establish detailed recommendations for best practices for patient groups and sponsors.

Key Themes Identified

Ultimately, the team identified three key themes which characterize successful patient group engagement: (1) establishing meaningful partnerships, (2) demonstrating mutual benefits, and (3) collaborating early and often.

On the first theme, the interviewees noted that meaningful partnerships require choosing partners based on complimentary interests, capabilities, expertise, and resources. Sponsors look to the following factors when choosing patient group collaborators: the size of their constituency and reach; the effectiveness of their website; their social media savvy; the group’s track record; the extent of their assets; and their level of expertise in trial recruitment.

The second theme, demonstrating mutual benefits, was important to interviewees because these benefits can serve as bargaining chips for the patient group in exchange for meaningful involvement in the clinical trial process. Some commonly cited assets of patient groups were patient registries, tissue or blood banks, and a nuanced understanding of the target patient population.

Third, despite the historical practice of seeking patient group input late in the clinical trial process, interviewees noted that patient groups can add value to clinical trial accrual and retention if they provide input early in the planning process. This input gives research sponsors the ability to make trials more relevant, acceptable, and tolerable for patients.

Best Practices for Engagement

Using the data and input collected from interviews and the expert meeting, the PGCT team formulated recommendations for best practices for effective patient group engagement. The recommendations were grouped into three categories: recommendations for all stakeholders, recommendations for research sponsors (academic and industry), and recommendations for patient groups.  Several of the recommendations are excerpted below:

• Engage the “patient voice” by establishing partnerships from the beginning of the research and development program to improve trial design and execution
• From the start, clearly define the expectations, roles, and responsibilities of all partners, including the resources being committed, data being shared, and objectives of the program
• Build the trust required for successful partnerships by being transparent and trustworthy, following through on commitments, and honoring confidentiality
• Ensure that [patient groups] are essential partners through the [research and development] process and not token voices
• Select sponsors who have a product or program with significant promise for your constituents and who are committed to engaging in a meaningful way

As suggested by the stakeholders who were interviewed and who attended the 2015 expert meeting, a significant barrier to patient engagement can be the lack of well-defined best practices and guidelines. These recommendations will hopefully address this barrier and serve as a helpful resource to research sponsors and patient groups seeking to collaborate to insert the patient voice into clinical trial design and medical product development.

Developing jurisprudence on FCA qui tam (whistleblower) cases, in addition to the important False Claims Act settlement discussed in a recent FDA Law Blog post (here), the First Circuit Court of Appeals issued a decision on July 26 in a case brought against DePuy Orthopaedics, Inc., alleging false claims had been submitted to government insurance programs for hip replacement prostheses. The holdings of the decision are clear. But the rationale for some of the holdings requires more discussion.

The decision (United States ex rel. Nargol v. DePuy Orthopaedics, Inc.) upheld the district court’s dismissal of claims relating to allegations of false statements made to FDA in connection with DePuy’s seeking clearance of the devices to be distributed in the United States. The First Circuit found that, even if DePuy had made false representations, any argument that those representations were materially false must fail, because FDA didn’t retract the devices’ clearance after the Agency had been informed of problems. “[I]t is not plausible that the conduct of the manufacturer in securing FDA approval constituted a material falsehood capable of proximately causing the payment of a claim by the government” when “there is no allegation that the FDA withdrew or even suspended product approval upon learning of the alleged misrepresentations,” the Nargol court said.  The court further affirmed the district court’s dismissal of plaintiff’s allegations about false statements to doctors caused the doctors to falsely certify the devices as “reasonable and necessary” for reimbursement, holding that plaintiff failed to adequately allege that differences in the devices’ stated failure rates could be material to a doctor’s decision whether to certify an FDA-cleared hip replacement as “reasonable and necessary.”

The second holding in the decision reversed the district court’s dismissal of the plaintiff’s claims alleging that large numbers of defective devices were paid for by the federal government. Specifically, the complaint alleged that devices were sold that did not comport with the specifications set forth in the devices’ FDA clearance. The District Court dismissed these allegations pursuant to Fed. R. Civ. P. 9(b), which requires claims that sound in fraud (including FCA claims) to be pleaded with particularity. The First Circuit disagreed with the District Court that plaintiff had failed to meet the 9(b) standard, and held that the plaintiff’s allegations were sufficient to survive a Motion to Dismiss on this claim: “the plain, specific misrepresentation (assuming the allegations to be true)” resulting in payment of government claims “was that the device was . . . an FDA-approved product, rather than a defectively manufactured, nonconforming variant.” But it’s more complicated than that.

Nargol’s lawyers alleged that DePuy’s sale of the out-of-specification, and thus defective, devices violated the federal FCA, and many state analogues. The First Circuit reversed the lower court’s dismissal of those claims under federal law and the laws of the State of New York, but affirmed the lower court’s dismissal of other state FCA claims. Here’s why:

Over the years, there have been many cases discussing whether allegations in FCA qui tam cases sufficiently described claims that were filed with the federal government (for Medicare, Medicaid, Veterans Administration sales, and for claims under the TriCare system that provides health insurance to military veterans and their families) for pharmaceuticals or medical devices. In early cases, motions to dismiss brought under Fed. R. Civ. P. 9(b) often succeeded because many of the whistleblowers alleging false claims for pharmaceuticals or medical devices were company employees who did not have access to information about specific claims that were filed for the products. Most courts held that it was not enough for these whistleblowers to allege, relying on statistics rather than specifics, that false claims must have been filed. The majority ruled that an FCA complaint must allege specific false claims that were actually submitted to the government. But some courts have continued to espouse a more “flexible” approach to Fed. R. Civ. P. 9(b) in FCA cases – including the First Circuit. In DePuy, the First Circuit determined that just two allegations were sufficient to keep the case against DePuy alive:

1. A “single exemplar false claim” originating when “surgeon at Stony Brook Medical Center in New York implanted” the device in a patient, and the device “failed ‘as a result of manufacturing defects in the device,’” resulting in submittal of a Medicaid claim.
2. Between 2005 and 2010, “New York State Medicaid paid for an average of approximately 1280 claims each year for total hip replacement devices,” Medicaid paid for 50 percent of the procedures, and given both DePuy’s market share and the percentage of sales of the relevant device in DePuy’s sales, “nearly 425” of the defective devices “would have been paid for by New York State Medicaid.”

The Nargol court noted that “a consensus has yet to develop” among the federal circuit courts “on whether, when, and to what extent a relator must state the particulars of specific examples of the type of false claims alleged.” In this case, the court reasoned, there was “no reason to suspect that physicians did not seek reimbursement” for the allegedly defective product, and “it is also highly likely that the expense is not one that is primarily borne by uninsured patients.” The court concluded that it is “virtually certain that the insurance provider in many cases was Medicare, Medicaid, or another government program.” Because “it is statistically certain,” assuming the complaint’s allegations to be true, that the defendant “caused third parties to submit many false claims to the government, we see little reason . . . to require Relators to plead false claims with more particularity than they have done here.” The First Circuit said the “complaint alleges the details of a fraudulent scheme with ‘reliable indicia that lead to a strong inference that claims were actually submitted . . . from the United States and from the State of New York.’”

Yet the court refused to extend the statistical analysis to claims brought under other states’ FCAs. With regard to other state Medicaid programs, the Court found that “Relators for the most part have made conclusory allegations that state and municipal analogues to the FCA were violated,” and the “complaint does nothing to allege” that the devices were “advertised to and implanted by physicians in . . . any other state or municipality except for the state of New York.” On those grounds, counts relating to claims under other state FCA analogues were correctly dismissed.

So, how much detail is enough about claims paid by the federal government? Under Nargol, description of one specific Medicaid claim, when combined with statistical projections of market share and payer mix suggesting that “many” claims were likely filed, can be enough.