In a stunning development, newly appointed FDA Commissioner Scott Gottlieb, M.D. held a briefing last Friday to announce a multi-year plan for tobacco and nicotine regulation.  The Commissioner’s remarks are available here, and a press release announcing the policy is available here. The Agency’s new approach places nicotine, and the issue of addiction, at the center of tobacco regulation efforts. The policy more formally embraces the notion that nicotine is delivered through products that represent a “continuum of risk,” and is most harmful when delivered through smoke particles in combustible cigarettes. Under this new plan, FDA will:

• Explore lowering nicotine levels in combustible cigarettes to non-addictive levels through product standards. The Agency will issue an Advance Notice of Proposed Rulemaking (ANPRM) to seek input on the potential public health benefits and possible adverse effects of lowering the level of nicotine in cigarettes.
• Extend timelines to submit tobacco product review applications for newly regulated tobacco products that were on the market as of Aug. 8, 2016. These timelines were already extended once (see our previous post  ), but FDA will issue a guidance extending application submission timelines for newly-regulated combustible products (such as cigars, pipe tobacco, and hookah tobacco) to August 8, 2021, and for non-combustible products (such as e-cigarettes) to August 8, 2022.
• Develop product standards to address public health risks, such as electronic nicotine delivery systems (ENDS) battery issues, and concerns about children’s exposure to liquid nicotine.
• Issue an ANPRM to seek public comment on the role that flavored tobacco products (including menthol) may play in attracting youth to consume such products, and in helping some smokers to switch to potentially less harmful forms of nicotine delivery.
• Issue an ANPRM to solicit additional comments and scientific data related to the patterns of use and resulting public health impacts from premium cigars, which were included in FDA’s 2016 deeming rule (see our previous post here).
• Examine actions to increase access and use of FDA-approved medicinal nicotine products intended to help smokers quit.
• Issue rules to make the product review process more efficient, predictable, and transparent, including regulations outlining the information the Agency expects in submissions of Premarket Tobacco Applications (PMTAs), Modified Risk Tobacco Product (MRTP) applications, and reports to demonstrate Substantial Equivalence (SE).

Mitch Zeller, J.D., Director of FDA’s Center for Tobacco Products, and Anna Abram, FDA’s Deputy Commissioner for Policy, Planning, Legislation and Analysis, took questions on the new policy in a conference call. Mr. Zeller emphasized that although nicotine itself is not associated with negative health consequences, the Agency was basing its policy on a recognition that the various nicotine delivery systems fall along a “continuum of risk.” Under this continuum, combustible cigarettes are the riskiest products, and nicotine replacement products sold for smoking cessation (i.e., nicotine gums, lozenges, and patches) are at the opposite end of the spectrum. He also emphasized that the new nicotine policy was “agency wide,” and specifically mentioned the Center for Drug Evaluation and Research, which will play a role with respect to the regulation of smoking cessation products and tobacco research.

FDA’s new approach to the regulation of nicotine will have profound effects on the tobacco product industry. We will continue to monitor this bold new plan as it unfolds.

FTC and FDA issued a blog posting co-authored by senior officials that encourages the public to report potentially violative dietary supplements to one or both agencies.  The posting lists the following as circumstances that should prompt a report:

• “You bought a dietary supplement that didn’t work as advertised – or you had an adverse reaction or illness.”
• “You’re suspicious that a company is making false or overstated claims in its labeling or marketing.”
• “You’re concerned about the content, purity, or safety of the product.”

The posting goes on to explain which agency has jurisdiction over which issues, but makes clear that mastering that jurisdictional divide is not a prerequisite for reporting:  “If you’re still not sure who to report to, just report it to one of us and we’ll sort it out – the important thing is that you report!”

For those who presumed that the current administration’s deregulatory agenda would reduce the likelihood of all regulatory activity, the posting is a timely reminder that some types of regulatory activity – especially in the enforcement arena – will remain relatively unaffected.

Earlier this week, we discussed in a post how FDA, under the Agency’s decades-old regulations defining the term “same drug,” evaluates orphan drug “sameness” in the context of fusion proteins.  At the end of that post we suggested that gene therapy “sameness” might be the next hot topic on FDA’s orphan drug “sameness” plate, and said that we would leave a discussion of that topic for another day.  Well, that’s today.

In our earlier post we went through how FDA approaches orphan drug “sameness” issues under the Agency’s regulations and how those determinations affect approval and exclusivity decisions. We won’t repeat all of that here, but note that for large molecules (i.e., macromolecules), structural “sameness” means that the second drug contains “the same principal molecular structural features (but not necessarily all of the same structural features)” as the previously approved drug.  FDA further defines structural “sameness” for different types of macromolecules, including proteins, polysaccharides (i.e., complex sugars), polynucleotides (e.g., nucleic acids like RNA and DNA), and partially definable drugs (e.g., live vaccines).

Gene therapy is a pretty hot topic these days. It was just earlier this month that FDA’s Oncologic Drugs Advisory Committee recommended that FDA approve the first gene therapy product: Novartis Pharmaceuticals Corporation’s BLA 125646 for Tisagenlecleucel for the treatment of pediatric and young adult patients 3 to 25 years of age with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia.

A search of FDA’s Orphan Drug Designations and Approvals Database shows that the Agency’s Office of Orphan Products Development (“OOPD”) has designated several gene therapy products as orphan drugs, including tisagenlecleucel for the treatment of diffuse large B-cell lymphoma. Although the issue of gene therapy “sameness” for orphan drug designation and exclusivity purposes has not yet been addressed by OOPD, the issue is almost certain to come up as FDA begins licensing BLAs for various products.  And although FDA has not yet spoken to the issue of gene therapy “sameness”, we think it’s possible to make some predictions as to where OOPD might end up if presented with a gene therapy “sameness” issue.

Gene therapy utilizes the delivery of DNA (or RNA) into cells. This delivery can be accomplished by several methods; however, the two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use “naked” DNA or DNA complexes (i.e., non-viral methods).  The use of recombinant viruses seems to be the focus of many manufacturers right now, so we’ll focus on that type of gene therapy.

A recombinant virus gene therapy product has two components: (1) the genetic component (DNA or RNA); and (2) the viral vector. Determining the “sameness” of two genetic components would certainly seem to be an easy issue, as the sequences/compositions of the genetic material can easily be compared.  That leaves the vector component.  The extent to which the vector component should be considered in an orphan drug “sameness” determination is likely to be the central issue for FDA and OOPD to address and resolve.  That is, whether or not the vector is part of the orphan drug, or whether it is merely part of the product “formulation” and serves as a route of delivery for the “true” orphan drug – the genetic component in a gene therapy product.

If FDA determines that both the genetic and vector components are relevant to a “sameness” determination because they both comprise the gene therapy product, then two gene therapy products that contain the identical genetic constituent would be considered different if different vectors are used. If, however, FDA determines that it is only the genetic component that is relevant to “sameness,” then different vectors are irrelevant, unless the vector can be argued to provide a basis for clinical superiority (i.e., greater efficacy, safety, or a major contribution to patient care).

Of the two options above, FDA seems may be more inclined to adopt the second option (i.e., the genetic component is the “drug” and the basis for a “sameness” determination, while the vector component is part of the “formulation” and the basis for a clinical superiority argument) than the first option.  To some extent, the second option is the simpler option to apply and could avoid (some) controversy.  For example, we understand that sometimes repeated rounds of gene therapy are needed, and that those subsequent rounds may require different vector serotypes.  If both the genetic component and the viral vector comprise the drug, then the use of different vector serotypes would undoubtedly complicate matters and create a “moving target” for orphan drug “sameness” purposes.  On the other hand, the second option has the potential to delay licensure of competing gene therapy products that include the identical genetic component.  In that case, it will fall on FDA to determine whether or not the use of a different vector provides a basis for arguing clinical superiority, thereby allowing licensure of a second product notwithstanding another sponsor’s unexpired period of orphan drug exclusivity.

FDA’s Orphan Drug Program, which traces its birth back to the January 4, 1983 enactment of the Orphan Drug Act (“ODA”) (see our previous post here), is probably one of the most successful FDA programs to date.  The success of the ODA is most apparent from the increasing number of orphan drug approvals and orphan drug designations each year (see our previous post here).  (In fact, there are so many orphan drug designation requests these days that FDA had to create an Orphan Drug Modernization Plan – here and here – “to both eliminate a backlog of existing designation requests, and to make sure that the agency can respond in a timely fashion to new applications.”)  But there are other, less visible measures of the success of the ODA, such as FDA’s ability to keep up with and address scientific advances in an aging regulatory paradigm.

Why are there so many orphan drug designation requests submitted to FDA? Well, as FDA notes in the Agency’s Orphan Drug Modernization Plan:

The uptick in designation requests reflects, among other factors, advances in science that allow researchers to target rare diseases that were previously not readily amenable to therapy. This is good news.  It is a reflection of substantial medical progress that’s allowing us to effectively target many vexing diseases.  It is also a reflection of our better understanding of the genetic basis of diseases, which unlocks our ability to define and target rare disorders.

With scientific advances, FDA is also faced with new questions about so-called orphan drug “sameness.”

By way of background, the FDC Act, as amended by the ODA, provides a 7-year period of exclusive marketing to the first sponsor who obtains marketing approval for a designated orphan drug. Once FDA approves a marketing application for a designated drug, the Agency may not approve another firm’s version of the “same drug” for the same disease or condition for seven years, unless the subsequent drug is “different” from the approved orphan drug (or because the sponsor of the first approved product either cannot assure the availability of sufficient quantities of the drug or consents to the approval of other applications).  In addition, FDA’s regulations provide that if the same drug has already been approved for the same orphan disease or condition, with or without orphan drug designation, a sponsor must provide “a plausible hypothesis that its drug may be clinically superior to the first drug” in order to obtain designation, and must demonstrate clinical superiority to obtain approval of a marketing application (if that application is blocked by another sponsor’s orphan drug exclusivity) and also to obtain orphan drug exclusivity.

According to FDA’s orphan drug regulations, a drug is “different” from an approved orphan drug (i.e., is not the “same drug”) if it is either demonstrated to be chemically or structurally distinct from an approved orphan drug, or “clinically superior” to the approved orphan drug.  The degree of chemical or structural similarity that allows FDA to determine whether two drugs are the “same drug” depends on whether the drugs are small molecules or large molecules.  Thus, FDA’s regulations at 21 C.F.R. § 316.3(b)(14) define the term “same drug” to mean the following:

(i) If it is a drug composed of small molecules, a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug, even if the particular ester or salt (including a salt with hydrogen or coordination bonds) or other noncovalent derivative such as a complex, chelate or clathrate has not been previously approved, except that if the subsequent drug can be shown to be clinically superior to the first drug, it will not be considered to be the same drug.

(ii) If it is a drug composed of large molecules (macromolecules), a drug that contains the same principal molecular structural features (but not necessarily all of the same structural features) and is intended for the same use as a previously approved drug, except that, if the subsequent drug can be shown to be clinically superior, it will not be considered to be the same drug. This criterion will be applied as follows to different kinds of macromolecules:

(A) Two protein drugs would be considered the same if the only differences in structure between them were due to post-translational events or infidelity of translation or transcription or were minor differences in amino acid sequence; other potentially important differences, such as different glycosylation patterns or different tertiary structures, would not cause the drugs to be considered different unless the differences were shown to be clinically superior.

(B) Two polysaccharide drugs would be considered the same if they had identical saccharide repeating units, even if the number of units were to vary and even if there were postpolymerization modifications, unless the subsequent drug could be shown to be clinically superior.

(C) Two polynucleotide drugs consisting of two or more distinct nucleotides would be considered the same if they had an identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone (ribose, deoxyribose, or modifications of these sugars), unless the subsequent drug were shown to be clinically superior.

(D) Closely related, complex partly definable drugs with similar therapeutic intent, such as two live viral vaccines for the same indication, would be considered the same unless the subsequent drug was shown to be clinically superior.

FDA’s “same drug” definition has been in place now for decades – since FDA’s December 29, 1992 final rule became effective on January 28, 1993 – and has withstood the test of time insofar as being able to accommodate scientific advances. Today’s post is an example of a more recent scientific advance that FDA has been able to accommodate under the Agency’s decades-old “same drug” rubric: fusion proteins.

The National Cancer Institute defines a “fusion protein” as:

A protein made from a fusion gene, which is created by joining parts of two different genes. Fusion genes may occur naturally in the body by transfer of DNA between chromosomes. For example, the BCR-ABL gene found in some types of leukemia is a fusion gene that makes the BCR-ABL fusion protein.  Fusion genes and proteins can also be made in the laboratory by combining genes or parts of genes from the same or different organisms.

A more expansive definition from Wikipedia says:

Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this fusion gene results in a single or multiple polypeptides with functional properties derived from each of the original proteins.  Recombinant fusion proteins are created artificially by recombinant DNA technology for use in biological research or therapeutics. Chimeric or chimera usually designate hybrid proteins made of polypeptides having different functions or physico-chemical patterns.  Chimeric mutant proteins occur naturally when a complex mutation, such as a chromosomal translocation, tandem duplication, or retrotransposition creates a novel coding sequence containing parts of the coding sequences from two different genes.

A search of FDA’s Orphan Drug Designations and Approvals Database shows that the Agency has designated several fusion protein products. Thus far, we are aware of two fusion protein BLA licenses issued by FDA.  Both products raised questions about orphan drug “sameness” at FDA, and have helped to solidify FDA’s position on when two products, one of which is a fusion protein, is considered the “same drug” as the “naked” (i.e., non-fused) product.  Specifically, FDA’s position is that a post-translational fusing of amino acids to the drug results in a “same drug” determination, while a pre-translational fusing of amino acids to the drug results in a “different drug” determination.

The “sameness” analysis above is apparent in FDA’s decision to grant a period of orphan drug exclusivity for ALPROLIX [Coagulation Factor IX (Recombinant), Fc Fusion Protein], which FDA licensed on April 28, 2014 under BLA 125444 for use in adults and children with Hemophilia B for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes. In an April 2014 email memorandum documenting the decision to grant orphan drug exclusivity for ALPROLIX, FDA commented:

[T]he Office of Blood and Blood products in CBER was contacted to discuss exclusivity for Coagulation factor IX, Fc fusion protein. It was noted that the protein that is fused to factor IX is a dimer.  One monomer of the dimer is manufactured fused to factor IX pretranslationally.  The second monomer is then a post-translational modification.  Therefore, the changes in structure to the factor IX protein do involve pre-trnaslational [sic] modification. It was agreed that this was a different product than recombinant factor IX and is thus eligible for orphan drug exclusivity. [(emphasis added)]

Another example of FDA’s application of the Agency’s “same drug” rubric in the context of a fusion protein is IDELVION [Coagulation Factor IX (Recombinant), Albumin Fusion Protein], which FDA licensed on March 4, 2016 under BLA 125582 for the (1) on-demand control and prevention of bleeding episodes, (2) perioperative management of bleeding, and (3) routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Although the sponsor of IDELVION initially thought that FDA might consider its product to be the same as another Coagulation Factor IX product, BeneFIX (BLA 103677), and thus require a plausible hypothesis of clinical superiority in order to obtain orphan drug designation, FDA determined otherwise. According to a March 2012 Memorandum from FDA’s Office of Orphan Product Development:

The sponsor has provided an adequate scientific rationale to support orphan designation. The sponsor presented two studies in FIX knock out mice and one study in a dog model of hemophilia B.  All three studies compared the effects of rIX-FP to the approved coagulant factor IX, BeneFIXfi. The sponsor contends that these animal studies demonstrated that rIX-FP displays an extended half-life as compared to BeneFIX, and thereby clinical superiority to the presently available therapy.  The sponsor stated that the clinical superiority would be based on fewer dosing administrations that the patients would have to undergo.

However, clinical superiority is only necessary and applicable if rIX-FP is indeed the “same drug” as the already approved recombinant factor IX. That is, according to CFR 316.20(b)(5), “where the sponsor of a drug that is otherwise the same drug as an already-approved orphan drug seeks orphan designation for the subsequent drug for the same rare disease or condition, an explanation of why the proposed variation may be clinically superior to the first drug” should be included in the request for designation.  FDA regulations also state that “Two protein drugs would be considered the same if the only differences in structure between them were due to posttranslational events or infidelity of translation or transcription or were minor differences in amino acid sequence; other potentially important differences, such as different glycosylation patterns or different tertiary structures, would not cause the drugs to be considered different unless the differences were shown to be clinically superior.”  It is known from the sponsor’s references that recombinant fusion protein linking coagulation factor IX with albumin with a linker peptide sequence is formed via a process in which Factor IX wild-type cDNA is cloned into an expression vector and prepared for genetic fusion with the linker and albumin cDNA. The fused genetic material is then used to produce recombinant factor IX fused with albumin.  FDA regulations state that two protein drugs would be considered the same if the only differences in structure between them were due to post-translational events (these are not post-translational events) or infidelity of translation or transcription or were minor differences in amino acid sequence.  The DNA is not equivalent because the DNA of the FIX-albumin molecule contains the DNA of albumin (and the linker, too). Thus, the sponsor is exempt from the clinical superiority explanation requirement for orphan drug designation of rIX-FP.  [(emphasis added)]

So what might be up next on FDA’s orphan drug “sameness” plate? With FDA on the verge of licensing the first gene therapy product, we think that gene therapy “sameness” might be the next hot topic.  But we’ll leave a discussion of that issue for another day.

In the almost four years since passage of Title I of the Drug Quality Security Act, (the Compounding Quality Act), FDA has inspected hundreds of pharmacies, issued numerous Form 483s and warning letters, and has requested both voluntary recalls and cessation of non-sterile and sterile operations.  It has similarly inspected outsourcing facilities, and issued Form 483s and warning letters, and requested recalls and voluntary cessation of operations.  The substantial majority (if not all) of FDA’s actions are set forth on FDA’s compounding or outsourcing facility pages on its website (here and here).

As FDA’s web pages reveal, on only a very few occasions (i.e., three) has FDA through the Department of Justice entered into a consent decree of permanent injunction or initiated a criminal action (i.e., four) with an offending compounding pharmacy. Based on a review of those few consent decrees and criminal matters, it seems that a key reason for the consent decree or criminal action is FDA’s finding of product contamination (i.e., mold found in the sterile injectable product) or complaints of illness directly related to use of the compounded preparations.

On July 5, 2017, the United States Department of Justice announced it entered into a consent decree of permanent injunction with now closed Alabama outsourcing facility Medistat RX LLC, its owners (chief executive officer), production manager, and pharmacist in charge/quality manager. The consent decree prohibits them for a period of at least five years from “manufacturing, holding or distributing drugs until they comply with the Federal Food, Drug and Cosmetic Act (FD&C Act) and its regulations, in addition to other requirements.”

The government’s action comes, in part, as a result of an inspection that occurred almost two years ago – in August and September 2015- following an earlier 2014 inspection where FDA claims that, notwithstanding promises to do so, the facility did not correct earlier observations. In addition, DOJ’s press release states that, in 2015, the Rhode Island Department of Health notified the Agency about a Staphylococcus aureus infection outbreak that was potentially linked to betamethasone manufactured by Medistat.  Thus, FDA’s 2015 follow-up inspection also revealed, after a review of Medistat’s own documents, that the facility itself had previously identified several types of microorganisms in the air and on surfaces used for sterile compounding.

The May 2017 complaint filed in the United States District Court for the Middle District of Alabama, claims among other things that, upon identifying the microbial contamination, defendants failed to “adequately investigate or take sufficient corrective action to alleviate insanitary conditions that resulted in the contamination in the sterile areas of the facility.” DOJ Press Release dated July 5, 2017.  Thus, notwithstanding the facility’s agreement to recall products, voluntarily cease all  compounding operations, and ultimately, not to renew its outsourcing facility registration, FDA took the additional step of filing a federal complaint and ultimately entering into the consent decree.

A final note: By our count based on public information in FDA’s website, the consent decrees involving compounding present a common enforcement theme: Each involve allegations of illness or visible contamination derived from compounded products prepared by the pharmacies. With respect to Medistat, FDA found evidence of environmental contamination at the facility as recorded in the facility’s own records, and Medistat’s compounded products allegedly made people sick. This scenario presents a cautionary tale for pharmacies and outsourcing facilities.  Medistat obtained a pharmacy license in 2007 and then obtained an outsourcing facility registration in November 2014, a year after enactment of Title I of the DQSA (the statute which created such facilities).  The conversion from a traditional compounding pharmacy to an outsourcing facility remains fraught with significant legal and regulatory hurdles, and both FDA and states are paying close attention.

In a case full of twists and turns, there’s a new twist!

In March 2017, we reported on the status of litigation between FDA and Ferring Pharmaceuticals Inc. (“Ferring”) over the availability of 5-year New Chemical Entity (“NCE”) exclusivity for Ferring’s colonoscopy preparation, PREPOPIK (sodium picosulfate, magnesium oxide, and citric acid) for Oral Solution (NDA 202535; approved on July 16, 2012). We noted that FDA quietly settled the case after dropping an appeal to the DC Circuit (see our previous post here), and that the settlement would have some pretty significant effects on FDA’s consideration of ANDAs for multiple drug products, including DUAVEE (conjugated estrogens/bazedoxifene) Tablets (NDA 022247; approved on October 3, 2013), STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (NDA 203100; approved on August 27, 2012), ANORO ELLIPTA (umeclidinium /vilanterol) Powder for Inhalation (NDA 203975; approved on December 18, 2013), and BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) Inhalation Powder (NDA 204275 ; approved on May 10, 2013).

Following the settlement, FDA responded to various pending Citizen Petitions (here and here) saying that in light of the U .S. District Court of the District of Columbia’s September 2016 decision in Ferring Pharmaceuticals, Inc. v. Burwell (see our previous post here), a decision with which FDA does not necessarily agree, the Agency would grant a period of NCE exclusivity.  Judge Rudolph Contreras’s September 2016 Memorandum Opinion granted a Motion for Reconsideration filed by Ferring requesting reconsideration of the DC District Court’s March 2016 ruling that FDA’s pre-October 10, 2014 interpretation of the FDC Act’s NCE exclusivity provisions as applied to a newly approved Fixed-Dose Combination (“FDC”) drug product containing an NCE and a previously approved drug, such as PREPOPIK was initially considered to contain (see our previous post here), was not arbitrary and capricious.  Although Judge Contreras initially backed FDA’s decision to deny NCE exclusivity for PREPOPIK, he reversed course after considering several precedents identified by Ferring in the company’s Motion for Reconsideration and remanded the matter to FDA.

Earlier this year FDA updated the Orange Book to show NCE exclusivity . . . but only for DUAVEE, STRIBILD, ANORO ELLIPTA, BREO ELLIPTA, and related NDAs for drug products that fall under the Agency’s NCE exclusivity “umbrella policy” – e.g., TYBOST (cobicistat) Tablets (NDA 203094; approved on September 24, 2014) and VITEKTA (elvitegravir) Tablets (NDA NDA 203093; approved on September 24, 2014).  FDA did not update the Orange Book to show the addition of a period of NCE exclusivity for Ferring’s PREPOPIK, which the Agency previously determined contained an NCE (i.e., sodium picosulfate).  Instead, in April 2017, FDA sent a letter to Ferring saying that the Agency was unlikely to grant NCE exclusivity for PREPOPIK:

Upon further review, it appears that bis-(p-hydroxyphenyl)-pyridyl-2-methane (BPHM, CAS: 603-41-8, UNII: R09078E41Y), the active moiety of sodium picosulfate (CAS: 10040-45-6, UNII: VW106606Y8), also seems to be the active moiety in bisacodyl [(4,4’-diacetoxydiphenyl(2-pyridyl)methane), CAS: 603-50-9, UNII: 10X0709Y6I. Bisacodyl was approved in Halflytely (NDA 021551) on May 10, 2004.  Based on the foregoing, it appears that Prepopik does not contain any active ingredient which contains no previously approved active moiety.

FDA gave Ferring (and other stakeholders) the opportunity to respond, which Ferring did in a April 19, 2017 FDA submission that expresses the company’s frustration with and opposition to FDA’s decision:

The April 5 letter is an abrupt and unexplained departure from the previous interpretation of the statutory and regulatory provisions as they apply to Prepopik. Not once in the nearly eight years in which FDA has been involved with the product — including the review and approval of Prepopik, an extensive citizen petition process, and litigation over the exclusivity of the product — has the agency identified picosulfate as anything but an active moiety.  Now, with no explanation, the agency appears to want to take the position that the covalently bound sulfur-based appendages in sodium picosulfate could be considered “esters.”

The time for a new interpretation of the definition of the term “ester,” or a new analysis of the chemistry of picosulfate, has long passed. Far too many regulatory and litigation decisions have been based on the agency’s original and oft-repeated determination that picosulfate is a novel active moiety, rather than an ester of a previously approved active moiety.  Moreover, the agency has provided no new information that would support its apparent change in interpretation, and therefore Ferring lacks any meaningful opportunity to comment upon or respond to the agency’s basis for its change in position.  If FDA intends to change its interpretation of the term “ester,” particularly in this case, the agency must follow appropriate administrative procedures.  In addition, whatever interpretation the agency elects to propose in the future, FDA cannot apply it to deny NCE exclusivity to Prepopik, nearly five years after its approval.  As detailed in this letter, and as the agency is well aware, Ferring has relied extensively on FDA’s previous interpretation that “picosulfate” is not an ester.

Depite Ferring’s arguments, FDA issued a 9-page Letter Decision on June 9, 2017 concluding that under the Agency’s structure-centric interpretation of “active moiety” (rather than an activity-based interpretation) (see here), PREPOPIK is not eligible for 5-year NCE exclusivity:

At the time thc Prepopik application was submitted, the Agency determined that sodium picosulfale was a new molecular entity (NME). It was believed that picosulfate was the active moiety of the drug substance sodium picosulfate, and that this active moiety had not been previously approved by FDA. It is not clear from the administrative record how the Agency determined that sodium picosulfate was considered to be an NME, as no documentation of a structural analysis of this active ingredient has been found.  Upon further evaluation of the structure of sodium picosulfate during FDA’s consideration on remand, the Agency determined that sodium picosulfate is the di-sodium salt of a di-sulfate derivative of bis-(p-hydroxphenyl)-pyridyl-2-methane (BHPM) (Figure I). After excluding the salt and ester portions of sodium picosulfate, as FDA’s regulations require, what remains is BHPM.  Therefore, BHPM is the active moiety in sodium picosulfate. BHPM is also the same active moiety as that of the drug substance bisacodyl, which was approved years before Prepopik.

In reaching this decision, the Agency considered whether a di-sulfate derivative is an “ester” derivative from both a scientific and regulatory standpoint. Under standard scientific definitions, picosulfate is an ester of sulfuric acid.  Esters are substances that result from the splitting-out of water from combining an alcohol and an acid, where the acid may be organic (e.g. acetic acid) or inorganic (e.g. sulftric acid).  FDA treats the combined product of an alcohol and sulftiHc acid, like sodium picosulfate, as an ester.  Finally, throughout the NDA for Prepopik, Ferring identified sodium picosulfate as an ester. . . .

FDA regrets this error and apologizes for informing Ferring of this determination almost 5 years after Prepopik’s approval and after litigation related to the exclusivity determination. However, under the applicable regulations, the Agency must evaluate the chemical structure of each drug substance in a drug product.  If a drug substance contains a previously approved active moiety, it is not an NCE.  If none of the drug substances in a fixed-combination is an NCE, then that drug product will not he eligible for 5-year NCE exclusivity.  Upon further review on remand, FDA has concluded that each drug substance in Prepopik contained a previously approved active moiety and none is an NCE.  Thus, Prepopik is not eligible for 5-year NCE exclusivity under either the Agency’s pre-Octoher 2014 interpretation or the new interpretation put forth in October 2014.

As you can imagine, FDA’s decision did not sit well with Ferring. Earlier this month, Ferring filed a Motion to Enforce Judgment with the DC District Court requesting that the court order FDA to recognize NCE exclusivity for PREPOPIK, and characterizing FDA’s exclusivity decision as an end-run around the court’s order:

Here, FDA’s actions on remand directly contravene the central premise upon which this Court’s judgment rested: that sodium picosulfate contained an active moiety (picosulfate) that had never been previously approved. The issue before the Court in this case—the propriety of FDA’s original interpretation of the NCE exclusivity statute as applied to fixed-dose combination products—would have been wholly academic if sodium picosulfate were not, in fact, a novel active ingredient.  By changing its position on this critical issue after the agency lost this case, and after both this Court and Ferring relied on the agency’s original position, FDA has run afoul of both the law of the case doctrine and judicial estoppel principles. FDA’s ill-considered decision also constitutes retroactive rulemaking, violates Ferring’s due process rights, and constitutes arbitrary and capricious agency decisionmaking in violation of the [Administrative Procedure Act].

FDA must file its opposition to Ferring’s motion on or before August 18, 2017, and Ferring must reply on or before September 8, 2017.

On July 11, 2017, the Department of Justice and the Drug Enforcement Administration (“DEA”) announced that Mallinckrodt LLC, a pharmaceutical manufacturer, agreed to pay $35 million to settle allegations related to the adequacy of its efforts to detect and inform DEA of suspicious orders of controlled substances.  Although DEA has reached similar settlements with distributors and pharmacy chains (see, e.g., here), this is the first settlement of its kind with an opioid manufacturer.  DOJ’s press release states that the settlement reflects manufacturers’ obligation to monitor orders not only from their own customers, but also between distributors and pharmacies and clinics downstream in the distribution chain.  However, this statement appears  inconsistent with the language in the settlement document, marks a stark shift in the prevailing understanding of manufacturers’ suspicious order monitoring obligations and raises serious questions about the legal basis and workability of such a requirement.

For years, DEA has been criticized for failure to provide guidance on the suspicious order monitoring regulation, 21 C.F.R. § 1301.74(b).  The language in that section has remained unchanged since its enactment in 1971 and while DEA issued informal guidance letters to certain industry groups in 2006, 2007 and 2012,  DEA’s interpretation of that regulation has evolved significantly beyond that guidance.  More important, a fundamental deficiency in the regulation is that it fails to recognize the differences between manufacturers and distributors, including the level of data available to each concerning sales between distributors and pharmacies.  Thus, the lack of a clear regulation has continued to hinder industry’s ability to meet DEA’s expectations.

Unfortunately for industry, in the last several years, DEA has set forth its evolving view of the regulation primarily in presentations at conferences, through Memoranda of Agreement (“MOAs”) related to enforcement actions and in the Southwood and, more recently, the Masters decisions. (see, e.g., here and here).  While this approach has allowed DEA to avoid the notice and comment rulemaking requirement under the Administrative Procedure Act (“APA”), it has also left industry with little clarity about their obligations around the reporting of suspicious orders. A critical element of notice and comment rulemaking is for an agency to solicit important industry input on the impact of potential rulemaking, with the ultimate goal being effective and clear regulations.  Such clarity would result in a more secure supply chain for controlled substances, which would better serve the public interest as the U.S. continues to struggle with the issue of opioid diversion and abuse.

The press release concerning the Mallinckrodt settlement, which purported to set out “groundbreaking” new rules, is another example of DEA establishing a new standard while avoiding notice and comment rulemaking.

The problem revolves around DEA’s discussion of chargebacks (which are a common pharmaceutical pricing feature), for the first time, and a critical discrepancy between the language set forth in the government’s press release and the obligation outlined in the MOA with Mallinckrodt.  (In general, a chargeback is a payment made by a manufacturer to a distributor to make the distributor whole when it sells the manufacturer’s product at a price below a specified rate. After a distributor sells a manufacturer’s product to the pharmacy, for example, it requests a chargeback from the manufacturer and to support that request for payment, the distributor identifies the product, volume and the pharmacy to which it sold the product.) In its press release, the government stated that, “[t]he groundbreaking nature of the settlement involves requiring a manufacturer to utilize chargeback and similar data to monitor and report to DEA suspicious sales of its oxycodone at the next level in the supply chain, typically sales from distributors to independent and small chain pharmacy and pain clinic customers.” (emphasis added). This appears to set forth DEA’s position that manufacturers must review chargebacks and report the underlying sales from the distributor to downstream pharmacies as suspicious orders.

However, we have reviewed Mallinckrodt’s MOA and it does not require reporting downstream transactions as suspicious orders.  Rather, the MOA provides that Mallinckrodt review chargeback data and alert DEA of pharmacies (not orders) that may be concerning.   The clear focus of the language is a reporting of pharmacies as a condition of the MOA, not the reporting of chargebacks as suspicious orders under 21 CFR 1301.74(b). Note, as of this writing, the MOA has not been posted to the government’s websites.

As an initial matter, it is not clear that DEA can create such a new requirement by announcing it in a press release. First, nothing in the language of 21 C.F.R. § 1301.74(b) suggests that a manufacturer must review orders between two downstream third parties and report them as suspicious. Second, we could find no prior public statement from DEA that a manufacturer must report such third party transactions as suspicious under 21 C.F.R. § 1301.74(b). Finally, if this really is “groundbreaking” – to use the government’s own word – surely such a change should warrant notice and comment rulemaking.

Moreover, there is no indication manufacturers’ attempts to monitor downstream transactions would be productive. It appears instead that manufacturers will be expected to second guess distributors’ decisions to fill orders from pharmacies (well after those sales have been completed), even though the manufacturers have far less information than the distributors have about those pharmacies. Distributors often have longstanding relationships with their pharmacy customers and sophisticated monitoring programs to evaluate pharmacy orders.  In contrast, a manufacturer can only see – after the fact – the manufacturer’s products a distributor sells to a pharmacy and for which the distributor submits a chargeback request. With such limited visibility, a simple and perfectly legitimate switch by a pharmacy from one manufacturer’s product to another’s, for example, could look like a suspicious “increase” in the distributor’s sales to that pharmacy.

DEA’s position raises many additional practical questions. If the manufacturer and distributor disagree about which orders are suspicious, will DEA hold manufacturers’ reports of suspicious orders against the distributor, even if the distributor is better positioned to assess those orders?  How many orders that appear “suspicious” to a manufacturer can be filled by a distributor before the manufacturer must stop selling to that distributor?  And how should a manufacturer structure a program designed to monitor distributor sales to tens of thousands of pharmacies with which the manufacturer has no contact?

Manufacturers will likely be struggling with these issues for years to come. That ongoing confusion and its negative impact on the security of the supply chain emphasizes, once again, the need for DEA to make clear the obligations of manufacturers through notice and comment rulemaking on this critical issue, especially as the country continues to struggle with the problem of opioid diversion and abuse.

On July 11, 2017, in the Federal Register, FDA published the finalized list of Class II devices that are now exempt from the 510(k) requirements. This list is identical in substance to the proposed list published on March 14, 2017 (see our prior post here). The only change noted is that FDA grouped those products that contain a limitation on the exemption, and those that do not. Companies with products in the former category are well advised to carefully read the limitations that apply to their product to make sure that they do not fall within a limitation. If they do, a premarket notification will be required. The limitations vary, including, for example, a partial limitation for enzyme immunoassays for amphetamine. For those immunoassays, the exemption applies only where the test system is intended for employment or insurance testing. The same test system used for other purposes, for example Federal drug testing programs, would not be subject to the exemption.

Notably, all products are subject to the .9 limitations, which require a manufacturer to obtain 510(k) clearance for an exempt device type, if either: (i) the device is intended for a use different from the intended use of a legally marketed device in that generic type of device; (ii) the device operates using a different fundamental scientific technology than a legally marketed device in that generic type of device; or (iii) if it falls within an enumerated list of IVDs, such as those used in the screening or diagnosis of familial or acquired genetic disorders.

Lastly, FDA notes in the Federal Register that companies with pending 510(k) submissions for devices now exempt from premarket notification, when taking into consideration any applicable limitations on those exemptions, should withdraw their submissions.

*Rachel Hunt not admitted in the District of Columbia.

On July 11, 2017, the Government Accountability Office (GAO) provided Congress with an assessment report on FDA’s Expanded Access (“EA”) program. EA programs allow patients with serious or life-threatening diseases and no satisfactory therapy available to access investigational drugs outside of a clinical trial (report available here). Among other things, GAO was asked to examine the following:

1. What is known about the number, type, and time frames of EA requests received by FDA;
2. What actions FDA and other stakeholders have taken to improve EA; and
3. How FDA uses data from EA in the drug approval process.

As part of its investigation, GAO reviewed FDA’s regulations, audited FDA documents, and analyzed FDA data on EA requests from FY2012 through 2015. GAO also interviewed FDA officials and other stakeholders, including nine manufacturers, as well as patient and physician representatives.

FDA’s Improvements and Successes

GAO found the following improvements and successes with regard to FDA facilitating access under its EA program:

Simplifying EA Requests

• FDA published a simplified website, guidance, and form required for the most common types of EA requests;
• FDA asked the Reagan-Udall Foundation to develop a web-based Expanded Access Navigator to help physicians and patients find relevant information about the process, including a directory of manufacturer’s EA policies; and
• FDA is assisting WCG Foundation in developing a project to streamline the IRB process and educate IRBs in single-patient IND situations.

Efficient Review of EA Requests Received

Of the nearly 5,800 EA requests that were submitted to FDA in FY 2012-2015 (96% of which were for single patients), the Agency allowed 99% to proceed. FDA typically responded to emergency single-patient requests within hours, and all other requests were considered within the allotted 30 days under its regulations (see table below).

Room for Improvement in the EA Program

While FDA grants requests for EA, the patient must first receive permission to access the investigational drug from the manufacturer. Despite FDA’s achievements, GAO found a remaining barrier to access: industry’s well-founded concern that adverse events experienced by EA patients in uncontrolled settings could compromise the drug development program despite the fact that patients are often very sick, out of treatment options and outside clinical trial inclusion/exclusion criteria, and often have conditions outside of the use being studied. Because the investigational drug is being administered in an uncontrolled setting, any data reported to FDA from such adverse events could (a) result in a clinical hold of ongoing clinical trials and/or (b) complicate the safety findings for that drug during FDA’s review and contribute to a decision to not approve the drug (or take other measures to mitigate the risk).

FDA must, of course, use knowledge generated from any and all patient exposures to an investigational drug to help characterize the safety profile. However, that view is at odds with GAO’s assessment on the issues, which finds FDA is not clear on how EA adverse event data are used in the review process. In the Agency’s only policy statement on this topic, its own EA guidance has acknowledged that this exact situation has occurred:

There are a small number of cases in which FDA has used adverse event information from expanded access in the safety assessment of a drug. However, FDA reviewers of these adverse event data understand the context in which the expanded access use was permitted (e.g., use in patients with serious or immediately life-threatening diseases or administered in a clinical setting (not clinical trial) and will evaluate any adverse event data obtained from an expanded access submission within that context. (see FDA guidance at p. 18 here).

GAO notes that FDA’s statement, while an improvement over no communication on the issue, is vague in that it contains few details and no specific examples.

GAO’s Recommendation & FDA’s Response

GAO’s report expresses concern that FDA’s lack of clear information may deter manufacturers from giving patients access to their drugs, rather than facilitating appropriate EA drugs to patients with serious or life-threatening diseases. This led to GAO providing a sole recommendation in its report to Congress: FDA should clearly communicate how the Agency will use adverse event data from EA use when reviewing drugs and biologics for approval.

While FDA agreed that “the review of adverse event reports that result from [EA] use must be interpreted with caution,” the Agency found the industry’s concerns related to FDA using such data to influence final approval decisions unfounded. In its response, FDA cited that there have only been two instances in which adverse event events from EA contributed to a decision to put a drug on clinical hold and in both instances the holds were lifted after issues were addressed.  Ultimately FDA agreed with GAO’s recommendation, recognizing that additional clarity on how the Agency uses adverse event data may help allay industry’s concerns.

We disagree with both GAO and FDA. While additional information from FDA is always helpful, the very notion that unexplained adverse events may occur disincentivizes companies from offering EA. FDA has no power to alter that reality. FDA’s confirmation in its own EA guidance and in its response to the GAO report that adverse events from EA patients can lead to a clinical hold or otherwise impact drug development – even if rarely – must be taken into account by responsible sponsors when deciding whether to offer EA.

With headlines focused on the Affordable Care Act (ACA) and the rapidly unfolding drama surrounding the repeal and replace efforts, one aspect of the ACA that could easily fly under the radar has been the subject of its own ongoing legal battles: menu labeling. To borrow a phrase from one recent political commentator, “It’s an unbelievably complex subject” that “nobody knew . . . could be so complicated.”

So where are we exactly with menu labeling? Here’s a brief recap of the last seven years: when the Affordable Care Act was enacted in 2010, it added to the Federal Food, Drug, and Cosmetic Act (FDC Act) calorie posting and other menu labeling requirements for chain restaurants and similar retail food establishments. FDA issued final regulations to implement those requirements in 2014. Enforcement was delayed – first by FDA at the request of industry, then by Congress – and eventually FDA established May 5, 2017 as the deadline for compliance. But on May 4, in an eleventh hour twist, FDA extended the compliance date to May 2018 to give the Agency time to reconsider certain aspects of and ambiguities in the rule. In response, two consumer advocacy groups sued FDA in an attempt to bring about a more immediate compliance date. That litigation is ongoing. In addition, just two weeks after FDA announced the extension, New York City announced that it would begin enforcing its own menu labeling requirements on May 22, 2017, with fines and notices of violation beginning on August 21, 2017.

Now, trade associations that represent convenience stores, grocery stores, and restaurants are asking a federal court to stop the City of New York from enforcing its menu labeling regulations. In a Complaint and Motion for Preliminary Injunction filed on July 14 in the U.S. District Court for the Southern District of New York, the National Association of Convenience Stores, New York Association of Convenience Stores, Food Marketing Institute, and the National Restaurant Association’s Restaurant Law Center argue that the City’s enforcement of menu labeling requirements before FDA’s May 2018 compliance date violates federal law.

The plaintiffs argue that the City is expressly and impliedly preempted from enforcing its menu labeling regulations on establishments subject to the federal requirements until FDA’s compliance date. The FDC Act expressly preempts states and localities from enforcing non-identical menu labeling requirements on establishments that are subject to the federal requirements (i.e., establishments with 20 or more locations or that voluntarily comply with the federal requirements): “[N]o State or political subdivision of a State may directly or indirectly establish under any authority or continue in effect . . . any requirement for nutrition labeling of food that is not identical to” the federal statutory menu labeling requirements. FDC Act § 403A(a)(4). New York City has said that its requirements are “identical to the federal requirements.” The plaintiffs assert that though the City may have intended for the substantive requirements of its regulations to be identical to the federal requirements, “requiring compliance a year in advance of the federal requirements” is an additional, non-identical obligation. (In addition, whereas the federal requirements apply to chains with 20 or more locations in the United States, the City’s requirements apply to chains with 15 or more.)

In support of their preemption argument, the plaintiffs cite a string of recent cases in which U.S. District Courts in California rejected consumer plaintiffs’ attempts to seek immediate enforcement – under California State law – of FDA’s requirement that food companies remove partially hydrogenated oils from their products by 2018. “Following the reasoning of these cases,” the plaintiffs argue, “the immediate enforcement of [New York City’s menu labeling rules] would greatly disrupt the FDA’s carefully considered compliance date of May 2018 by requiring immediate compliance with the federal standard in New York City.”

Absent an injunction, convenience stores, restaurants, and other covered establishments will face a risk of irreparable harm in at least two ways, according to the complaint: “(i) they face enormous and ultimately unrecoverable costs to comply with a regulatory regime now that is likely to change by May 2018, and (ii) they face fines, business disruptions and other harms from having to comply with regulatory rules that are so unworkable that the FDA saw fit to delay their implementation.”

On July 18, 2017, FDA held a highly anticipated public meeting discussing the balance between pharmaceutical competition and innovation. Titled “Administering the Hatch-Waxman Amendments: Ensuring a Balance Between Innovation and Access,” the meeting drew a tremendous response from industry with dozens of non-FDA or FTC speakers, and scores of other attendees who packed into the “Great Room” in Building 1 on FDA’s White Oak Campus. Academics, payors and providers, pharmaceutical developers and associated representatives, and representatives of the consumer and patient perspective all provided input to a panel of FDA and Hatch-Waxman all-stars (picture below).

FDA Commissioner Scott Gottlieb opened the meeting with a discussion of the Agency’s position and the announcement of the intended 2017 release of two new documents to improve the generic approval process as part of his Drug Competition Action Plan announced earlier this year. The first document, a Good ANDA Assessment Manual of Policy and Procedures (MaPP), will be an internal CDER policy to streamline the ANDA review process inside FDA without lowering approval standards. As part of this MaPP, Complete Response Letters will make clear what aspect of the application needs improvement to obtain approval. The second document is a Good ANDA Submission Practices Guidance, which will point out common recurring deficiencies in ANDA and provide advice on avoiding them in an effort to ensure better higher quality submissions.

Dr. Gottlieb explained that his goal for the Drug Competition Action Plan is to ensure that the competition Congress intended when it passed the Hatch-Waxman Amendments actually occurs. While FDA doesn’t have a direct role in drug pricing, Dr. Gottlieb explained that the acceleration of drug development should lead to a reduction in drug prices. To that end, Dr. Gottlieb said that FDA needs to address “gaming” the system to keep generics off the market, which undermines the balance between affordability and innovation. FDA is therefore looking to identify rule changes that will help ensure competition, alleviate scientific or regulatory obstacles to generic entry, and improve efficiency of generic drug evaluation.

CDER Director Janet Woodcock also discussed FDA’s role in preserving the balance set forth by Congress in the Hatch-Waxman Amendments. Dr. Woodcock highlighted the progress CDER has made in the last five years in addition to new challenges that have arisen: establishing “sameness” of non-traditional complex drugs, drug-device combinations, and setting up a biosimilar pathway. While FDA is addressing these issues, Dr. Woodcock emphasized the importance of establishing the “root cause” of the lack of competition to avoid shortages or price spikes. Markus Meier, of the Bureau of Competition at the FTC also spoke, highlighting the intersection between FDA and FTC.

Most of the presentations addressed the questions posed by FDA in the Agency’s Federal Register notice announcing the meeting and as discussed in our previous blog post. Patient advocates and generic drug industry representatives who spoke focused on:

• the potential use of REMS to block generic competition through protracted shared REMS negotiations;
• innovators’ refusal to provide samples to generic manufacturers;
• the practice of introducing new patented products with minor improvements and subsequent withdrawal of the original (called “product hopping,” incremental innovation, or the seemingly repurposed term “evergreening”);
• the potential to misuse the citizen petition process to delay generic drug approval; and
• pay-for-delay arrangements.

Conversely, innovators maintained that “incremental innovation” is the heart of further development and cited the fear of liability for refusal to provide samples. Meanwhile, they lamented the deterioration of patent and market exclusivity and cited articles (e.g., “Do Fixed Patent Terms Distort Innovation?: Evidence from Cancer Clinical Trials”) indicating a need for revised incentives. (As we previously reported, Professor Erika Lietzan of the University of Missouri School of Law has been looking into this issue, dubbed the “Drug Innovation Paradox.”)

In addition to comments from meeting participants, several written comments have already been submitted to the docket (Docket No. FDA-2017-N-3615).  In fact, former Representative Henry Waxman, of Hatch-Waxman notoriety, even submitted comments! His comments provided FDA with a copy of a recent Commonwealth Fund Report, titled “Getting to the Root of High Prescription Drug Prices.” In addition to the areas highlighted in the Federal Register notice, Rep. Waxman suggested that FDA permit the reimportation of single-source drugs, monitor the drug market to identify conditions that could lead to shortages or other reasons for significant increases in price, expedite review, and allow for early disclosure of patents to generic and biosimilar manufacturers. Consumer groups that spoke at the meeting also submitted comments in advance, as did some individuals. FDA will be accepting comments until September 18, 2017.

Unsurprisingly, quite a few presentations left the Hatch-Waxman track to discuss biosimilars. And others talked more about competition in the market generally and focused on areas in which FDA really can’t do anything, such as the consolidation of purchasers. But FDA panelists tried hard to redirect the conversation back to the issues under consideration and that FDA could actually address.

In fact, FDA panelists actively participated in the discussion with questions for many of the meeting speakers. FDA seems focused on tangible answers to the questions the Agency posed rather than theoretical competition policy or a list of problems in the industry. It seemed clear from the questions raised that FDA is looking for specific tools to address these competition issues while not sacrificing incentives for innovation. None of the speakers offered the magic bullet, but FDA seems to hope that reviewing all of the comments will at least set it on the right track.

FDA panelist questions, combined with Commissioner Gottlieb’s opening remarks, indicates just how serious FDA sees this issue. FDA panelists pushed some of the presenters on their suggestions to determine whether they were actually practical, such as requiring a preliminary finding that Citizen Petitions are likely to be granted or a finding that a reformulated product should prove a benefit in a Prior Approval Supplement.

FDA appears very open to concrete, well-thought out suggestions. Make sure you get yours in by September 18th!

Courts continue to wrangle over last year’s Supreme Court decision in United Health Services v. United States ex rel. Escobar, 136 S. Ct. 1989 (2016), and as reported here and here, there appeared to be an emerging trend of courts narrowing the types of False Claims Act (FCA) theories that could survive the more stringent test for materiality established by Escobar.  On July 7, 2017, the Ninth Circuit bucked the trend, reversing the lower court’s dismissal of an FCA case against Gilead Sciences, Inc.

In United States ex rel. Campie v. Gilead Sciences, Inc., the Ninth Circuit revived a complaint that the district court had twice dismissed in 2015 for failure to state a claim under Federal Rule of Civil Procedure 12(b)(6).  The United States had declined to intervene in the matter, but submitted an amicus curiae brief supporting reversal of the district court decision.  In its opinion, the Ninth Circuit set forth an in-depth interpretation of the Escobar materiality standard, which was issued post-dismissal, but declined to decide whether the complaint satisfied the heightened pleading standard under Rule 9(b).

The relators alleged that their former employer, Gilead, made false statements to FDA about its compliance with regulations for its HIV drugs. Namely, the allegations concerned Gilead’s concealed use of unapproved ingredients in its drugs, and a failure to report manufacturing problems to FDA.  According to the relators, had FDA been aware of these regulatory violations, it would not have permitted Gilead to market these products.

The court analyzed the three alleged bases for potential FCA liability and determined that the relators alleged sufficient facts to state a claim for relief under all three theories. First, relators alleged that Gilead made false statements that its products were FDA-approved when they were not in fact FDA-approved (“factually false certification” theory); the court confirmed that “a claim for nonconforming goods must include an intentionally false statement or fraudulent course of conduct that was material to the government’s decision to pay.”

The second theory, “implied false certification,” was based on relators’ allegations that by submitting, or causing others to seek, claims for reimbursement for its drugs, Gilead represented that it provided medications approved by FDA that were manufactured at approved facilities and were not adulterated or misbranded. Under Escobar, this theory can be a basis for FCA liability only if (1) the claim makes specific representations about the goods or services provided, and (2) the failure to disclose noncompliance with material requirements makes those representations misleading half-truths.  In determining the first prong, the Ninth Circuit confusingly equated the company’s use of the drug’s names in its reimbursement claims as a representation of regulatory compliance (“these drug names necessarily refer to specific drugs under the FDA’s regulatory regime”).  The court also “assuaged to some degree” the lower court’s concern that the fraud was directed at the wrong agency (FDA rather than the payor agency, CMS), by noting that both agencies fall under the Department of Health and Human Services so that “the fraud was, at all times, committed against [HHS].”

It was undisputed that the government continued to make direct payments and provide reimbursement for the drugs after knowledge of the manufacturing issues. Nevertheless, in determining whether FDA approval was material to the payment decision, the court was persuaded by the United States and relators’ arguments that it should not read too much into FDA’s continued approval of the drugs, and concluded that the issues are matters of proof, not legal grounds for dismissal.  In doing so, the Ninth Circuit reached the opposite conclusion from the First Circuit, which also recognized the practical problems for proof regarding FDA’s actions or inactions, but dismissed the FCA case for a lack of materiality.

The court characterized the relators’ third theory as “promissory fraud,” also known as a “fraud-in-the-inducement” theory. Relators alleged that FDA approval for the HIV drugs was obtained through false statements or fraudulent conduct (i.e., that Gilead lied to FDA regarding manufacturing issues), and thus that each subsequent claim submitted was false due to the original fraud.  The court cursorily concluded that the allegations contained in the complaint supported this theory.

This decision was only the second time the Ninth Circuit has had occasion to apply Escobar; earlier this year, the court affirmed summary judgment in United States ex rel. Kelly v. Serco, Inc., 846 F.3d 325 (9th Cir. 2017) (here), on the grounds that the alleged regulatory violations were not material to the government’s decision to pay.  The Gilead court sought to justify its departure from precedent by describing Gilead’s alleged regulatory violations as affirmative false statements that were intended to conceal noncompliance (altering inventory codes, mislabeling or altering shipping and tracking information) or to obtain FDA approval.  In Kelly, the court was convinced that “there [was] no evidence that [the defendant’s] public vouchers contained any false or inaccurate statements.”  The Kelly court concluded that there was no false claim on which FCA liability could attach.

The Gilead case may be an outlier in the post-Escobar world that can be distinguished by the bad facts alleged in the Complaint.  The standard of review applied by the Ninth Circuit required the court to assume the facts as alleged to be true.  Gilead had no opportunity to respond or rebut these allegations.  It remains to be seen whether those facts are pled with the requisite specificity required for FCA cases, no less proved at trial.

Back in mid-May 2017, when FDA issued the fourth cumulative supplement to the 37th edition of the Orange Book, observant readers may have noticed a couple of interesting entries on page A-7 of the publication. There, in the “PATENT AND EXCLUSIVITY DRUG PRODUCT LIST,” FDA showed the additon of several patents and two periods of exclusivity for Teva Pharmaceuticals, Inc.’s “(Teva’s”) AUSTEDO (deutetrabenazine) Tablets: (1) a period of New Chemical Entity (“NCE”) exclusivity expiring on April 3, 2022; and (2) a period of orphan drug exclusivity expiring on April 3, 2024.

FDA approved AUSTEDO on April 3, 3017 under NDA 208082 for the treatment of chorea associated with Huntington’s disease. What makes AUSTEDO particularly interesting is that it is the first deuterated drug product approved by FDA.  And it is a deuterated version of a previously approved drug: XENAZINE (tetrabenazine) Tablets, which FDA approved on August 15, 2008 under NDA 021894 for the treatment of chorea associated with Huntington’s disease.

What is a deuterated drug? Deuterium (containing one neutron, one proton, and one electron) is a non-radioactive isotope of hydrogen that is a different atom than hydrogen (containing one proton and one electron).  A deuterium atom may be covalently linked to a carbon atom and cannot be removed from the carbon or exchanged with hydrogen.  A deuterated compound can have significantly different metabolic stability and/or pharmacokinetics compared to the non-deuterated version of the compound.

A couple of years ago we speculated that because of FDA’s structure-centric interpretation of “active moiety” (rather than an activity-based interpretation) (see here), under which a drug is classified as a NCE regardless of which portions of the active ingredient contribute to the overall therapeutic effect of the drug, FDA would likely determine that deutetrabenazine (known then as SD-809) is an NCE eligible for 5-year exclusivity. We also speculated that, as a designated orphan drug, FDA would grant a period of 7-year orphan drug exclusivity upon the approval of deutetrabenazine without requiring the NDA sponsor to demonstrate that the drug is “clinically superior” to XENAZINE on the basis that deutetrabenazine and tetrabenazine are not the “same drug.”  (Under FDA’s orphan drug regulations at 21 C.F.R. § 316.3(b)(13)(i), the term “same drug” means, in part, “a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug. . . .”)

While FDA’s Orange Book entries show that Teva was, in fact, awarded both NCE and orphan drug exclusivity, we thought there might be a more robust analysis explaining the Agency’s decision. And there is!  But it’s not in FDA’s Approval Package for AUSTEDO NDA 208082.  It’s in a July 31, 2015 memorandum from the CDER Exclusivity Board that we were able to obtain. That memorandum from the CDER Exclusivity Board documents the recommendation of the CDER Exclusivity Board regarding whether dutetrabenazine has a different active moiety from tetrabenazine:

The Board concluded that tetrabenazine and dutetrabenazine are not the same active moiety under FDA’s regulations and precedent. Therefore, dutetrabenazine and tetrabenazine are not the “same drug” under the statute and regulations governing orphan drugs and it is appropriate to grant orphan drug designation to dutetrabenazine without a plausible theory of superiority to tetrabenazine.  In addition, we concluded that the active moiety dutetrabenazine has not yet been previously approved in any new drug application (NDA).

FDA’s rationale for determining that tetrabenazine and dutetrabenazine are not the same active moiety comes down to a single, simple paragraph in the 5-page memorandum:

The Board applied FDA’s “structure-based” approach to determine the active moiety for each molecule and considered whether there are any structural differences between tetrabenazine and dutetrabenazine that involve non-ester covalent bonds. The only structural difference between tetrabenazine and dutetrabenazine molecules is that the latter contains deuterium instead of hydrogen on the two methyl groups present in tetrabenazine.  The deuterium atoms in dutetrabenazine are covalently bonded to the carbon atom.  Thus, based on the different structures of the two molecules and FDA’s structural approach to determining “active moiety,” tetrabenazine and dutetrabenazine are different active moieties, and thus not the “same drug” under the statute and regulations governing orphan drugs.

There you have it! FDA’s form over function approach means that relatively small changes to a molecule, including deuterium analogues, qualify for NCE exclusivity, while more significant changes that improve the activity of a drug, but that do not change the molecule that is the active moiety, don’t result in NCE exclusivity.

The American Conference Institute’s (“ACI’s”) 5th annual “FDA Boot Camp: Devices Edition” conference is less than two weeks away! The conference will take place from July 26-28, 2017 in Chicago, Illinois. 

Jonette Foy, Ph.D., Associate Director for Policy (acting), CDRH, FDA will be presenting a keynote address, and Hyman, Phelps & McNamara, P.C.’s Jeffrey N. Gibbs will be speaking at a session titled “Low to Moderate-Risk Devices: Weighing the Pros and Cons of 510(k) Clearance vs. De Novo Pathways.” FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount.  The discount code is: P10-670-FDALB17.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

In late June, Pacira Pharmaceuticals informed the FDA, the European Medicines Agency, and Health Canada that the company had filed a notice with the U.S. Securities and Exchange Commission, advising of its intent to discontinue all future production of DepoCyt® due to “…persistent technical issues specific to the DepoCyt(e) manufacturing process…” suggesting that the company was having significant cGMP issues. Pacira added that the decision did not affect any product that had already been distributed to customers or administered to patients.

DepoCyt® (cytarabine liposome injection) (approved under NDA 021041) is indicated for the intrathecal treatment of lymphomatous meningitis, and has been manufactured at the Pacira facility in San Diego, California since approval was first obtained in 1999. That was an accelerated approval, and full approval followed in 2007.  The Orange Book lists other manufacturers of cytarabine, including Hospira, Mylan, West-Ward, and Fresenius-Kabi (Teva is known to have exited the cytarabine market relatively recently), though none of those products appear to be in exactly the same dosage form as DepoCyt, as none of them are “liposomal” cytarabine.

It is unclear whether this difference in dosage form will prevent physicians from using them to treat lymphomatous meningitis as, according to the U.S. National Library of Medicine, the other approved cytarabine products are indicated for use alone or with other chemotherapy drugs to treat other conditions, including certain types of leukemia, including acute myeloid leukemia, acute lymphocytic leukemia, and chronic myelogenous leukemia, and some are not approved for intrathecal use as was DepoCyt. That said, some medical sources list therapeutic alternatives to DepoCyt as including non-liposomal cytarabine (for example, the European Medicines Agency).

Cytarabine was on the CDER drug shortage list in 2010 and 2011 as some of the manufacturers had cGMP issues and another had difficulty obtaining enough of the Active Pharmaceutical Ingredient, all of which impeded manufacturing and distribution of the drug.

Regarding Pacira’s DepoCyt, the San Diego facility was inspected as recently as 2015 by FDA, and that inspection as well as the prior several are all listed as Voluntary Action Indicated (“VAI”) on FDA’s website. Furthermore, a review of the Pacira 483s from 2014 and 2012 does not provide much insight as to the types of “persistent technical issues” that Pacira might be referring to.   (We were unable to obtain the 2015 483 Inspectional Observations for review).

On the other hand, a July 2012 inspection carried out jointly by the United Kingdom and French medicines regulatory agencies identified a number of “manufacturing deficiencies.” According to the agencies, the more serious findings related to “a lack of adequate sterility assurance in the manufacturing process…” and these findings “posed a theoretical risk of sterility failure…”  As a result, the European Medicines Agency recalled DepoCyte from all European countries where suitable alternative treatments were available.

It is unclear whether the current problems also relate to a lack of sterility assurance. A Pacira spokesperson stated that “[g]iven that alternative therapies are available for patients with lymphomatous meningitis, Pacira believes that it is in the best interests of patients to permanently discontinue the product, rather than face the prospect of prolonged uncertainty about product availability.”

One can only hope that the cytarabine market is not headed towards another shortage situation.