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  • CDER Exclusivity Board: Barium is Not an NCE Eligible for 5-Year Exclusivity

    We recently came into possession of a small stack of Letter Decisions issued by the Exclusivity Board in the Center for Drug Evaluation and Research – the “CDER Exclusivity Board” – and decided that a series of posts on each decision would be an entertaining way to delve into and discuss various issues that arise with both 5-year New Chemical Entity (“NCE”) exclusivity and 3-year new clinical investigation exclusivity.

    By way of background, the CDER Exclusivity Board was established to “oversee certain exclusivity determinations, including whether and what type of exclusivity should be granted and the appropriate scope of exclusivity grants,” and to ensure consistency and accuracy among exclusivity determinations.  The Board has been in existence for quite some time.  While it’s been almost 6 years since FDA publicly announced, in Fall 2012, the establishment of the Board (see our previous post here), the Board had already issued decisions before then (for example, with respect to the availability of 3-year exclusivity for an NDA supplement for VANCOCIN (vancomycin HCl) Capsules (NDA No. 050606) – see here).

    During the past 6-plus years, the CDER Exclusivity Board has issued scores of Letter Decisions (and there are more to come – see, e.g., page 26 here, as well as a recent Citizen Petition [FDA-2018-P-3284]).  Not all of the Board’s Letter Decisions are publicly available, and those that are public are not always easy to find as they can be buried in NDA Approval Packages.  But we’ve been able to rustle up some of them.

    First up is the CDER Exclusivity Board’s October 2016 Letter Decision on eligibility for 5-year NCE exclusivity for E-Z-HD (barium sulfate) Powder for Oral Suspension, 98% (w/w). FDA approved E-Z-HD under NDA 208036 – a “literature-based” 505(b)(2) application – on January 11, 2016 for use in double contrast radiographic examinations of the esophagus, stomach and duodenum to visualize the gastrointestinal tract in patients 12 years and older.

    NDA 208036 was (and continues to be) identified in FDA’s drug approval database as a “Type 7 – Drug Already Marketed without Approved NDA” application. FDA’s MAPP 5018.2, titled “NDA Classification Codes,” describes a “Type 7” NDA as follows:

    A Type 7 NDA is for a drug product that contains an active moiety that has not been previously approved in an application, but has been marketed in the United States. This classification applies only to the first NDA approved for a drug product containing this (these) active moiety(ies).

    Type 7 NDAs include, but are not limited to:

    (1) The first post-1962 application for an active moiety marketed prior to 1938.

    (2) The first application for an active moiety first marketed between 1938 and 1962 that is identical, related or similar (IRS) to a drug covered by a Drug Efficacy Study Implementation (DESI) notice.

    (3) The first application for an IRS drug product first marketed after 1962.

    (4) The first application for an active moiety that was first marketed without an NDA after 1962.

    Whether the Type 7 (mis)classification or something else triggered a review by the CDER Exclusivity Board is unclear; however, the Board’s Letter Decision provides a nice reference tool for a point we’ve made in the past: An analysis of NCE exclusivity eligibility requires more than just consulting Drugs@FDA and the Orange Book, because those databases are incomplete. It requires, at the very least, a look-back at all NDAs approved by FDA under FDC Act § 505 since the FDC Act was signed into law by President Roosevelt on June 25, 1938, including those many, many NDAs whose approvals were withdrawn in the early 1970s under FDA’s NDA “clean-up initiative” (35 Fed. Reg. 11,929 (July 24, 1970)).

    And that’s exactly what the CDER Exclusivity Board did in determining that E-Z-HD is not eligible for 5-year NCE exclusivity. According to FDA:

    At least one drug product, Metabarin, containing barium sulfate as its active ingredient has been previously marketed under an NDA in the United States. On December 2, 1948, C.S.C. Pharmaceuticals, a division of Commercial Solvents Corporation, submitted an application (NDA 6624) for Metabarin under section 505(b) of the FD&C Act.  The application became effective on December 9, 1948.  As described in NDA 6624, Metabarin, an oral suspension, is a barium contrast medium used in the roentgenographic (X-ray) visualization of the esophagus, stomach, and intestinal tract.  The NDA indicates that Metabarin contains 99.656% barium sulfate (USP) along with a suspending agent, intended to provide a high degree of dispersibility, and two flavoring agents. . . .

    The FD&C Act and FDA’s regulations preclude eligibility for 5-year NCE exclusivity when the drug contains an active moiety that has been previously approved in an application under section 505(b) of the FD&C Act. E-Z-HD contains barium sulfate, the sulfate salt of barium, as its active ingredient.  The active moiety in E-Z-HD is barium.21 Likewise, barium sulfate is the active ingredient and barium is the active moiety in Metabarin.  As noted above, the NDA for Metabarin became effective in 1948 and was deemed approved through the 1962 Amendments to the FD&C Act.  FDA’s regulations make clear that a drug product that is the subject of an application that was “deemed approved” under the 1962 Amendments is considered to be approved in an application under section 505(b) of the FD&C Act for purposes of determining whether certain products qualify for 5-year NCE exclusivity under section 505(c)(3)(E)(ii) and 505(j)(5)(F)(ii) of the FD&C Act.  Therefore, because the active moiety in E-Z-HD has been previously approved in an application under section 505(b) of the FD&C Act, i.e., the Metabarin NDA, E-Z-HD does not contain a new chemical entity and is not eligible for 5-year NCE exclusivity.

    FDA is able to review drug approvals going back to 1938 because the Agency has a tool at its disposal that most folks do not have: the so-called “Ever-Approved List.” The Ever-Approved List a list of drug products purported to have been approved by FDA since 1938 under a marketing application submitted pursuant to FDC Act § 505.  Fortunately, we have a copy of the Ever-Approved List, which we understand the Agency will now supply through a FOIA request (though you might what to specify whether or not you would like the nearly 5,400-page PDF list or the Excel database. . . or perhaps both).  The list certainly comes in handy when speculating about the prospects of 5-year NCE exclusivity (see our previous post here).

    OPDP Issues First Efficacy-Only Enforcement Letter in Over 3 Years

    In its fourth enforcement letter of 2018, the Office of Prescription Drug Promotion (OPDP) takes aim at a marketed drug’s sell sheet solely on the basis of misleading efficacy claims, the first letter to do so in over 3 years.

    The letter, issued August 16 to Ascend Therapeutics, asserts that promotional statements claiming EstroGel (estradiol gel) provides the lowest effective dose of estradiol therapy are misleading as there are other estrogen therapies approved for the same indications with lower doses. While the letter is fairly unremarkable in content, the concept of an enforcement letter based solely on efficacy claims is something that we have not seen in several years.

    In June 2015, OPDP issued a letter to Ascend about misleading promotion for EstroGel through omission of important risk information. Since this letter, OPDP continued the trend in each of its letters about marketed products, citing risk communication issues, even where OPDP also took aim at efficacy presentations.

    In looking back at this trend, we saw that after a letter in August 2015, OPDP enforcement took a hiatus for the remainder of that year. This coincided with Pacira Pharmaceutical’s September 8, 2015 filing of a Complaint against FDA [hyperlink to 12/15/15 blog post] seeking to prevent FDA from bringing an enforcement action against the company for truthful and nonmisleading speech. In December 2015, FDA rescinded a September 22, 2014 OPDP Warning Letter issued to Pacira. We suspected that OPDP’s 2016 enforcement letters were carefully crafted to avoid issues raised in the Pacira case as well as other First Amendment cases (and FDA losses) brought by industry (see our previous post here).

    Do we think that OPDP’s recent letter marks a shift in this approach? Not really. Given the particular statements at issue, we think that OPDP felt confident about the misleading nature of the “lowest dose” claims given the approval of lower dose products. We also note that the promotion meets several stated OPDP priorities for enforcement (e.g., Boxed Warning product, product cited for past violations). The takeaway for industry is that pushing the envelope on efficacy still needs to fall within a gray area – overtly misleading claims may still trigger enforcement, particularly if promotion falls within a stated OPDP priority.

    FDA Seeks Comments on Proposed List of Medical Device Accessories Suitable for Class I Classification

    Comment one, comment all! As part of FDA’s ongoing effort to clarify the classification for medical device accessories (see our previous posts here, here, and here), on August 17, 2018, FDA issued a notification  requesting comments on a proposed list of accessories that FDA believes are suitable for classification in Class I, separate from their higher-classification parent device.

    As mentioned in our previous posts, FDA’s approach to classifying medical device accessories has led to a confusing regulatory scheme in which some accessories are being over-regulated because they were classified according to the parent device (which may be riskier than the accessory) while other accessories have their own separate classification regulations.

    In order to further clarify classification of accessories, on August 18, 2017, section 707 of the FDA Reauthorization Act of 2017 (FDARA; Pub. L. 115-52) amended section 513(f) of the Federal Food, Drug, and Cosmetic Act (FDC Act) and, among other amendments, created a process for FDA to reclassify certain accessories, including proposing a list of accessories suitable for distinct classification into Class I. In accordance with the procedures established by FDARA, FDA published the notification that includes an initial list of eight accessories that the Agency believes are suitable for Class I and is seeking public comment.  These eight accessory types are: (1) gastroenterology-urology accessories to a biopsy instrument; (2) penile implant surgical accessories; (3) ureteral stent accessories; (4) biliary stent, drain, and dilator accessories; (5) suprapubic catheter accessories; (6) implanted mechanical/hydraulic urinary continence device surgical accessories; (7) air-handling apparatus accessory; and (8) corneal inlay inserter handle.

    FDA mentions that it considered accessory types appropriate for inclusion on this list if:

    1. they are not for use in supporting or sustaining human life, or of substantial importance in preventing impairment in human health;
    2. they do not represent a potential unreasonable risk of illness or injury; and
    3. general controls alone would be sufficient to provide a reasonable assurance of safety and effectiveness of the accessory (e.g., design controls are not required).

    The Agency’s notification states that it is open to considering additional accessory types that meet the criteria above and interested parties should comment with their recommendations and rationales for inclusion on the final list.

    FDA’s notification also, separately and somewhat unrelated to the proposed list, clarifies its policy regarding orthopedic manual surgical instruments that are appropriately classified as Class I pursuant to 21 C.F.R. § 888.4540. According to the Federal Register notice, instruments that are designed for use with a specific orthopedic implant are generally accessories to the parent device, not Class I orthopedic manual surgical instruments.  In addition, FDA states that these implant-specific instruments are typically included in the same premarket submission as the parent device (e.g., 510(k) or PMA).  On the other hand, FDA considers orthopedic manual surgical instruments to be those that are for “general use” apparently meaning that they are capable of use with more than one implant type.  FDA’s rationale appears based, in part, on the fact that the implant-specific instruments should be subject to design controls to ensure they are safe and effective for use with the parent device (e.g., orthopedic implant).  Therefore, they would not be eligible for Class I.

    This policy appears to be more than a mere “clarification,” and those in the orthopedic implant and instrument market will want to carefully consider their current instrument classification. According to FDA’s policy, there are now three types of orthopedic manual surgical instruments: (1) those that are appropriately classified under 21 C.F.R. § 888.4540 because they are for “general use;” (2) those that were included in a parent-device premarket submission and are appropriately Class II or III consistent with the parent device classification; and (3) those that were included in a parent-device premarket submission but may be over-regulated based on the parent device’s classification.

    With regard to this third group, companies have two options:

    1. Comment on FDA’s proposed list to recommend adding such instruments to FDA’s final list of Class I accessories. Any proposal should include a clear justification for why the proposed accessory type meets the criteria for Class I.
    2. Request separate accessory classification of such instruments via section 513(f)(6)(D) of the FD&C Act.

    Going forward, if an orthopedic company has a new instrument that will be referenced in a parent-device premarket submission, the company can request classification of the instrument separately from the parent device in the parent device’s 510(k) or PMA in accordance with section 513(f)(6)(C) of the FD&C Act (as described in FDA’s accessory classification guidance).

    The comment period on the proposal ends on October 16, 2018. In addition to comment on FDA’s proposed list of Class I accessories, companies should feel open to commenting on FDA’s policy regarding orthopedic manual surgical instrument.

    Categories: Medical Devices

    A Possible Solution to the Jurisdictional Issues Related to Cultured Meat; Have FDA and USDA Share the Responsibility

    As we previously reported, the most critical issue facing the animal cell cultured industry is a need for clarity on which federal agency – FDA or USDA – will exercise jurisdiction over which aspects of production and distribution. Earlier this year, the discussion heated up when the U.S. Cattlemen’s Association filed a Petition asking USDA to define meat so that it would exclude products created by animal cell culture. .  Other parties in the animal industry, however, argued that USDA should assert jurisdiction over these products to level the playing field.   Then, maybe somewhat unexpectedly to some in the industry, FDA announced a public meeting that suggested that FDA was claiming jurisdiction. Subsequently, on June 27, 2018, there was a congressional briefing on cellular agriculture on Capitol Hill, hosted by Research & Development (R&D) Caucus co-chairs, Representative Bill Foster (D-IL) and Representative Barbara Comstock (R-VA). In addition, there were several legislative efforts to place cell cultured meat and poultry under USDA jurisdiction.

    An Aug. 23, 2018 letter to President Trump cosigned by Memphis Meats and the North American Meat Institute (NAMI) suggests a possible solution to this turf war. In the letter, NAMI and Memphis Meats propose that FDA should have oversight of pre-market safety evaluations for cell-based meat and poultry products. Then once safety is established, USDA should regulate cell-based meat and poultry products, as it does with all other meat and poultry products.  In certain respects, the proposed approach is not new.  In fact, with new ingredients intended for use in meat or poultry a similar approach is applied; under an MOU established in 2000, FDA and USDA cooperate in the review of such ingredients.

    The authors of the letter suggest that the proposed approach plays into the strengths and experience of both agencies. They request a combined meeting between the White House, USDA, FDA and both conventional and cell-based meat and poultry industry stakeholders.

    We will be monitoring developments.

    Is Fairness in the Eye of the Beholder? Pfizer Citizen Petition Looking for Fair and Level Playing Field Between Biologics and Biosimilars

    An interesting Citizen Petition popped up earlier this week in which pharma giant Pfizer has requested FDA guidance on sponsor communications about biosimilar products.  This is not a new campaign for Pfizer, who has emphasized the need to address anticompetitive exclusionary practices, “misinformation,” and market access issues with respect to biosimilars for at least the last year. Pointing to the same anticompetitive behavior that FDA Commissioner Gottlieb has admonished recently in both the biosimilar and the generic space, Pfizer raises concerns that the lack of market confidence in biosimilars resulting from the proliferation of false and misleading information by reference product sponsors has stymied market acceptance and uptake.

    We’re used to seeing big pharma companies on the other side of these types of petitions – brand name sponsors are more often accused of exclusionary behavior than attempting to combat it. But the biosimilar market is a different beast than the traditional small molecule generic market.  With resource-rich companies acting as both reference product and biosimilar sponsors, the game can be played a little differently.  Indeed, Pfizer has approval for two biosimilars, RETACRIT (epoetin alfa-epbx) and NIVESTYM (filgrastim-aafi), and is a commercial partner to Celltrion Healthcare with respect to INFLECTRA (infliximab-dyyb), in addition to several BLAs.

    Looking to Europe’s “robust” uptake of biosimilars, Pfizer’s Citizen Petition posits that payer incentives and inducements to switch patients to biosimilars is an effective strategy to encourage widespread acceptance of biosimilars. Though Pfizer praised FDA’s efforts to foster biosimilar development and adoption, including the recently announced Biosimilars Action Plan, the Citizen Petition cited the payer reimbursement policies and the dissemination of false or misleading information about biosimilars as the biggest obstacles to biosimilar acceptance in the U.S. Pfizer recognizes that payer decisions about reimbursement are outside of the FDA’s purview, but instead encourages FDA to take steps to ensure that reference product sponsors disseminate only truthful and nonmisleading information in an effort to help shape payers’ views on biosimilars and their reimbursement.

    Specifically, Pfizer alleged that “certain reference product sponsors . . . disseminate false and misleading information that casts doubt about the safety and efficacy of biosimilars in the minds of patients and prescribers.” The Citizen Petition includes examples of some of the alleged false and misleading information disseminated by reference product sponsors that undermines public confidence in the safety and effectiveness of biosimilars, including:

    • A textual summary comparing biosimilars to generics on a sponsor’s website explains that “FDA requires a biosimilar to be highly similar, but not identical to the [reference product]”, but fails to state that an approved biosimilar must have no clinically meaningful differences from the reference product.
    • A recent tweet suggesting that biosimilars are not the same as the biologics they reference: “Biologics or biosimilars? It’s not just apples to apples. While #biosimilars may be highly similar to their #biologic reference products, there’s still a chance that patients may react differently. See what you’re missing without the suffix: http://bit.ly/2G2zGTa.”
    • A patient brochure stating that a “biosimilar is not approved as interchangeable . . . ” and “switching or alternating back and forth between the interchangeable biologic and [the reference product] would not cause any changes in safety or how well the treatment works – no infliximab biosimilar has yet proven this.”

    According to Pfizer, these statements create confusion as to biosimilarity and interchangeability, inflate the risks associated with a physician-directed switch to a biosimilar, and cast doubt of the safety and efficacy of biosimilars generally.

    To address these concerns, Pfizer’s Citizen Petition requests that FDA publish Guidance advising on communications characterizing reference products and biosimilars. The Guidance should address misleading representations and suggestions that biosimilars are not as safe or effective as corresponding reference products; misleading comparisons and implied reference product superiority claims; and claims that sow mistrust among patients and physicians in biosimilar products.  Additionally, Pfizer asks FDA to provide examples of communications that would not be considered false or misleading in addition to clarification that a biosimilar sponsor may discuss with physicians and in promotional materials clinical and other data for a biosimilar product whether or not such data is included in the biosimilars labeling.

    Given FDA’s commitment to biosimilars and to addressing the high costs of medicines, it wouldn’t be surprising if the Therapeutic Biologics and Biosimilars Staff is already hard at work establishing some sort of guidelines for communication about the relationship between biologic reference products and biosimilars. Indeed, FDA has emphasized the need to develop “effective communications to improve understanding of biosimilars among patients, clinicians, and payors.” But it’s still early in the implementation of the Biosimilar Action Plan, and FDA will be hearing many more suggestions about the biosimilars marketplace next week.

    Facing Continuation of the Endo/Par Vasopressin Lawsuit, FDA Publishes Notice Concerning List of Drug Substances for Which there is [NOT?] a Clinical Need under Section 503B

    For regular readers of compounding news on our FDA Lawb Bog, the “bulks” saga for outsourcing facilities continues with a whirlwind of activity.

    A bit of background: FDA published a new bulk substances list for Section 503B outsourcing facilities on July 23, 2018, where vasopressin somewhat surprisingly remained on FDA’s Bulks List 1.  Proposing to compound using vasopressin, outsourcing facility Athenex, Inc., successfully intervened in the Endo/Par federal district court lawsuit against FDA over the Section 503B Bulks List, and its inclusion of vasopressin in particular (see our previous posts here and here).  Athenex also filed a motion for a declaratory judgment against Endo/Par in New York federal district court.  On August 25, 2018, the U.S. District Court for the District of Columbia lifted the stay in the Endo/Par federal lawsuit at the request of the parties.  Yesterday, Endo/Par filed a Motion for Preliminary Injunction in its D.C. lawsuit.

    Throughout its blistering Memorandum in Support of its Motion for Preliminary Injunction filed in that case, Counsel for Plaintiffs dubs FDA’s Section 503B interim Policy on Bulk Substances a “Bulk Compounding Decree,” which it claims is “flatly violative of the law.” It further states that FDA is permitting compounders to “sidestep” the drug approval process –an interesting legal theory given FDCA Sections 503A and 503B explicitly exempt compounders from FDA’s drug approval process (i.e., FDCA Section 505).

    FDA published today its Notice of Intent to remove vasopressin from Section 503B Bulks List 1.  In addition to seeking to remove vasopressin from the list, FDA’s Notice also addresses its intent to not include two other substances on Section 503B’s Bulks List 1.  These substances are bumetanide and nicardipine hydrochloride.  FDA had previously placed bumetanide, vasopressin, and nicardipine hydrocholoride on Bulks List 1 after those substances were originally nominated under FDA’s published 2014 nomination process (see our previous post here).  Notwithstanding FDA’s original Bulks List I decision for all three substances, reflecting FDA’s determination the substances met FDA’s prior published interim criteria for inclusion on the list, FDA seems to have changed its mind.  (Note Bumetanide was nominated back in June 2017 by QuVa Pharma, the same entity that nominated vasopressin).  FDA’s motivation (at least in part) for seeking an exclusion of vasopressin from Bulks List 1 likely is the renewed interest in and continuation of the Endo/Par lawsuit.  However, we are left guessing why FDA seeks the early cut for the other two substances.  FDA also acknowledges in footnote 11 of its Notice that the Drug Quality and Security Act (DQSA) requires notice and comment rulemaking when seeking to include a drug substance on the Bulks List, yet not when it intends to remove the substance after the nomination and evaluation process.  FDA states it will take input from both public comments and its Pharmacy Compounding Advisory Committee (PCAC).  It will also continue to review the clinical need determinations for these and other nominated substances, and intends to evaluate nominated bulk substances on a rolling basis.

    We continue to wonder why (and possibly how…) FDA can publish its proposal to eliminate three substances from its Bulks List 1 for Section 503B facilities when FDA has not yet issued final guidance on the nomination process itself (recall FDA’s latest draft guidance on the process, published in March 2018, here).  FDA also relies on its proposed draft nomination process (and not its prior process to which the three bulks substance nominations at issue adhered) to show why these three substances should not be used in compounding (i.e., whether the approved drug product sufficiently meets patients’ clinical needs, whether there is a showing of clinical need by the compounded formulation that is unmet by the approved product etc.).  FDA’s prior nomination process did not include such a rigorous clinical need review compared to what FDA now seems to now expect.

    FDA is accepting comments on the three substances for the next 60 days after publication of today’s Notice intending to exclude the substances. Will FDA now receive comments addressing the clinical need component for compounded versions of vasopressin, bumetanide, and nicardipine hydrochloride?  And, other than vasopressin, why did FDA choose to remove these two other bulk substances?  Does the Agency intend to review every single substance on Section 503B’s Bulks List 1 to determine whether their first “clinical need” determination was correct, or that the nominator otherwise made an adequate showing?  Will FDA conduct such a review using its “old” nomination process, from 2014, which facilities relied on at that time (and expended significant resources), or its new process, which is the subject of the March 2018 draft re-nomination guidance (and likely prompted by the Endo/Par lawsuit)?  In addition,  we wonder where this leaves FDA’s Section 503A interim bulk substances policy, in which FDA had adopted a similar approach to nominations (but for the fact that Section 503A explicitly permits pharmacies to compound using components of approved drugs).  It also seems that, notwithstanding the Endo/Par lawsuit, hospital system pharmacies would be able to continue compounding using vasopressin and other components of approved drugs, and provide the compounded formulations to its hospital patients under other current FDA guidance.   Inquiring minds …. so much to resolve.

    One more Note: FDA’s Division of Drug Information’s announcement on the release of the Notice also mentions that its action on the Bulks List is part of a series of steps that FDA intends to take:

    between now and the end of 2018 to further implement the DQSA. It specifically mentions that it will be issuing this year a revised draft Memorandum of Understanding with states that will describe a more flexible approach to addressing certain distributions of compounded products by 503A compounders; a revised draft guidance on insanitary conditions at compounding facilities that will, among other things, address concerns that were raised by providers around the potential implications of the agency’s prior draft guidance; and a revised guidance on current good manufacturing practice (CGMP) requirements for outsourcing facilities that, we believe, will take a more tailored approached to make it more feasible for more 503A pharmacies to become 503B outsourcing facilities.

    As always, stay tuned.

    Draft Guidance Falls Short on Providing Clarity for Companies Denied Certificates to Foreign Government

    One of the most painful consequences of a bad inspection at a U.S. facility is FDA’s resulting refusal to issue certificates to foreign governments (CFGs) until the issues are resolved. CFGs are quite often a requirement to renew licenses and permits to sell in various foreign markets. Although typically linked to a warning letter, sometimes a Form 483 can trigger this refusal. Sometimes it can take many months, or more than a year, for FDA to begin issuing CFGs again. During that time period, a manufacturer may find itself unable to sell product into certain foreign countries.

    Section 704 of the FDA Reauthorization Act (FDARA) amended Section 801 of the Federal Food, Drug, and Cosmetic Act to require FDA to provide additional clarity to the bases for denying CFGs. The statute requires that:

    • FDA must provide a written statement of the basis for denying a request for a CFG “and [must] specifically identify the finding upon which such denial is based.”
    • If the denial is based on a routine inspectional finding that a facility is out of compliance with the QSR, FDA must “provide a substantive summary of the specific grounds for noncompliance.”
    • A CFG may not be denied if it is solely based upon the issuance of a Form 483 if the manufacturer “has agreed to a plan of correction in response.”

    FDARA also directed FDA to set up a process that appears to be essentially equivalent to supervisory appeals of significant decisions. A manufacturer denied a CFG may at any time “request a review in order to present new information” relating to corrective actions.

    In accordance with FDARA, on August 17, FDA issued draft guidance, “Process to Request a Review of FDA’s Decision Not to Issue Certain Export Certificates for Devices.” The short, seven-page guidance is intended, according to FDA, to clarify the new statutory requirements related to CFG denials. In our reading, however, it leaves open more questions than answers and mainly reiterates the statutory requirements.

    For example, the statute states that a CFG may not be denied based solely upon a Form 483 if the manufacturer “has agreed to a plan of correction in response.” The guidance requires the following steps to satisfy this standard:

    1. The owner, operator, or agent in charge of the establishment should submit a plan of correction in writing to the appropriate FDA office. The plan should include steps the owner, operator, or agent in charge of the establishment will take to correct observations documented and timeframes for completing such steps.
    2. The FDA will review the plan and notify the owner, operator, or agent in charge of the establishment whether the plan is sufficient to address the violations documented in the inspectional observations. If the plan is agreed to, FDA will issue a CFG.

    Step 1 sounds to us like a well-prepared 483 response. As any manufacturer will tell you, FDA virtually never notifies a company that it is in agreement with its corrective actions outlined in a 483 response. The Agency’s agreement is commonly assumed through Agency silence (e.g., lack of a Warning Letter or other enforcement action) and is often confirmed when an Establishment Inspection Report is issued documenting that the Agency has closed out the inspection.

    Therefore, Step 2 appears to be entirely new requiring FDA to affirmatively notify the company that its plan is “sufficient to address the violations documented in the inspectional observations.” FDA provides no details about how this process will unfold. For example, how long will it take FDA to review a company’s response? What if a plan is generally sufficient but the Agency has minor changes, will FDA provide that feedback to the company so it can modify its plan and then reach agreement? We hope that FDA will provide additional clarity regarding this new process in the final guidance.

    Another area that warrants further clarification is the process for reviewing a CFG denial. The statute required FDA to set up a process for a company to “request a review in order to present new information” relating to corrective actions. The guidance essentially states that if a manufacturer wishes to obtain such a review, it should email the applicable export branch (CDRH or CBER) and provides the respective email addresses. The guidance states “if the issue cannot be resolved by the [applicable export branch], each Center’s review process will be followed.”

    For CDRH appeals, the guidance references another guidance document specific to the CDRH appeals process, but notes that the request is not considered to be a 517A “significant decision,” and therefore is not subject to the 30 day filing and review timeframes. (For CBER-regulated products, FDA references the Formal Dispute Resolution Request process, but explicitly disclaims its ability to resolve issues within 30 days per the FDRR guidance.) It provides no further information as to how long it might take for the export branches to address a request for review. Nor does it state whether or how an export branch might communicate its process, timeline, or status to a company with a pending request for review. In our view, these additional details are essential to a well-established process. We hope that FDA will provide additional clarity in its final draft so that the positive intentions of Section 704 of FDARA may be realized for industry.

    Categories: Medical Devices

    Third Circuit Affirms False Claims Act Dismissal Based on Reasonable Interpretation

    In United States of America ex rel Streck v. Allergan Inc., a federal False Claims Act (FCA) case alleging that several pharmaceutical manufacturers knowingly calculated false Average Manufacturer Prices (AMPs) that affected their Medicaid rebate payments, the U.S. Court of Appeals for the Third Circuit agreed with the district court that the relator failed to adequately plead such a claim. Hyman, Phelps & McNamara, P.C. represented two of the manufacturers in the case.

    We previously posted here about the district court’s decision. The relator alleged that the manufacturers had failed to include so-called “price appreciation credits” as a price adjustment in calculating AMP. The issue considered on appeal by the Third Circuit was whether the relator had pled that the manufacturers had acted “knowingly,” a required intent for an FCA claim. In concluding that the relator had not done so, the court quoted from a D.C. Circuit decision reasoning: “Consistent with the need for a knowing violation, the FCA does not reach an innocent, good-faith mistake about the meaning of an applicable rule or regulations. Nor does it reach those claims made based on reasonable but erroneous interpretations of a defendant’s legal obligations.” (quoting U.S. ex rel Purcell v. MWI Corp., 807 F.3d 281, 287-288 (D.C. Cir. 2015).

    Relying on Purcell, the Third Circuit applied a three part test: (1) whether the relevant statute was ambiguous; whether the defendant’s interpretation was objectively reasonable; and (3) whether the defendant was “warned away” from that interpretation “by available administrative and judicial guidance.” With respect to the last item, it is noteworthy that Purcell, citing to the Supreme Court’s 2007 decision in Safeco Insurance Co. of America v. Burr, made it clear that such guidance must be “authoritative guidance” because “[i]n Safeco the Supreme Court explained that informal guidance . . . is not enough to warn a regulated defendant away from an otherwise reasonable interpretation.” The FCA violations alleged by the relator took place between 2004 and 2012. The Third Circuit found that, during that period, the available CMS guidance on calculating AMP in general “failed to articulate a coherent position on AMP and, specifically, price-appreciation credits.” Under those circumstances, the court found that the relator had failed to plead that the defendants were “warned away” from their interpretation that price appreciation credits were excluded from AMP.

    Based on the Purcell framework, the Third Circuit agreed with the district court that the manufacturers’ alleged failure to include price appreciation credits as a price adjustmemt in calculating AMP could not sustain an FCA claim, because even if their interpretation was incorrect — which the Third Circuit did not decide but assumed for purposes of its analysis — it was not unreasonable.

    It is important to note that, following the period of the violations alleged in the Streck case, CMS did specifically address price appreciation credits. In the preamble to a 2016 regulation, CMS expressed its view that price appreciation credits amount to a price adjustment that should be recognized in AMP. 81 Fed. Reg. 5170, 5228 (Feb. 1, 2016). Therefore, although the Third Circuit’s decision provides helpful support for the proposition that an FCA claim may not be proven based on an innocent mistake about the meaning of ambiguous regulations or guidance, it is questionable whether the exclusion of price appreciation credits from AMP could be defended based on Purcell and the Third Circuit’s decision in Streck after CMS’s 2016 preamble statement.

    Categories: Enforcement |  Health Care

    The Third Cut Is the Deepest: DEA’s Continued Slashing Of Annual Quotas Lacks A Clear Rationale

    In an effort to address, in Attorney General Jeff Sessions’ words, “the worst drug crisis in American history,” the U.S. Department of Justice (“DOJ”) and the Drug Enforcement Administration (“DEA”), are for the third straight year proposing to reduce the quantity of Schedule II opioid pain medications that can be manufactured. DOJ, Press Release, Justice Department, DEA Propose Significant Opioid Manufacturing Reduction in 2019 (Aug. 16, 2018). For 2019, in addition to reducing the Aggregate Production Quotas (“APQs”) of oxycodone, hydrocodone and fentanyl, DOJ/DEA also proposes to further reduce the quantities of morphine, hydromorphone and oxymorphone. Proposed Aggregate Production Quotas for Schedule I and II Controlled Substances and Assessment of Annual Needs for the List I Chemicals Ephedrine, Pseudoephedrine, and Phenylpropanolamine for 2019, 83 Fed. Reg. 42,164, 42,168 (Aug. 20, 2018).

    We continue to be troubled by the paucity of scientific and medical support for this three-year trend that has resulted in a dramatic decrease in quotas for much needed pain medicine. Continuing to generally blame the opioid crisis for such reductions is in our opinion short-sighted and pre-supposes that simply reducing the amount of available inventory will reduce abuse and diversion. Moreover, we do not believe the DEA or DOJ is showing appropriate concern for legitimate patients and the impact on medical care.

    The DEA must establish APQs on an annual basis which limit the total amount of a certain drug that can be manufactured in a given year. Moreover, each manufacturer must apply for an individual manufacturing quota and the sum of these quotas may not exceed the APQ.

    The proposed APQ reductions in 2019 of the six opioids equate to between seven percent (morphine for sale) and 15 percent (oxymorphone for sale) compared to 2018 levels. DEA reduced the APQs for these opioids minimally in 2018, but had reduced them in 2017 by at least 27 percent of 2016 levels, with hydrocodone, fentanyl, morphine and oxymorphone levels reduced by at least 40 percent. The 2017 APQ reductions eliminated a 25 percent buffer that DEA had added to APQs annually between 2013 and 2016 to guard against shortages. See DEA, Press Release, DEA Reduces Amount of Opioid Controlled Substances To Be Manufactured in 2017 (Oct. 4, 2016).

    These huge cuts in opioid production will eventually lead to shortages for legitimate medical use. The Attorney General, in discussing the proposed reductions, further observed that “President Trump has set the ambitious goal of reducing opioid prescription rates by one-third in three years.” DOJ, Press Release, Justice Department, DEA Propose Significant Opioid Manufacturing Reduction in 2019 (Aug. 16, 2018). We understand the rationale in proposing to reduce the quantity of highly abused opioids that will be manufactured next year and recognize that state Prescription Drug Monitoring Programs and the Centers for Disease Control and Prevention (“CDC”) opioid prescribing guidelines have led practitioners to prescribe these medications in fewer quantities. However, DOJ/DEA should not make the reductions simply to meet an arbitrary benchmark; the reductions must be based upon meaningful data.

    We also note that these reductions come on the heels of DEA recently modifying the criteria it would use to establish quotas. Controlled Substances Quotas, 83 Fed. Reg. 32,784 (July 16, 2018). That rule, which became effective on August 15, 2018, adds two additional factors for consideration:

    • The extent of any diversion of the controlled substance; and
    • Relevant information obtained from the Department of Health and Human Services, including FDA, the CDC, and the Centers for Medicare and Medicaid Services, “and relevant information obtained from the states.”

    However, this DEA rulemaking also fails to provide sufficient rationale or guidance on how DEA will determine what the “extent of any diversion” means. Also, the involvement of the states in the DEA quota process also raises more concern about the impact on DEA’s timely establishing of such quotas. For example, if one state raises objections about the quota for a drug, it appears that DEA may then need to hold hearings on the quota which could again result in delays in granting of individual manufacturing quotas.

    In short, reducing the APQs in 2019 may lead to less opioid medications available for potential diversion from legitimate channels to misuse and abuse in 2019, but will also result in less supply that is available for the millions of patients who legitimately need them. Simply reducing the quantity of opioids manufactured does not in itself ensure that only legitimate patients, rather than those who would misuse and abuse the medications, will have access to them. There is the risk with reduced APQs that supply will not meet legitimate needs if doctors and other practitioners are not diligent about issuing prescriptions only to the patients who need them.

    Written comments on the proposed APQs must be postmarked on or before September 19, 2018.

    House and Senate Bills Would Require Reporting of Biosimilar Agreements to the DoJ and FTC

    Last month, Representatives John Sarbanes (D-MD) and Bill Johnson (R-OH) introduced H.R. 6478, the “Biosimilars Competition Act of 2018.”  The bill would amend the Public Health Service Act (“PHS Act”) to require that certain agreements between biosimilar applicants and reference product sponsors be reported to the Department of Justice (“DoJ”) and to the Federal Trade Commission (“FTC”).  According to Rep. Sarbanes, the bill is intended to address so-called “pay-for-delay” agreements.

    Specifically, H.R. 6478 would amend PHS Act § 351(l) to add item “(10)” to require the reporting of any agreement between a biosimilar applicant and a reference product sponsor, or an agreement between two or more biosimilar applicants, regarding the manufacture, marketing, or sale of the biosimilar product(s) for which a 351(k) aBLA was submitted to FDA, or the brand-name reference product. Such agreements also include agreements that are contingent upon, provide a contingent condition for, or that otherwise relate to an agreement regarding the manufacture, marketing, or sale of the biosimilar or reference products. Agreements that solely concern purchase orders for raw material supplies, equipment and facility contracts, employment or consulting contracts, or packaging and labeling contracts would be excluded from reporting under H.R. 6478.

    While the House considers H.R. 6478, the United States Senate is considering legislation concerning the reporting of patent settlement agreements involving biosimilars. Specifically, S. 2554, the “Patient Right to Know Drug Prices Act,” would amend the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (“MMA”) – and, in particular, Sections 1111-1118 – to require that certain agreements reached between biosimilar applicants and reference product sponsors be reported to the FTC. Section 1112 of the MMA requires that certain types of agreements executed on or after January 7, 2004 between a brand-name drug company and a generic drug applicant be filed with the FTC and the DoJ; MMA § 1113 states that “[a]ny filing required under Section 1112 shall be filed with the DoJ and the [FTC] not later than 10 business days after the date the agreements are executed;” and MMA § 1115 provides that the failure to timely file applicable agreements may result in a civil penalty of $11,000 for each day that a required filing has not been made. (For additional information on current FTC reporting requirements and reports, see here and here.)

    The reporting requirements proposed in S. 2554 for biosimilar agreements would be similar to the requirements currently in place for drug products regulated under the FDC Act. S. 2554 is making its way through the Senate as calls for reporting of biosimilar agreements to the FTC have increased in the past couple of months (see here).

    Its Getting Bulkier Every Day for This Section 503B Facility: Athenex Announces a Product Launch, Moves to Intervene in the Endo/Par Bulks Lawsuit Against FDA, and Files a Declaratory Judgment Complaint

    On August 13, 2018, Buffalo, New York-based Athenex Pharma Solutions, LLC and Athenex Pharmaceutical Division, LLC (Athenex) announced the launch of their vasopressin compounded formulation injection ready-to-use product line (see Press Release here). It also moved to intervene (either as of right or permissively) in a pending lawsuit filed in October 2017 by Par Sterile Products and Endo Par Innovation Company (Endo/Par) (blogged about here). In yet a third punch, Athenex also filed a declaratory judgment action against Endo/Par in the United States District Court for the Western District of New York alleging non-infringement and invalidity claims for several of the defendant’s Vasostrict® patents.

    The 2017 Endo/Par lawsuit against FDA involves seeking a judicial determination about whether FDA’s inclusion of vasopressin (the active ingredient in Endo/Par’s FDA-approved drug product Vasostrict®) on FDA’s Section 503B Bulks List is appropriate. Endo/Par’s lawsuit also seeks a determination concerning whether FDA’s 2017 Section 503B Bulk Substances Interim Policy violates the Administrative Procedures Act’s notice and comment rulemaking requirements. Recall that Endo/Par stated in a press release earlier this year that, based on FDA’s January 2018 public statements reflecting the Agency’s “intent to alter its compounding policy and comply with the DQSA, as well as subsequent discussions among the parties’ counsel, Endo previously agreed to FDA’s request to stay the litigation until March 30, 2018.” (See Press Release here). After FDA’s publication of new draft guidance revisiting the 503B bulks nomination process in March 2018 and discussions between the parties, Endo/Par agreed to extend the stay of the lawsuit for an additional 180 days as “FDA works toward implementation of the new compounding policy.” Under the terms of the proposed stay, Endo stated that it “will retain the ability to terminate the stay by notifying FDA that it believes that an entity has commenced or is likely to commence bulk compounding of any vasopressin-containing drug product under Section 503B.” Most interestingly, FDA released a new Bulks List on July 25, 2018, here, which list still includes vasopressin on Bulks List 1.

    FDA’s March 2018 draft guidance indeed seeks significant changes to the nomination process for bulk substances for use in Section 503B Outsourcing Facilities. FDA’s proposed changes come almost six years after implementation of the Drug Quality and Security Act (Title 1), which created Outsourcing Facilities, and almost four years after FDA published its detailed bulk substances interim policy… pursuant to which the compounding industry nominated hundreds and hundreds of bulk substances, and after FDA, with the assistance of the Pharmacy Compounding Advisory Committee (PCAC) already made determinations concerning the propriety of using those substances in compounded medications. After receiving a nomination for the bulk substance vasopressin, FDA added that substance to the list in the summer of 2017. That listing decision led to the Endo/Par lawsuit against FDA described above.

    Next enters Athenex and its Motion for Intervention in the Endo/Par litigation. Evidently it was Athenex’s nomination for vasopressin that FDA reviewed (and thus added the substance to Bulks List 1) last July. Athenex’s Memorandum in Support of its Motion to Intervene describes the Company’s significant investment in, and commitment to, its 503B outsourcing facility operations, and its flagship compounded formulations, including ready-to-use vasopressin products. It also describes in detail how Athenex has devoted considerable financial and other resources to preparing compounded vasopressin products in reliance on FDA’s 2017 inclusion of the substance on Bulks List 1.

    Athenex also notes that vasopressin been used intravenously in hospitals, mostly in emergency scenarios, from almost 100 years. Notwithstanding, Athenex alleges that after Par received FDA approval for its product, Par “leveraged its exclusivity to maximize sales,” and the “average wholesale price of intravenous vasopressin surged 3141% — from $4.27 to $148.40 per vial. (Memorandum in Support at 8, 21). From 2013 to the present, annualized sales increased from $4 to $400 million. We have heard this very familiar sounding Shkrellianesque tale through the years…but will the pricing trevails move the Court? Athenex also describes the many differences between the FDA-approved version (Vasostrict®) and compounded formulations of vasopressin, including the ready-to-use compounded form offered by Athenex.

    In addition to other arguments supporting its intervention in the lawsuit, Athenex argues that compounding from bulk substances (nonsterile-to-sterile compounding) is safer than compounding using the approved product (i.e., using Vasostrict® in a sterile-to-sterile compounding process). And, it claims that, contrary to Endo/Par’s allegations, compounding with vasopressin is not unsafe and there is a clinical need for the compounded product. Athenex argues that because answers to these issues are also “central” to deciding the underlying lawsuit, the district court should grant its motion to intervene.

    For those in the continuing compounding regulatory fray, these latest events are noteworthy. The Motion is, in turn, supportive of FDA’s efforts in the nomination process, and one could argue defends the Agency’s prior actions (and considerable efforts) involving its earlier bulks list determinations. It also challenges whether Endo/Par’s lawsuit is appropriate on its face because FDA’s earlier interim bulks policy is not “final agency action” upon which the lawsuit may be based. Furthermore, it states FDA’s decisions on bulk substance nominations to date, in particular the Agency’s exercise of enforcement discretion, is not reviewable by a court, at least at this point. Stay tuned for updates on this continuing saga.

    FDA’s IVD TA: It’s Not Just Technical Assistance

    Since 1992, the Food and Drug Administration’s (FDA’s) efforts to regulate laboratory developed tests (LDTs) have been one of the most controversial device regulatory topics.  We have written about this topic multiple times (see our list at the end of this post).

    The focus of many of these posts has been FDA’s efforts to use guidance documents to regulate LDTs under the Federal Food, Drug, and Cosmetic Act.  In short, we have questioned the legality of those efforts, and given the constraints imposed by the existing legal framework, its desirability.

    However, there is another way to approach LDT regulation: by enacting legislation.  That would address the legality issue, and, if properly crafted, its desirability.  A new law could provide an unassailable legal framework, while also addressing multiple concerns that have been raised: LDTs and kit manufacturers should be on a level playing field; the regulatory requirements should be based on the clinical role and risk of the test, not whether it was an LDT or distributed test kit; the role played by laboratories in innovation and meeting underserved populations; recognition that labs are already subject to extensive regulation under the Clinical Laboratory Improvement Amendments (CLIA); etc.  FDA was asked to provide Technical Assistance (TA) regarding legislation, the Diagnostic Accuracy and Innovation Act (DAIA), that is designed to accomplish these and other goals.

    In response, FDA went much further than providing technical comments on the legislation.  FDA has instead advanced a different framework, with different statutory language, which would substantially change the regulatory regime for in vitro diagnostics (IVDs).  As FDA said in accompanying comments, the agency is “taking a fresh look at how the Agency is encouraging the development of innovative tests and continuous improvements to diagnostics already on the market.”  Underscoring that the TA is not just tweaking existing mechanisms, FDA says it “believes it is necessary to create pathways” (emphasis added).

    The Medical Device Amendments of 1976 placed diagnostics into the same category as all other devices.  The definition of device included the term “diagnosis,” but otherwise did not recognize that IVDs existed except as part of the broader world of devices.  Although the statute has been amended multiple times since then, diagnostic products have continued to be lumped in with all other devices.  The issue that FDA has decided to address head on is whether that should continue.  And FDA answered with a strong “no,” by introducing novel concepts such as “priority review,” “precertification,” “provisional approval,” and “test groups.”

    FDA’s TA document is not tinkering with the regulatory regime for IVDs. It is a revamp of how all IVDs should be regulated, LDTs and distributed diagnostic products alike.  (DAIA, of course, also proposed significant revisions to how diagnostic tests are regulated; the purpose of this blog is not to compare and contrast the new proposals.  Notably, the TA does not attempt to address the role of CLIA.)

    For LDTs, it would mean a new regulatory framework.  Some labs have voluntarily submitted 510(k)s or premarket approval applications (PMAs) to FDA.  If FDA’s proposal were adopted, labs and manufacturers would be subject to the same criteria for when applications would need to be submitted.  Labs would also be subject to other FDA requirements beyond the submission of marketing applications.

    Putting kits and LDTs on the same footing, though, is not the most striking aspect of the proposal.  Rather, it is FDA’s rewriting of the IVD regulatory process, both for entering and remaining on the market.  Many of the regulatory terms and constructs that have governed IVD regulation for decades ‒ would be discarded.  A whole new vocabulary would be adopted, complete with their own statutory definitions, e.g. “in vitro clinical test” and “developer” and “test group” and “analytical validity” and “first-of-a-kind.”  This legislation, although it borrows from some past concepts, should be viewed as revolutionary, not evolutionary.

    We will be writing about more of the details later.  One example, though, suffices to show how FDA’s proposal would dramatically alter the regulatory system.  For 42 years, the primary route for FDA review of new IVDs has been the 510(k) premarket notification.  To obtain a 510(k) clearance, a company has had to show “substantial equivalence” to a “predicate device.”  Those terms ‒ 510(k), substantial equivalence, and predicate device ‒ have been part of regulatory lingo for over four decades.  Under FDA’s framework, they would disappear.

    The concept of “predicate device” is dropped.  A new phrase is created: “test group.”  The squishiness of the term “predicate device” vanishes; a more precise and multifaceted term is created.   A test group means tests that have the following common elements: 1) the substance measured, 2) the type of specimen, 3) the test method, 4) the test purpose, e.g., screening or monitoring, 5) the disease or condition, 6) the patient population, and 7) the place of use, e.g., OTC or clinical lab.  Yet, the role the “test group” concept plays is not analogous to that of ‘predicate devices.’”  The TA is not simply displacing one definition with another, but falling within – or outside ‒ a “test group” has different consequences than being able to cite a single device as a predicate for a 510(k), e.g., it becomes a factor in determining whether a modification to a marketed device needs prior approval.

    FDA’s TA will unquestionably be controversial.  There will certainly be numerous questions about the specifics.  One provision reads: “any interested person may obtain review, in accordance with section [appeals], of an order of the Secretary approving an application.”   As written, this would suggest third parties could readily challenge an approval obtained by another company, an outcome that FDA would not want.  Another example: limiting the criterion for exemption for rare diseases to fewer than 8000 patients in the U.S. who require testing will substantially limit the utility of this provision. And another one: The TA would also confer upon FDA the power to withdraw the approval of a product if “there is a reasonable likelihood that the in vitro clinical test would cause death or serious adverse health consequences, including by causing the absence, delay, or discontinuation of appropriate medical treatment.”  This would give FDA a power that it currently lacks for 510(k)-cleared tests, as well as tests that have gotten de novo authorization.

    Rewriting the laws for IVDs is a complicated business, and every word needs to be scrutinized, both for what is intended and for potential unintended consequences.  There are multiple pieces to the new jigsaw puzzle FDA has proposed.  When all the pieces are placed together, will they create a coherent image?  In its transmittal explanatory note, FDA states, “DAIA could have the unintended consequence of creating inconsistencies in the marketplace.”  FDA’s proposal also needs to be carefully vetted for its own possible unintended consequences.

    But beyond the question of the specifics of the legislation, there is the most basic question of all: should the laws governing the entry on to the market of IVDs be updated.  There are good reasons to say the answer is yes.

    Over time, the fit between novel IVDs and the existing regulatory framework has become increasingly uneasy.  Today’s IVDs are much more heterogeneous than when the FDC Act was enacted.  IVDs play widely divergent roles.  They are evaluated in ways differently than most other products, with the need to show analytical performance.  (The TA has multiple provisions explicitly dealing with analytical testing.) Clinical performance is judged through different kinds of metrics, such as sensitivity and specificity, positive predictive value and negative predictive value, positive and negative percent agreement.  Those concepts don’t always align neatly with the language of substantial equivalence or even de novo.  Yes, other devices have their own vocabulary and requirements, but this issue of fit is even more pronounced for IVDs as a class of products.

    More pressing, the rate of change in the industry is accelerating.  With next generation sequencing and proteomics and metabolomics and artificial intelligence and deep learning and liquid based biopsies (predicted to be a $2 billion market in four years) and other new tools and methods, the ability of IVDs to be cut or tugged into the standard regulatory Procrustean bed is fraying.  The challenge of squeezing these new tests into the existing framework is made even worse by the need for these IVDs to be updated rapidly.  The plodding model of obtaining 510(k) clearance/de novo/PMA using standards that do not take into account some of the unique attributes of IVDs, assess whether a change requires a new application (note that the guidance document for when to submit a 510(k) for changes devotes many pages to IVDs), and then submitting and waiting for a decision simply will not work for some of these new products, where the clinical market needs much faster modifications and updates.  The current approach also causes its own headaches for FDA and how it does reviews and allocates resources.  The statutory provisions governing regulation and product review should be more explicitly based on risk.

    The momentum for overhauling the way IVDs are regulated is growing.  Multiple stakeholders have endorsed the concept. FDA’s TA is consistent with the principle that change is necessary, albeit there are numerous differences in approach and details.  FDA was asked for its views, and it was not going to throw away its shot by limiting itself to minor technical comments.

    Last week, two of my colleagues began their blog post by quoting Foreigner.  For this post, a somewhat more obscure song reference (War of the Worlds) seems appropriate.  While I would not analogize FDA’s TA to post-apocalyptic Earth after a Martian invasion, the lines “In a brave new world  . . . We’ll start all over again” seem appropriate for labs, manufacturers, and FDA.

    FDA Law Blog LDT Posts

    • FDA Considers Fundamental Shift in Federal Oversight of Laboratories (link) – June 20, 2010
    • FDA Reopens Oversight of Laboratory-Developed Tests Comment Period; Will Accept Comments Until September 15 (link) – August 19, 2010
    • FDA Plans to Regulate Laboratory Developed Tests; Many Questions Remain as to Details of Regulatory Scheme (link) – July 27, 2010
    • FDA Commissioner Calls for More Active FDA Regulation of Laboratory-Developed Tests, and ACLA Promptly Responds with a Petition Opposing FDA (link) – June 5, 2013
    • FDA Notifies Congress of Draft Guidance Documents Regarding LDTs (link) – Aug. 4, 2014
    • TRICARE Announces Demonstration Program that Would Expand LDTs Eligible for Coverage During 3-Year Period and Possibly Beyond; Coalition Urges FDA to Create Single Framework for both Diagnostic Kits and LDTs (link) – June 27, 2014
    • Senators Send Letter to OMB Requesting Release of LDT Draft Guidance (link) – July 6, 2014
    • FDA Issues Draft LDT Guidance Documents; Provides 120-Day Comment Period and will Host October Public Meeting (link) – October 2, 2014
    • CDRH Holds Webinar on Draft LDT Guidances – Highlights that Guidances Hold More Questions than Answers (link) – October 28, 2014
    • OIR Head Alberto Gutierrez Discusses Draft LDT Framework at Federal Laboratory Advisory Committee Meeting; Provides Additional Insights on Agency Plans to Regulate LDTs (link) – November 11, 2014
    • LDT Battle Lines Drawn: FDA Announces Jan. 8-9 Public Meeting on LDT Framework; Lab and Medical Groups Send Letter to FDA Commissioner Urging Notice-and-Comment Rulemaking; FDA and Patient Groups Advocate for LDT Framework on Hill (link) – November 25, 2014
    • As Part of Effort to Prepare 21st Century Cures Legislative Discussion Draft, House Committee Seeks Comment on FDA Proposed Framework to Regulate LDTs (link) – December 12, 2014
    • As Snow Falls, We See a Flurry of Developments Related to FDA Efforts to Actively Regulate LDTs (link) – February 22, 2015
    • Diagnostic Test Working Group Proposes Alternative to FDA’s LDT Framework (link) – April 16, 2015
    • Molecular Pathologist Group Proposes Legislative Solution to Modernize CLIA, Including CMS/Third-Party Premarket Review, as Substitute for FDA’s LDT Framework (link) – August 14, 2015
    • Back from Break: FDA Issues Letter to Pathway Genomics for Cancer Screening LDT; Proposed Legislative Alternatives to FDA Framework Continue to Emerge (link) – September 29, 2015
    • FDA Plans to Issue Final LDT Framework in 2016; Subcommittee Members, CMS and FDA Officials Critique Proposed Legislative Approach that Would Give CMS LDT Premarket Review Authority (link) – December 20, 2015
    • FDA Will Not Finalize Draft LDT Guidances in 2016 – But That’s Not the End of LDT Regulation (link) – November 21, 2016
    • No Final LDT Guidance, But FDA Provides Insight into What a Future Guidance Might Contain (link) – January 26, 2017
    • LDTs: The Saga Continues (link) – May 14, 2017

    ACI’s 32nd FDA Boot Camp – Boston Edition

    The American Conference Institute’s (“ACI’s”) popular “FDA Boot Camp” – now in its 32nd iteration – is scheduled to take place from September 26-28, 2018, at the Omni Parker House, in Boston, Massachusetts. The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.

    ACI’s FDA Boot Camp will provide you not only with the essential background in FDA regulatory law to help you in your practice, but also key sessions that show you how this regulatory knowledge can be applied to situations you encounter in real life. A distinguished cast of presenters will share their knowledge and provide critical insights on a host of topics, including:

    • The organization, jurisdiction, functions, and operations of FDA
    • The essentials of the approval process for drugs and biologics, including: INDs, NDAs, BLAs, OTC Approval, the PMA process and the Expedited Approval Process
    • Clinical trials for drugs and biologics
    • Unique Considerations in the approval of combination products, companion diagnostics, and stem cell therapies
    • The role of the Hatch-Waxman Amendments in the patenting of drugs and biologics
    • Labeling in the drug and biologics approval process
    • Off-Label use and a New World Order
    • cGMPs, adverse events monitoring, risk management and recalls

    Highlights from this year’s program include an up-to-the-minute “Ripped from the Headlines” section covering recent hot issues such as the FDA Reauthorization Act, states attempts to affect drug pricing, and the potential effects of the mid-term elections on federal legislation and FDA regulations.

    Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst and Axinn, Veltrop & Harkrider LLP’s Suchira Ghosh will present in a session titled “Navigating the Approval Process for Drugs and Biologics.”

    FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. 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.

    The Center for Food Safety Pushes AMS to Finalize BE Labeling Rule; Sues Seeking to Force AMS to Act

    As readers of this blog know, the Agricultural Marketing Service of the USDA (AMS) is mandated to implement the 2016 National Bioengineered Food Disclosure Standard (“NBFDS” or the “Standard”). Congress set a time line for AMS to take certain actions toward implementing the Standard.  AMS, however, has had trouble staying on schedule.  Although the Agency was required to issue the final regulation and standard for disclosure statements on bioengineered (BE) foods by July 2018, in fact it issued the proposed rule barely three months before that deadline.  It is, therefore, no surprise that AMS did not meet its statutory deadline.  And it is questionable whether AMS will be able to complete the rulemaking any time soon.  According to the latest count, it received more than 14,000 comments to the proposed NBFDS rule.

    Meanwhile, the Center for Food Safety (CFS) has consistently acted to keep pressure on AMS, and move the rulemaking along. In September, 2017, CFS sued AMS for failing to release in a timely manner the results of a study on possible technical challenges to obtaining BE information through electronic or digital disclosure methods mandated by NBFDS.  Shortly after CFS filed its complaint, AMS did release the study results.

    On July 3, 2018, CFS again sued the government in connection with the NBFDS. This time it sued the Office of Budget Management’s (OMB’s) for its alleged failure to produce records in response to CFS’s FOIA request.  As described in the complaint, CFS submitted a FOIA request to OMB on May 3, 2018 and as of early July, a mere two months later, had not received the requested documents.

    Now, a week ago, two days after the statutory deadline, CFS (together with the Center for Environmental Health) has again sued AMS. This most recent suit alleges that AMS has unreasonably delayed the BE labeling rulemaking and has failed to meet the mandatory deadline set by Congress, in violation of the Administrative Procedures Act (APA) § 702.  In their complaint, Plaintiffs take the position that AMS’s “failure to implement a national disclosure standard is withholding information from the public, a practice that is inimical to the democratic process. U.S. consumers have already waited decades for mandatory GE labeling, and further delay of the final rule has caused still more harm to the public and the stakeholders.”

    Plaintiffs ask that the Court order AMS “to finalize and issue the regulations implementing the statute as soon as reasonably practicable, according to a Court-ordered timeline.” They further ask that the Court retain jurisdiction to ensure compliance with the ordered time line.

    We will be monitoring further developments.

    It Feels Like the First Time: FDA’s First Competitive Generic Therapy Approval

    Well, we haven’t quite waited the lifetime that Foreigner did, but it’s exciting nonetheless. Only about one year after signing the provisions into law, FDA announced the approval of the first generic drug with a Competitive Generic Therapy (“CGT”) designation: ANDA 211067 for potassium chloride oral solution in 20 and 40 MEQ/15 mL strengths. Created to expedite the development and approval of generic drugs for reference products that lack significant competition, a CGT designation offers applicants benefits, like enhanced communications with FDA officials, expedited ANDA review, and potential eligibility for CGT exclusivity. A reference product that lacks significant competition is one for which there is no more than one approved ANDA for a specific reference product listed in the Orange Book.

    In announcing the approval of Apotex ANDA 211067, FDA Commissioner Gottlieb touted the effectiveness of the Agency’s new Drug Competition Action Plan, explaining that the product was approved in its first cycle of review. Potassium chloride oral solution is intended for the treatment and prevention of hypokalemia (low potassium blood levels) in patients on diuretics when dietary management with potassium-rich foods is insufficient or diuretic dose reduction is not possible.

    We haven’t yet seen the ANDA Approval Letter or any approval materials, and there are several Potassium Chloride products listed in the Orange Book. Only one of the Potassium Chloride products is included on the current List of Off-Patent, Off-Exclusivity Drugs, FDA’s “hit list” for generic manufacturers, published in December 2017 (another Potassium Chloride product was included on the original June 2017 list, but because an ANDA referencing the NDA has been approved since the previous list publication, it was moved to the Appendix). By deductive reasoning, the Reference Listed Drug (“RLD”) for Apotex’s ANDA is Potassium Chloride approved under NDA 206814 in December 2014. Apotex’s version is the second approved generic drug referencing NDA 206814, with another generic drug manufacturer receiving approval of ANDA 210041 without CGT status on July 19, 2018.

    Apotex’s CGT-designated ANDA additionally received CGT exclusivity, which provides a “first approved applicant” for a product with “inadequate generic competition” with 180 days of exclusivity. A “first approved applicant” is defined in the statute as (1) any applicant with an ANDA approved on the first day that any ANDA for a designated CGT is approved; (2) that is not eligible for Paragraph IV 180-day exclusivity; and (3) is not a drug for which all drug versions have forfeited eligibility for 180-day exclusivity. 21 U.S.C. § 355(j)(5)(B)(v)(III)(bb). “Inadequate generic competition” is defined as a drug for which there is no more than one approved ANDA for the corresponding reference product. 21 U.S.C. § 356h(e)(2). Assuming Apotex starts commercially marketing within 75 days of approval, a subsequent generic will not be approved to market for 180 days after launch. However, this exclusivity will not preclude the marketing under ANDA 210041, which received approval prior to the Apotex even though Apotex is technically the “first approved applicant.” This is because “first approved applicant” applies only to CGT-designated applicants.

    Apotex has only 75 days to start commercially marketing to block the approval of other applicants for 180 days, but nothing in the statutory language precludes FDA from approving other applicants prior to Apotex’s commercial launch (and the triggering of CGT 180-day exclusivity). The statute prohibits FDA from approving subsequent applicants only if the first approved applicant has commenced commercial marketing. And applicants approved prior to Apotex’s commercial launch wouldn’t be blocked from marketing during Apotex’s 180- day exclusivity period because the statute blocks only the approval of a subsequent applicant for 180 days after commercial launch – not the marketing. Contrast this with Paragraph IV 180-day exclusivity, which blocks the approval of a subsequent applicant after a first applicant has submitted an application containing a Paragraph IV certification thereby preserving the first applicant’s exclusivity until commercial launch or forfeiture.

    Once Apotex actually starts commercially marketing, the CGT exclusivity will block the approval of all applications for the RLD. This too differs from 180-day exclusivity for Paragraph IV filers, which blocks approval of only ANDAs containing Paragraph IV certifications.

    Apotex has significant incentive to start commercial marketing as soon as possible, but it will be interesting to see how all of these potential scenarios play out if Apotex delays.

    We talked to our friend, Terri Stewart of Abraxeolus Consulting (and former VP of Global Regulatory Policy, Intelligence & Compliance at Teva Pharmaceuticals) about how the CGT program came about. Terri is credited with developing the CGT pathway (and therefore, we’ll say she’s the Mother of the CGT Program). Here’s what Terri had to say:

    In 2015, Congress began paying very close attention to rising prices of several older medicines. After oversight hearings to examine the steep price increases of medicines such as Daraprim, Epipen, Nitropress, and Isuprel, they passed legislation that would impose an additional rebate or consumer price index (CPI) penalty on generic medicines that increase their prices beyond the rate of inflation. However, this did little to solve the underlying problem, due in large part to the fact that these medicines, while on the market for decades, were brand drugs. Generic manufactures had either not targeted or not successfully gotten approval for these medicines, the step the health system relies upon to decrease prices. When the FDARA legislation presented an opportunity to once again address the issue and create a way to insert competition into the market it was the Schrader and Bilirakis offices that sought the advice of the pharmaceutical industry to find a new policy. I worked closely with their staff to develop what is today the Competitive Generic Therapy exclusivity, an incentive not for the filing of an ANDA for one of these older medicines but a benefit that is bestowed upon approval. Since passage of the legislation, I have discussed with many in the industry the impact that this has had on product selection and in may ways the return for these medicines of the promise of generic drugs – to insert competition into the market.  We often take for granted the impact that generics have for patients until we see these instances where they are not present within the life cycle of a medicine. With today’s first approval under the new pathway, I am hopeful that our efforts to solve one of the key drug pricing issues of today will continue to be successful.

    Thanks Terri! We look forward to seeing additional CGT approvals and what new and interesting 180-day exclusivity issues might arise.