Historically, the Food and Drug Administration has called its decisions not to pursue enforcement against or prosecution of legal violations an exercise of “enforcement discretion,” which is a misnomer.  In reality, such decisions are an exercise of “nonenforcement discretion.”  But, whatever it is called, rarely do federal courts rule that FDA must take enforcement actions against violative products.

There have been some exceptions.  See, for example, the decision by Judge Leon of the federal district court in the District of Columbia about FDA’s failure to ban imports of a lethal drug (thiopental) used in prisoner executions, which we blogged about here, and which was affirmed by the D.C. Circuit Court of Appeals.  Beaty v. FDA, 853 F. Supp. 2d 30 (D.D.C. 2012), aff’d, 733 F.3d 1 (D.C. Cir. 2013).  In the same current, but bucking a tidal wave of contrary decisions refusing to order FDA to take enforcement action, comes a recent decision by Judge Grimm in federal court in Maryland, holding that FDA cannot delay or relax enforcement requirements mandated by the Tobacco Control Act, and holding that FDA must require manufacturers of tobacco and other nicotine products (with grandfathered exceptions) to submit applications to market those products before FDA’s announced deadline of 2021 and 2022.  Mem. Op., Am. Acad. of Pediatrics v. FDA, No. PWG-18-883 (D. Md. May 15, 2019) [hereinafter “Grimm Mem. Op.”].

At issue was an FDA August 2017 Guidance that postponed deadlines until at least 2021 or 2022 for manufacturers and distributors of e-cigarettes (and other types of nicotine-containing products) to submit applications for marketing approval, pursuant to the “Deeming Rule” that we blogged about here.  Judge Grimm held that the plain language of the Tobacco Control Act prohibits relevant products “from entering the market without the FDA’s approval,” and that FDA’s “‘wholesale suspension’ of the application filing and approval requirements constitutes a rule amendment or revocation that is subject to review by this Court.”  Grimm Mem. Op. at 32.  Judge Grimm’s opinion went on to hold that “the FDA ‘must’ require filings from manufacturers and approve or deny those filings, that is, it must take actions that are ‘necessary to fulfilling the purposes of the [Tobacco Control] Act.’”  Id. at 33.  FDA’s announcement “in the August 2017 Guidance that certain products that had been deemed to be tobacco products could remain on the market for five years or more without premarket review” was a “‘definitive legal position’ regarding its statutory authority . . . that certain products that had been deemed to be tobacco products could remain on the market for five years or more without premarket review.”  Id. at 40.  He held that FDA’s position “defeats, rather than furthers, the purpose of the Tobacco Control Act by allowing unapproved tobacco products to be manufactured, advertised, and sold for five years or longer.”  Id. at 44.

Judge Grimm noted that “the Supreme Court ‘has recognized on several occasions over many years that an agency’s decision not to prosecute or enforce, whether through civil or criminal process, is a decision generally committed to an agency’s absolute discretion.’”  He cited the decision in Heckler v. Chaney, 470 U.S. 821 (1985), the landmark case on unsuccessful efforts to secure a court order requiring FDA to ban allegedly violative products (Chaney was brought by prison inmates seeking administrative action banning drugs used to administer lethal injections).  But, said, Judge Grimm, Chaney stands only for the proposition that “FDA may decide not to enforce the provisions of the Tobacco Control Act with regard to specific products,” and does not support FDA’s “decision to hold in abeyance” for five or more years “enforcement of mandatory provisions of a statute that Congress viewed as integral to address public health dangers [especially from e-cigarettes and other vaping products] that the agency itself acknowledges are alarming.”  Grimm Mem. Op. at 45-46.  Judge Grimm said that it is not sufficient for FDA to claim it needs “five or more years while it tries to figure out how it will implement the statute, all the while affording those manufacturers responsible for the public harm a holiday from meeting the obligations of the law.”  Id. at 46.  In other words, Judge Grimm said, the assertion of “enforcement discretion” in this case is a “red herring.”  Id. at 45.

FDA had argued to Judge Grimm that the August 2017 Guidance was a policy statement and therefore not a final agency action, so the court had no business considering whether it was legal.  Judge Grimm rejected that argument, holding that “the August 2017 Guidance is not a policy statement; it is tantamount to an amendment to the Tobacco Control Act.”  Id. at 52.  The “August 2017 Guidance implements ‘changes to the statutorily established process,’” he continued, and “[t]hose changes have ‘legal consequences.’”  Id.

This blogpost is not a law review article.  But it bears mentioning that Judge Grimm’s decision brooks a large number of cases in which a court has refused to order FDA to enforce the law.  Years ago, our firm tried to convince a court to order FDA to decide whether to pull generic drug marketing exclusivity from Ranbaxy for its serious data integrity and other manufacturing violations, a request that was denied.  Mylan Pharms. v. FDA, 789 F. Supp. 2d 1 (D.D.C. 2011).  Curiously enough, our firm then represented a different client, allied with FDA, when FDA decided to pull exclusivity on esomeprazole manufactured by Ranbaxy for the same reasons (see here).  Mem. Op., Ranbaxy Labs, Ltd. v. Burwell, No. 14-1923 (BAH) (D.D.C. Mar. 11, 2015).  In addition to Chaney, the following are selected cases that upheld FDA inaction:

• The D.C. Circuit Court of Appeals in Community Nutrition Institute v. Young, 818 F.2d 943, 950 (D.C. Cir. 1987), refused to order FDA to take action against the blending of “contaminated corn with uncontaminated corn,” saying that “FDA enjoys complete discretion not to employ the enforcement provisions of the FDC [Food, Drug, and Cosmetic] Act, and those decisions are not subject to judicial review.”
• The same court ruled in Cutler v. Hayes, 818 F.2d 879, 892 (D.C. Cir. 1987), that it could not order FDA to take enforcement action against “an OTC [over-the-counter] drug that is safe but demonstrably ineffective for its intended use.”
• A court in the Western District of Michigan (Judge Bell) refused a request from Pan American Pharmaceuticals, Inc. that FDA be required to “enforce the pre-approval provisions for new animal drugs against all persons.” Order, Pan Am. Pharms., Inc. v. Kessler, No. 90-1063 (W.D. Mich. Mar. 4, 1991).
• K-V Pharmaceutical Co. tried, and failed, to secure a court order that FDA should pursue pharmacy compounders that were making copies of its approved drug Makena. K-V Pharm. Co. v. FDA, 889 F. Supp. 2d 119, 137 (D.D.C. 2012). (the decision was vacated and remanded, citing Cook v. FDA, 733 F.3d 1 (D.C. Cir. 2013) (the appellate decision on Beaty), and the Drug Quality and Security Act, Pub. L. No. 113-54, 127 Stat. 587 (2013); the case was eventually dismissed with prejudice in July 2014).
• Reversing a district court decision, Natural Resources Defense Council v. FDA, 760 F.3d 151 (2d Cir. 2014), held that a court could not order FDA to renew proceedings to determine whether FDA should withdraw approval of use of penicillin and tetracycline in livestock for subtherapeutic purposes.
• In a case we blogged about here, a court in California held that FDA would not be ordered to require egg producers to label commercial eggs as being from “free range” or “cage free” hens, or from “caged hens.” Compassion over Killing v. FDA, No. 13-cv-01385-VC (N.D. Cal. Dec. 19, 2014).

Judge Grimm has ordered the parties to submit briefs about what remedy he should order, and that process starts within a couple of weeks.

We should also note that our firm has represented clients that manufacture or distribute products that contain tobacco or nicotine.  Our practice is more fully described here.

In a document as interesting for the “why” as the “what,” the Department of Justice, Office of Legal Counsel (“OLC”) recently issued a memorandum legal opinion concerning “Whether the Food and Drug Administration Has Jurisdiction over Articles Intended for Use in Lawful Executions.”

The issuance of an OLC opinion related to the FDC Act, while notable is not, in itself, surprising.  As the DOJ website explains:  OLC “drafts legal opinions of the Attorney General and provides its own written opinions and other advice in response to requests from the Counsel to the President, the various agencies of the Executive Branch, and other components of the Department of Justice.  Such requests typically deal with legal issues of particular complexity and importance or those about which two or more agencies are in disagreement.”

In the past OLC has, for example, offered opinions solicited by FDA’s Chief Counsel, the HHS Acting General Counsel, and joint EPA and FDA requests.  In the present opinion, there is no indication that FDA requested an opinion.  In a footnote, the opinion notes that OLC “solicited and considered the views of FDA and of the Office of the Associate Attorney General.”  What the opinion does not say is why OLC is opining on FDA’s jurisdiction.  The Agency regularly makes jurisdictional determinations and DOJ represents FDA in court when those determinations are challenged.  The opinion notes a current injunction and an FDA position articulated in 2017, but if FDA had re-evaluated the FDC Act, as the opinion notes, the Agency could have simply explained why it did so.  Under Supreme Court precedent, FDA’s interpretation of ambiguous jurisdictional statutory authority is entitled to deference.   Instead, OLC issued an opinion.

OLC concluded that articles intended for use in executions carried out by a state or the federal government cannot be regulated as “drugs” or “devices” under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and that FDA therefore lacks jurisdiction to regulate articles intended for that use.  The OLC opinion may allow states to begin importing a drug used in lethal injection protocols that is no longer available in the US, contrary to a permanent injunction that has banned its import.

In concluding that FDA cannot regulate articles intended for use in lawful executions, the OLC cites to FDA v. Brown & Williamson Tobacco Corp.  In Brown & Williamson (here), the Supreme Court held that Congress had not given the FDA the authority to regulate tobacco products, because if tobacco products were subject to FDA regulation, the FDCA would require their prohibition because they are not safe or effective or any intended use.  FDA v. Brown & Williamson Tobacco Corp, 529 U.S. 120, 137–39 (2000).  The OLC is extending the same reasoning to the FDA regulation of articles intended for use in lawful executions.  OLC’s opinion is not limited to drugs used in lethal injection, a common method of capital punishment, but is broad and covers articles intended for use in lawful executions generally (e.g., electric chairs, gas chambers, gallows, firearms used by firing squads).

The OLC opinion begins with a summary of the regulatory structure of the FDCA and the history of its intersection with capital punishment.  OLC explains that an article may be a “drug” or “device” for some uses but not for others, depending on whether the product is intended to be used to treat disease or other conditions, or to otherwise affect the structure or function of the body.  For example, FDA regulates “medical gases,” but not industrial gases that are chemically identical because the latter do not have a medical purpose.  OLC also explains that FDA does not regulate the “off-label” prescribing of a drug or device for a use not approved by FDA, as off-label prescribing is considered the practice of medicine, which is beyond FDA’s regulatory purview.  According to OLC, state use of FDA-approved drugs in lethal injection essentially amounts to off-label use.

In recent years, many states have had difficulty accessing drugs used in lethal injection protocols from US suppliers.  Many pharmaceutical companies that manufacture drugs used in lethal injection protocols, as well as wholesalers that distribute said products, have publicly objected to their drugs being used in capital punishment and will not sell them to states for that purpose.  In 2009, the only US manufacturer of sodium thiopental, a barbiturate commonly used in multi-drug lethal injection protocols, ceased production of the drug entirely.  When states were no longer able to access sodium thiopental domestically, they then began to import it from international suppliers.  A group of death row inmates challenged the state import of sodium thiopental for lethal injection and the court issued a permanent injunction requiring FDA to block the importation of sodium thiopental on the grounds that it was unapproved and misbranded.  Beaty v. FDA, 853 F. Supp. 2d 30 (D.D.C. 2012) (here; see our previous post here).

After setting forth a history of the FDCA and capital punishment, OLC turns to the aforementioned Brown & Williamson, which established that FDA lacks jurisdiction to regulate articles intended for a use not traditionally regulated by FDA, when those articles cannot be safe and effective for such intended use, and Congress has otherwise made clear its expectation that at least some of those articles shall remain lawful and available for that use.  OLC then extends the same analysis to articles used in capital punishment and comes to three main conclusions:

1. If FDCA applied to electric chairs, gallows, gas chambers, firearms used in firing squads, and substances used in lethal-injection protocols, the statute would effectively ban those articles
2. The Constitution and laws of the United States allow for the continued availability of capital punishment
3. FDA did not expressly assert the authority to regulate articles intended for use in executions at any time before 2017 and that such an assertion cannot be reconciled with the FDCA and other federal law.

In several spots, the OLC opinion notes the limits of its analysis.  For example, it notably declines to discuss whether this analysis of FDA jurisdiction extends to drugs used in physician assisted suicide, stating that “In marked contrast with capital punishment and tobacco products, at the time of the FDCA’s enactment, there was not—so far as we are aware—any history of federal or state laws authorizing human euthanasia.”  OLC Opinion at 25.

Despite these disclaimers, substantively, the OLC opinion provides potential fodder for future jurisdictional fights with FDA. Procedurally, it is a reminder of an additional agency with the executive branch that can opine on FDC Act questions.  As for the “why”, the opinion never explains who requested it.  The Attorney General, White House Counsel?  Was it the result of a dispute between FDA and another agency?  The opinion raises other questions.  Will DOJ and FDA use the opinion in the Beaty litigation?  If so, will the court give it Chevron deference?  We’ll be watching and posting about further developments.

On May 6, 2019, the United States District Court for the District of Columbia issued a Memorandum and Opinion concerning the remedy available to Plaintiffs following the same court’s earlier decision (see our previous post regarding the court’s earlier decision here) invalidating a final rule issued by the Centers for Medicare and Medicaid Services (CMS) that would have altered the methodology for Medicare hospital outpatient payment rates for 340B drugs. In accordance with D.C. Circuit precedent, the court remanded the matter to CMS to remedy the unlawful change to the 340B drug payment methodology under the final rule. See Am. Hosp. Ass’n v. Azar, No. 18-2084, 2, 22 (D.D.C. May 6, 2019).

As background, under the Social Security Act, CMS must set reimbursement rates for certain separately payable hospital outpatient drugs, including 340B drugs, under the Medicare Part B hospital outpatient prospective payment system (OPPS). Since 2005, CMS has set those rates based on average sales price (ASP) plus 6%. However, in 2017, CMS proposed to revise the reimbursement formula for 340B drugs effective January 1, 2018. Concluding that hospital Covered Entities profited too much from reimbursement for 340B discounted drugs, CMS reduced the payment amount for hospital outpatient separately payable 340B drugs to ASP minus 22.5%. The American Hospital Association (AHA) and various other hospital associations and non-profit hospitals submitted comments opposing this change to the calculation methodology, arguing that CMS was not authorized to make the change. Despite these comments, CMS asserted that it had the statutory authority to set the rate based on the average price for the drug “as calculated and adjusted by the Secretary” and finalized the rule.  The AHA, along with other hospital associations and non-profit hospitals, filed a lawsuit against CMS seeking to enjoin the final rule from further effect and to remedy the use of the unlawful payment methodology in determining 340B drug payments.

In its December 2018 ruling, the court granted Plaintiffs’ motion for a permanent injunction, holding that CMS had “fundamentally altered the statutory scheme,” thereby exceeding its authority to “adjust[]” the reimbursement rate. However, the court did not rule on the appropriate remedy for CMS applying the 2018 revised payment methodology rule. Among other relief, Plaintiffs sought a retroactive increase in payment rates for 340B drugs to ASP plus 6% for 2018. However, because of a statutory requirement that all OPPS payment rates be budget neutral, increasing hospital reimbursement rates for 340B drugs retroactively for 2018 would also require retroactive offsets in payments for other items and services paid under the Medicare program. Therefore, the court decided to postpone a decision on an appropriate remedy, ordering the parties to provide supplemental briefing on this issue.  In the meantime, CMS issued a rule to continue the ASP minus 22.5% payment rate reduction through 2019. 83 Fed. Reg. 58818, 58822 (Nov. 21, 2018). Plaintiffs supplemented their Complaint to petition the court to vacate both the 2018 and 2019 rules, order CMS to reimburse Plaintiffs for the difference in payments between the 2017 (i.e., ASP + 6%) and 2018/2019 (i.e., ASP – 22.5%) rates, and order CMS to use the ASP + 6% methodology for claims not yet paid. CMS, however, sought to have the 2018 and 2019 OPPS rules remanded to CMS without vacating them or imposing specific duties on CMS.

The court, in the May 2019 ruling, concluded that “[r]emand, rather than injunction is the better course of action here.” The court cited to numerous precedential cases in the D.C. Circuit where, upon setting aside unlawful agency action, the agencies were given the initial task to fashion an appropriate remedy. In fact, the D.C. Circuit has held that a district court order to an agency to take specific action in such circumstances is reversible error. The court also noted that Plaintiffs have the option to seek judicial review of an agency’s remedy if they are not satisfied with it.

In deciding whether to remand or vacate the 2018 and 2019 OPPS rules, the court applied the Allied-Signal standard in which the court must weigh the seriousness of the agency’s deficiencies against the disruptive consequences of vacating the agency’s action. Id. at 16 (citing Allied-Signal, Inc. v. U.S. Nuclear Regulatory Comm’n, 988 F.2d 146, 150-51 (D.C. Cir. 1993). On the one hand, the court found that CMS’s “deficiencies here were substantial” and that CMS “patently violated the Medicare Act’s text.” But, on the other hand, vacating the 2018 and 2019 OPPS rules would be “highly disruptive,” given the budget neutrality requirement. Vacating the 2018 and 2019 OPPS rules would likely require CMS to retroactively recoup payments made to providers for non-drug items and services whose rates were increased because of the reduction in reimbursement rates for drugs; CMS estimated that to recoup such payments would take a year and result in administrative costs between $25 and $30 million. Furthermore, retroactive recoupment would also negatively affect Medicare beneficiaries because of the impact on amounts they paid under their cost-sharing obligations during that period. In addition, the court noted that the Plaintiffs themselves conceded that there were multiple ways CMS could remediate the underpayments for drugs under the violative 2018 and 2019 OPPS rules. Finally, the court determined that “no amount of reasoning on remand will allow [CMS] to re-implement the 340B rates in the same manner” as the unlawful 2018 and 2019 OPPS rules. For these reasons, the Court granted, in part, the Plaintiffs’ motion for permanent injunction and ordered the parties to submit, by August 5, 2019, a status report on the progress to remedy the unlawful payment methodology implemented by CMS in 2018 and 2019.

We will continue to track developments in this case.

FDA recently finalized its guidance document intended to assist protein biosimilar manufacturers in demonstrating interchangeability, Considerations in Demonstrating Interchangeability With a Reference Product.  Interchangeability, as of now, is nothing more than a pipe dream; no biosimilar has been declared interchangeable and therefore fully substitutable for its reference product.  But FDA is hoping that this guidance will help address that.  This guidance finalizes FDA’s expectations and updates the draft version of the guidance to provide more clarity.  Of note, this guidance document is directed specifically toward proposed therapeutic protein products, which include those products scheduled to transition from drug products to biologic products on March 20, 2020 under the “deemed to be a license”  provision of the Biologics Price Competition and Innovation Act.

The draft version of this guidance was published in January 2017 and triggered over 50 separate (mostly substantive) comments from a variety of stakeholders arguing the merits of each recommendation made in the guidance.  Some, for instance, suggested that interchangeability should be established individually for all conditions of use while others contend that extrapolation across intended uses is sufficient; similarly, some argued that immunogenicity in product switches must be robustly assessed while others contend that immunogenicity is a “hypothetical concern”.  Comments also provided line-by-line analyses of the text, often requesting clarity, as well as concerns about the specific testing parameters set forth in the guidance.

In the almost 2.5 years since the publication of the draft, FDA has made some changes but not many significant ones.  Indeed, even though the 2019 version clocks in at 7 pages less than the draft, the final version is largely the same as the draft.  Though much of the language has been revised, the two versions differ mainly in detail and clarity.  For example, while the concepts remain, terminology like “fingerprint-like” demonstrations of biosimilarity and “residual uncertainty” has been scrapped.  More substantively, the final guidance omits discussion of the specific analyses FDA expects for product presentation, design, and administrative characteristics.  For that reason, the Appendices also differ between the draft and the final, with the draft’s appendix detailing considerations in Comparative Use Human Factors Studies replaced by an example of switching study design in the final.

The meat of the guidance document remains largely unchanged.  As in the draft, the final provides an overview of the important scientific considerations in demonstrating interchangeability with a reference product.  A product is interchangeable if it is biosimilar to the reference product and can be expected to produce the same clinical result as the reference produce in any given patient.  To demonstrate interchangeability, the risks involved in switching from the reference to the biosimilar may not be any greater than the risk of solely using the reference product when a biological product is intended to be administered more than once to an individual.  To meet this standard, the guidance discusses the:

• Data and information needed to support a demonstration of interchangeability;
• Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability;
• Considerations regarding the comparator product in a switching study or studies; and
• Abbreviated considerations for developing presentations, container closure systems, and delivery device constituent parts for proposed interchangeable products.

FDA also provides a list of factors that may be required for demonstrating interchangeability but emphasizes that the data necessary may vary based on the nature of the proposed interchangeable product, as not all factors may be necessary.  The product’s degree of structural and functional complexity may influence the data required.  Clinical experience with the reference product may also affect the data and information needed to support a demonstration of interchangeability.  In such cases, FDA will require a scientific rationale for extrapolation of data and other information to support interchangeability.

FDA applies a presumption that switching studies are required for demonstrations of interchangeability.  Again, when a sponsor believes that switching studies are not necessary, the sponsor must provide a justification for not needing such data to demonstrate interchangeability.  Switching studies should be designed based on clinical practice and risk-based treatment scenarios, and FDA therefore has outlined a flexible approach regarding study design.  Primary endpoints should assess the impact of switching on PK and PD (if available), as well as descriptively assess immunogenicity and safety.  Assessments of efficacy endpoints can be used as supportive information, as may postmarking data of a product previously licensed as biosimilar (rather than interchangeable).  The guidance provides significant detail on suggested study design and analysis.  The final guidance also reiterates the need for “bridging” studies should the study use a comparator that is a non-U.S. version of the reference product.

Though the initial publication of this guidance was welcomed by industry, its impact remains unclear.  In the years since the publication of the draft, FDA still has not determined that a single drug is interchangeable to its reference product.  There is no telling when FDA will license its first interchangeable product, and it is clear that reference product sponsors will not make acceptance of biosimilars – interchangeable or not – an easy feat.  But if this now-final guidance has its intended effect, reference product sponsors will not be able to cast doubt on the sameness of biosimilars anymore.  Interchangeability should make the notion that “anything a biosimilar can do, the reference product can do better” a thing of the past, but this is all conjecture until a sponsor can actually demonstrate interchangeability.

On April 26, 2019, CDRH released the final guidance, Recommended Content and Format of Non-Clinical Bench Performance Testing Information in Premarket Submissions (“Final Guidance”).  We previously blogged on the draft version (“Draft Guidance”) here.  Overall, the Final Guidance is much the same as the Draft Guidance, though FDA has added more detailed descriptions of the recommended information.

Like the Draft Guidance, the Final Guidance provides recommendations for Test Report Summaries and Complete Test Reports to be submitted in premarket submissions, including “premarket approval (PMA) applications, humanitarian device exemption (HDE) applications, premarket notification (510(k)) submissions, investigational device exemption (IDE) applications, and De Novo requests.” Final Guidance at 3.  Test report summaries should include the following elements:  tests performed; objective(s) of the test(s); a brief description of the test methods, including sample size, device(s), and any consensus standard(s) utilized; pre-defined pass/fail criteria (when applicable); results summary; discussion/conclusions; location of complete test report and summary table (optional).  Complete test reports should include:  test performed; objective of the test; description of test methods (test sample information, test sample size/selection, test methods); pass/fail criteria; data analysis plan; test results (data, data analysis, protocol deviations); and discussions/conclusions.

There are a few notable differences, first of which is the title.  The Draft Guidance included “Complete Test Reports” in the title whereas the Final Guidance’s title covers “Information” more broadly than just complete test reports.  That being said, the overall guidance does not broaden in scope and the name change appears a more appropriate description as the guidance covers both complete test reports and summary information included within a premarket submission.

The Final Guidance also adds clarity to several points, including:

• The recommendations are applicable for non-clinical testing performed by either a device manufacturer or a third-party testing facility.
• Bench tests using ex vivo, in vitro, and in situ animal or human tissue are within the scope of a non-clinical bench performance test. A new footnote is also added where FDA states their support of reducing, refining, and replacing animal testing when feasible and alternate methods are “suitable, adequate, validated, and feasible.” at 3.
• For testing excluded from the scope of the guidance, reprocessing validation, human factors validation, software verification and validation, and computational modeling studies are added in addition to biocompatibility evaluation and sterilization validation.
• Test report summaries should be provided either within an executive summary section of the premarket submission or provided as a separate document within the premarket submission. An example summary table has been added including columns for test performed, device description/sample size, test method/applicable standards, acceptance criteria, unexpected results/significant deviations, and results.  Complete test reports, when submitted, should be provided as separate attachments.
• A complete test report means the “entirety of the testing documentation submitted for a study” which may be included in a single document or within multiple documents in the premarket submission. at 8.
• There are situations where pre-defined pass/fail criteria may not be applicable, such as tests conducted for characterization purposes. In these situations, a description of the acceptance criteria used to allow for interpretation of the data should still be provided.
• A data analysis plan used to analyze results, including all planned quantitative and/or qualitative assessments, is recommended in the test report.
• When recommended information comes from an FDA guidance document or FDA-recognized consensus standard, the full information can be replaced with the full reference to the cited document. If there are options or choices within the referenced document, the options selected or choices made should be included.

The Final Guidance no longer recommends including information in test reports justifying why the test methods or results support substantial equivalence.  As we noted in the prior blog, the test report is not the place for this information as the connection between an engineering test and a planned 510(k) submission may not be known by an engineer performing testing and writing a test report.  This information is certainly important within a 510(k) and the Final Guidance now more broadly states “[y]our premarket submission should also discuss how the non-clinical bench performance test results support the overall submission” and that the “information can be provided in the test report summary or another location in your premarket submission.” Id. at 5.

The Quality System Regulation (QSR), in 21 C.F.R. § 820.30 Design Controls, includes requirements for design verification and validation, yet these requirements are not mentioned anywhere within the guidance.  While the Final Guidance may appear on its surface to provide a comprehensive list of information to include within “complete test reports,” it fails to identify some information required for verification and validation results by the QSR (e.g., the date, and the individual(s) performing the tests).  Also, as we noted in the prior blog, the Final Guidance still recommends that test reports state whether the test sample is a final, finished device though this may not be known at the time many test reports are written during product development.  With the recently announced CDRH reorganization and creation of a new Super Office, Office of Product Evaluation and Quality (OPEQ), we hope to see better alignment in the future between what is expected in a premarket submission and what is already required of device manufacturers in the QSR.

The Final Guidance may be helpful to companies in writing or revising their design controls procedures as it does provide useful descriptions of information to include within test reports.  However, it is important to ensure the procedures cover QSR requirements as well as the recommendations of the guidance to ensure the resulting test reports are considered complete for both a premarket submission and in an FDA inspection.

On May 8, 2019, the FDA published a new draft guidance for industry titled “Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics.”

This draft guidance was produced as a joint effort from CDER and CBER and is intended to provide guidance about how to use Real World Data (RWD) and Real World Evidence (RWE) in regulatory submissions to the agency.

The use of RWD and RWE is an area of great interest yet has little regulatory precedent. The Agency was mandated by section 3022 of the 21^st Century Cures Act to, among other things, provide guidance to industry on how RWE might be used to support drug development and new drug and biologic approvals (see previous coverage of the 21^st Century Cures Act and this provision here). Section 3022 required the Agency to track submissions to INDs, NDAs, and BLAs that use RWE to support regulatory decisions related to safety and efficacy.

The draft guidance clearly defines the terms RWD and RWE which is helpful. One of the most significant parts of the draft guidance is that it clearly states that RWE may be used in single arm studies that use RWE as an external control. This is a paradigm shift for the Agency and opens doors to many potential, as of yet unexplored and untested, approaches to drug development.  On the topic of external controls, FDA similarly discussed the use of natural history data as historical controls in a recent draft guidance, which the Agency does not view as RWE (see coverage here).  Beyond use as an external control, the draft guidance also notes that RWE may be captured through (1) conduct of randomized clinical trials, (2) observational studies to support an efficacy supplement, and (3) studies to fulfill postmarketing requirements to further evaluate safety and effectiveness.

The draft guidance does not provide much detail on how RWE might be used and barely mentions any caveats.  Therefore, this draft guidance should be viewed in combination with FDA’s December 2018 “Framework for FDA’s Real-World Evidence Program” (available here), where the Agency began to articulate how it will assess fitness of RWD for use in regulatory decisions.  Existing precedent has been limited to using data on historical response rates drawn from chart reviews and expanded access, primarily in cancer and rare diseases; however, FDA seems to instead be promoting the generation of RWE through randomized trial designs that take place in “pragmatic clinical trial” settings that more resemble real-world care and use. This seems to be the most promising “type” of RWE to support evidence of safety or effectiveness for a new product approval, which the draft guidance notes is a potential use for this evidence.

It is well known that there is an enormous amount of RWD in existence but there are also many challenges to figuring out how to use that data. There are issues related to getting informed consent from the people who are the source of the data, issues of statistical analysis and the introduction of bias, issues of data quality, lack of comparability between the RWE control arm and the study population, and generally the potential for making flawed conclusions.  In the words of FDA’s past Principal Deputy Commissioner:

Thus, although we are optimistic about long-term prospects for the evolution of mature, robust methodologic approaches to the incorporation of real-world evidence into therapeutic development and evaluation given the intensive efforts now under way, caution is still needed, and expectations of “quick wins” resulting from the use of such evidence should be tempered accordingly.

Sherman, et al. Real-World Evidence – What Is It and What Can It Tell Us? 375 NEJM 23, at 2295 (December 8, 2016)

Much of this will have to be figured out by trial and error and lots of conversation. This area of development holds a lot of promise but will require a lot of scientific thought and evaluation to find a path forward.

Colorado and Florida have joined Vermont in the list of states seeking to combat high prescription drug prices by establishing programs to import drugs from Canada.  On April 29, 2019, the Florida legislature passed CS/HB 19, which directs the state’s Agency for Health Care Administration to establish the Canadian Prescription Drug Importation Program.  On May 6, 2019, the Colorado legislature passed SB19-005 to create the “Colorado Wholesale Importation of Prescription Drugs Act.”  Neither bill has been signed into law yet, but the Governors’ signatures are expected.

Similar to the Vermont law passed last year (see our summary here), the Colorado and Florida bills require the states to develop Canadian drug importation programs that comply with federal drug importation laws (21 U.S.C. § 384), including limitations on eligible drugs.  Each state’s program must meet the federal requirements that the imported drugs will not pose additional risk to public health and will generate cost savings for consumers.  By July 1, 2020, Florida’s Agency for Health Care Administration must submit a request to the U.S. Secretary of Health and Human Services (HHS) for approval of the state’s program.  The Colorado Department of Health Care Policy and Financing must submit its request for program approval to the Secretary of HHS by September 1, 2020.

Florida’s bill also allows for the development of an “International Prescription Drug Importation Program,” which will permit the state to import drugs from “foreign nations with which the United States has current mutual recognition agreements, cooperation agreements, memoranda of understanding, or other federal mechanisms recognizing their adherence to current good manufacturing practices for pharmaceutical products.”  FDA currently has a “Mutual Recognition Agreement” in place with the European Union and Cooperation Arrangements for drug products in place with Australia, Canada, Japan, Russia and Sweden.

Under the Florida bill, drugs imported under the Canadian Prescription Drug Importation Program will be limited to use for Medicaid and certain institutions owned, operated, or supported by the state or county governments.  However, Florida’s International Prescription Drug Importation Program will not be restricted to state and county purchasers, nor will the Colorado program have such limitations on use.

Federal law requires that drug importation programs generate substantial cost savings for American consumers.  Donald Trump recently said that his administration will allow states to import drugs if they can be purchased at a lesser price.  However, it is unclear whether a lesser purchase price will equate to substantial cost savings for American consumers.  Despite public opinion that drugs can be purchased at significantly lower costs from Canada and other countries, proving that importation results in cost savings may be a difficult hurdle for states to overcome.  As we previously reported (see here), Vermont’s Agency of Human Services, in designing that state’s “Canadian Rx Drug Import Supply Program,” issued a report suggesting that it may cost more to implement and operate a drug importation program than the amount of savings the state would recognize from such a program.  Vermont’s formal request for approval of the state’s drug importation program is due to the Secretary of HHS by July 1, 2019.

Although state drug importation programs seem to have gathered some steam, it still remains to be seen whether these programs can be designed to meet the federal requirements and whether the Secretary of HHS will approve such programs.  We will continue to monitor and report on federal and state developments and actions related to regulating drug pricing.

The Centers for Medicare & Medicaid Services (CMS) has finalized its proposed rule requiring pharmaceutical manufacturers to disclose the Wholesale Acquisition Cost (WAC) in Direct-to-Consumer (DTC) television advertisements for certain prescription drugs and biological products (the Final Rule). The Final Rule will appear in the Federal Register on May 10, 2019 and will become effective on July 9, 2019.  It is largely unchanged from the proposed rule, which we previously blogged on here.

The Final Rule requires that any advertisement on TV (including broadcast, cable, streaming, or satellite) for a prescription drug or biological product for which reimbursement is available under Medicare or Medicaid must include the following statement:

“The list price for a [30-day supply of] [typical course of treatment with] [name of prescription drug or biological product] is [insert price]. If you have health insurance that covers drugs, your cost may be different.”

The “list price” to be inserted is the WAC, which is defined as the manufacturer’s published list price for the most recent month available, not including discounts or rebates. The list price should reflect the WAC for a typical 30-day regimen or typical course of treatment, as appropriate, and as determined on the first day of the quarter during which the advertisement is being aired on television or otherwise broadcast. For a drug with multiple indications, the list price to be used is the one for the course of treatment associated with the indication advertised. The statement must appear at the end of the advertisement in legible text with a style, font, and duration that allows it to be read easily. The preamble to both the Proposed Rule and the Final Rule (though not the regulation itself) states that manufacturers would also be permitted to include truthful and non-misleading information about a competing product’s current WAC, so long as the provision of such information is consistent with current law.

The Final Rule applies to prescription drugs for which payment is available, directly or indirectly, under Medicare or Medicaid, with the exception of products with a WAC of less than $35 per month for a 30-day supply or typical course of treatment. The only penalty for a failure to provide the statement would be inclusion of the manufacturer on a publicly available “shame” list on CMS’s web site. However, CMS states in the preamble to the Final Rule that it believes the primary enforcement mechanism will be the threat of private actions under the Lanham Act for false or misleading advertising, asserting optimistically that the threat of meritless lawsuits is “acceptably low.”

According to CMS, the Final Rule seeks to address the rising prices of prescription medicines and the impact that such costs have on the Medicaid and Medicare programs. It also seeks to address over-utilization of prescription drugs caused by patients requesting “costly drugs and biological products seen on television.” Finally, CMS asserts, in the Final Rule, that DTC advertising lacking information about a drug’s price is potentially misleading. CMS states that if patients better understand the costs associated with prescription drugs or biological products, they will make “good health care choices,” which will in turn promote efficiency in the Medicaid and Medicare programs. CMS rejected arguments that the WAC itself is misleading because it does not reflect actual out-of-pocket costs paid by consumers.  CMS cited a 2019 study published in the Journal of the American Medical Association as support for the proposition that consumers are better able to estimate their out-of-pocket costs knowing the WAC than without knowing it.

We will continue to report on drug pricing regulations and legislation at the federal and state level.

Responding to objections from New Jersey healthcare practitioners, hospitality and restaurant businesses, and the pharmaceutical industry, the New Jersey Attorney General published an amendment to the state’s rules restricting the acceptance of remuneration by prescribers from pharmaceutical manufacturers.  The final amendment, which appeared in the May 6 New Jersey Register and immediately became effective, relaxes some of the restrictions in the original rule (see our post on that rule here.)  Following are the significant changes from the original rule:

• Meals at Education Events: The original regulation permitted prescribers to accept “modest meals” provided through the event organizer at an education event, and a “modest meal” was defined as one with a fair market value of $15 or less.  The $15 limit has been removed.  In addition, the amendment clarifies that an education event includes an event that focuses on disease states and treatment approaches, and also includes an event that that meets the rule’s definition of “education event” even if FDA classifies that event as promotional.
• Promotional Programs: The prior rule on accepting modest meals provided by drug manufacturers during promotional activities remains in place and is still capped at $15 for lunch, but the cap on dinners has been increased from $15 to $30 (adjusted for inflation after 2018).  Also, the previous limit of four such meals per year has been removed.
• Bona Fide Service Fees: The Attorney General rejected recommendations that the existing cap on bona fide service fees accepted from all pharmaceutical manufacturers during any year be increased from the current $10,000.  Fees for research and for speaking at education events continue to be exempt from this cap, and the preamble clarifies that research includes both pre-market and post-market research.
• No application to devices: The regulation continues to apply only to gifts and payments from pharmaceutical manufacturers, but a helpful clarification has been added that the rules do not apply to prescribers’ interactions with pharmaceutical manufacturers that also manufacture medical devices if the interactions are directly solely to medical devices.

As FDA continues to approve biosimilar drug products, and as sponsors participate – or rather choose not to participate – in the Biologics Price Competition and Innovation Act (“BPCIA”) version of the patent dance, more questions arise about the remedies reference product sponsors have when certain steps are not followed.  As we have detailed extensively (here, here, here, and really any post tagged under the “biosimilars” category of the FDA Law Blog), new questions about the BPCIA patent dance continue to pop-up and make for interesting new lawsuits.  Such is the case with FDA’s April 25, 2019 approval of Samsun Bioepis’s Eticovo, a biosimilar to Amgen’s Enbrel, which has resulted in another lawsuit, this time asking the Court to enjoin marketing of Eticovo until it provides the 180-day notice required under the BPCIA.

In a Complaint filed on April 30, 2019, Amgen alleges that Samsung Bioepis infringed the multiple unexpired patents covering Enbrel.  Originally licensed in 1998, Enbrel is now approved for multiple indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.  Samsung Bioepis’s Eticovo is approved for the same indications and route of administration, and it shares the same dosage form and strength as an approved version of Enbrel.  The suit alleges that Samsung Bioepis infringed five patents covering Enbrel and asks for a declaratory judgment that Samsung Bioepis has infringed and/or would infringe one or more claims of each of the patents at issue, as well as injunctive relief preventing Samsung Bioepis from commercial marketing consistent with the 180-day notice period under the BPCIA.

Samsung Bioepis declined to participate in the patent dance, as it is entitled to do under the Supreme Court’s 2017 decision in Amgen v. Sandoz, so Amgen brought this declaratory judgment action to enforce its patent rights under section 351(l)(9)(C) of the Public Health Service Act (42 U.S.C. § 262(l)(9)(C)).  But because Samsung Bioepis did not participate in the exchange of patent information, Amgen posits that it is “reasonable to infer that Bioepis might not provide notice to [Amgen subsidiary] Immunex in accordance with § 262(l)(8)(A).”  Indeed, Amgen alleges that “Bioepis is prepared imminently to begin to use, offer, for sale, and sell in the United States, and import into the United States, its etanercept biosimilar product.”  As such, Amgen seeks a temporary restraining order and injunction to prohibit Samsung Bioepis from commercial launch of Eticovo until 180 days after it provides notice of intent to market to Amgen’s subsidiary and Enbrel BLA holder (and co-Plaintiff) Immunex.

While the Supreme Court has determined that the patent dance and provision of the 351(k) biosimilar application is not mandatory, the Court further determined in Amgen v. Sandoz that the notice provision is.  But the Act doesn’t contemplate failure to provide this notice, and it is not clear what remedies are available at this juncture.  It’s not clear that a Court would grant injunctive relief here when there is no assurances that Samsung Bioepis is actually intending to launch in the near future (and without notice).

Patent remedies based on the submission of Samsung Bioepis’s aBLA are most likely available.  Certainly, in this situation, an aBLA sponsor would be launching at risk and potentially be liable for treble damages but like with premature at-risk launch of generic small molecule drugs, the bell can’t be unrung once the product floods the market.  That biosimilars are not automatically substitutable for their RLDs makes such an act less of a threat to Amgen’s market share.  But chances are high that an influx of Eticovo would still undercut Amgen’s Enbrel market, at least to some extent.  If there is no further recourse for Amgen other than the treble damages award arising from patent infringement, it raises questions of whether an at risk launch of a biosimilar will result in significantly smaller damages awards for reference product sponsors.  Is it possible that the treble damages award could be less than attorneys’ fees (we note that Amgen here is seeking attorneys’ fees)?  And if so, is treble damages enough to deter at risk launch when each biosimilar needs to find a way to get individual attention?  In other words, could the publicity of an at risk launch be worth the treble damages in news coverage and publicity?  Probably not but given all of the moving parts in the BPCIA and the uncharted market, it seems fair to say that “business decisions,” as opposed to legal decisions, may end up the driving force as this market develops.

As you may have noticed, FDA recently unveiled a new website.  As part of this redesign, FDA “enhanced” the Product-Specific Guidances (“PSG”) for Generic Drug Development web page.  The “enhanced” version of the website includes new database and search function features, export features, and paginated search results.  The new search functions will allow users to perform text searches of PSGs by active ingredient, by Reference Listed Drug application number, or Reference Standard application number and will allow further filtration of search results.  Of course, the guidances are still available to browse alphabetically rather than search (and there are 1685 of them for your reading pleasure).

As exciting as the new website is, FDA really buried the lead when it announced the new website.  In response to common complaints from industry, FDA has adopted a new resource for PSGs, a dynamic web page entitled “Upcoming Product-Specific Guidances for Complex Generic Drug Product Development.”  This web page contains a list of PSGs for complex generic products that are currently under development or for a which a revision is planned in the next year.  The list reflects FDA’s efforts to be transparent regarding plans for development and revision of PSGs so that sponsors can be aware of what is in the pipeline and discuss with FDA the appropriate testing as necessary.

Generic manufacturers have found that FDA’s bioequivalence recommendations for a given product may have changed during development of a generic.  Sometimes, these recommendations change after a product has been submitted but before FDA has completed its review, requiring sponsors to perform additional studies after submission.  In fact, this situation has occurred enough that Congress carved out an exception from the 180-day exclusivity tentative approval forfeiture provisions for it.  As Brian McCormick, Vice President & Chief Regulatory Counsel Teva Pharmaceuticals USA, Inc. explained during the Incentivizing Generic Competition Panel at FDLI’s Annual Conference last week, such changes to bioequivalence requirements “midstream” can throw off the years of planning that goes into large ANDA development programs and may have ripple effects in the development of other ANDA products in the pipeline.  To paraphrase Wag the Dog (and Abraham Lincoln): You don’t change horses in midstream.

While obviously no one advocates for the approval of a generic product with a less than robust demonstration of bioequivalence, transparency in the publication and the revision of these guidances would go a long way to alleviate some industry complaints.  To that end, FDA’s list of planned PSG revisions announces the PSGs in development, as well as those under revision in the next year, so that sponsors can plan accordingly.  According to Dr. Robert Lionberger, Director of FDA’s Office of Research and Standards, the intent of this list is to provide the notice and transparency that industry seeks to alleviate surprises that may arise after an application is submitted.  FDA is aware of the issue and is therefore attempting to be more open with sponsors about changes in the pipeline.

The PSG list information includes the active ingredient(s), route of administration and dosage form, and RLD application number.  Additionally, the PSGs undergoing revision are also assigned a “planned revision category.”  The revision categories are “Major Revisions,” “Minor Revisions,” and “Editorial Revisions.”  “Major Revisions” are defined as the revision of PSGs to include additional bioequivalence studies or evidence recommended to support FDA approval.  “Minor Revisions” are any revisions not considered major, including the removal of certain studies, providing alternative and less burdensome approaches to currently recommended studies, to add information on newly approved strengths of the RLD, or to make other recommendations that would not result in the requirement of a new bioequivalence study.  “Editorial Revisions” are non-substantive changes, updates of external references, corrections of grammatical issues, and changes to formatting.

This new system isn’t perfect.  Some companies rely on these PSGs years in advance of submitting an ANDA, so notice of new bioequivalence requirements only a year in advance might not be a panacea.  Further, the list only covers “complex” generics, and if there are any changes to PSGs for more basic generics, sponsors may not have the same transparency.  But there is little doubt that the Agency’s efforts to remediate at least some of the generic industry’s complaints in this area provides at least a bit of relief to sponsors.  We’ll have to see how well FDA keeps this list updated and how helpful this list actually is given how early some companies start development of new generics.  But if nothing else, FDA’s continued work to make the generic development process easier and more accessible demonstrates that the agency’s commitment to generic competition has not waned in the post-Commissioner Gottlieb era.

Hi-Tech Pharmaceuticals, Inc. (Hi-Tech) and its President and Chief Operating Officer filed suit in the U.S. District Court for the District of Columbia to enjoin FDA from continuing to seek removal of DMHA products from commerce through the issuance of warning letters and “pressure… to remove and destroy DMHA containing products.”  Plaintiffs allege that FDA has failed to meet its burden of proof in showing adulteration, as required by section 402(f)(1) of the FFDCA, and that the agency is circumventing its statutory obligation to engage in rulemaking to “formally ban” DMHA.

Plaintiffs argue that DMHA “is a natural constituent of walnut trees” with “an extensive history of use in dietary supplements,” and that “there is a significant body of scientific evidence supporting the safety of DMHA for human consumption.”  Although Plaintiffs do not explicitly state whether the DMHA in their products is naturally derived or synthetically produced, they assert that “[d]ietary ingredients include both naturally occurring and synthetically produced versions of the same ingredient,” and that “FDA has recognized the equivalence of natural vs. synthetically produced dietary ingredients in the context of several vitamins and other ingredients.”

Plaintiffs allege that FDA’s actions violate the Administrative Procedure Act in that they are contrary to law, exceed the agency’s statutory authority, and are arbitrary and capricious.  Plaintiffs further allege that FDA’s actions violate the Fifth Amendment by depriving Plaintiffs of due process.

As noted in the complaint, Hi-Tech is already engaged in litigation with the government over the regulatory status of DMAA.  That case is currently under review by the 11th Circuit Court of Appeals.  We’ll be keeping an eye on both cases as the litigation unfolds.

A recent decision out of Pennsylvania caught our eye, not because it applied a new enforcement strategy by FDA, but to the contrary, because it relied on FDA’s “oldie but goodie” Inspection Warrant authority.  Not a search warrant, which is subject to the same “probable cause” standard as all criminal search warrants, but an administrative tool that is rooted in the inspection provisions of the FDC Act, 21 U.S.C. § 374(a).  FDA admits it rarely uses this authority: “FDA does not routinely request inspection warrants in order to conduct investigations or inspections of regulated industry. However, warrants have been used effectively to gather information that has been refused improperly.”

FDA’s Regulatory Procedures Manual requires the following criteria to seek an inspection warrant:

1. FDA is entitled by statute or regulation to inspect the facility and to have access to the information which has been refused; and
2. there is a compelling FDA need for that information, and
3. the firm/individuals have refused to allow inspection or access to information in spite of a clear demonstration or explanation of appropriate statutory authority.

In the reported decision, In the Matter of Administrative Establishment Inspection, No. 1:18-MC-546, 2019 U.S. Dist. LEXIS 65476 (M.D. Pa. Apr. 17, 2019), FDA tried five times to inspect Spa & Organic Essentials after a nationwide outbreak of salmonella was linked to kratom distributed by the company.  Kratom is a food, as defined by the FDC Act, and Spa & Organic Essentials is subject to regulation by FDA as a food manufacturer and distributor.  Despite evidence linking the company to the contaminated kratom, the company refused to cooperate with FDA inspectors.  Thus, FDA turned to this rarely used tool, described as an “Inspection Warrant” by FDA, but termed an “Administrative Search Warrant” by the court.  The court issued the warrant on September 27, 2018, and FDA executed the warrant on October 3, 2018.  Both parties filed motions related to the warrant: Spa & Organic Essentials sought to quash the warrant, and FDA sought to require Spa & Organic Essentials to make statements and provide passwords for computers seized by FDA.

The court denied both motions.  The court recognized the strong deference afforded to the magistrate judge’s determination of probable cause, and also reinforced the well-settled proposition that “probable cause” in the criminal law sense is not required for an administrative warrant.  Rather, probable cause may be based on either:

• A particularized showing that the manufacturing plant targeted for the search is the location of suspected . . . violations; or
• A showing that the industry in general poses certain hazards to workers coupled with a showing that the targeted facility was selected at random as part of a general plan to pursue and eliminate suspected industry-wide violations.

The court concluded there was “ample probable cause for the FDA to conduct this search.”  The court was persuaded by the evidence linking Spa & Organic Essentials as the potential source for the salmonella-tainted kratom, and the company’s refusal to cooperate with other investigative measures.

The court denied as premature FDA’s request to compel the company to speak with investigators on the ground that the warrant did not affirmatively require the company to engage in testimonial conduct, just the seizure of records.   Thus, the court instructed FDA to take steps to first compel production of the information. But how can FDA take those steps? As noted above, the administrative warrant is rooted in the FDC Act inspection provisions. There is nothing in those provisions that requires an inspected entity to “allow” FDA to interview the entity’s employees. Thus, short of obtaining a criminal search warrant or getting a criminal subpoena, there is simply no step that FDA can take to compel interviews of the inspected entity.

This case serves as good reminder to all FDA-regulated entities of the arsenal of tools FDA has to conduct its regulatory oversight.  However the case also is a reminder of a key limitation on FDA’s inspectional authority, namely the absence of any statutory authority to compel any company employee to speak about any topic during an FDA inspection. Thus, regulated industry must remember that allowing its employees to speak during an FDA inspection is a purely voluntary decision, and not one that FDA has any statutory authority to compel under the FDC Act.  We assume FDA will only use the Inspection Warrant in limited circumstances, as proscribed by the RPM, but companies should know that a decision to refuse an inspection may be short-lived.

The Department of Justice (“DOJ”) has been touting for years the common interest that government and industry share in promoting an ethical corporate culture.  This week, DOJ reinforced the importance of a robust, well-designed, and effective corporate compliance program in DOJ’s determination of whether to prosecute, impose monetary penalties, and require compliance obligations on a company accused of misconduct.

In an updated guidance document, DOJ expands on the types of questions prosecutors should be asking to evaluate a company’s compliance program.  The questions fall under three main categories:

• Is the corporation’s compliance program well designed?
• Is the program being applied earnestly and in good faith? In other words, is the program being implemented effectively?
• Does the corporation’s compliance program work in practice?

If the questions are answered positively, then DOJ may decline to prosecute the company, focus efforts on prosecuting individuals, or provide leniency in the fine or imposition of a monitor.

For the first question, DOJ evaluates the comprehensiveness of the program (i.e., whether there is a clear message from the top that misconduct is not permitted).  To do this, DOJ instructs its attorneys to review a company’s policies and procedures for assigning responsibility, training, and disciplining.  DOJ specifically highlights the diligence process associated with M&A activities.  Although it is our experience that companies already include compliance issues as part of its due diligence, this recent statement by DOJ heightens the priority companies should place on these issues pre- and post-closing.

For the implementation question, the key issues relate to the commitment by management to foster the culture of compliance.  DOJ wants to see commitment from not just the Board of Directors or Senior Executives at a company, but also wants to see that “middle management” is reinforcing these standards.   And to evaluate the last category of questions, whether the program actually works, DOJ looks at how misconduct is identified, and whether there is adequate analysis and remediation of the misconduct once uncovered.

Notably, these same questions are those that drug and device companies routinely ask in the context of evaluating complaints about the company’s products.  The Quality System Regulation requires medical device companies to establish procedures to implement corrective and preventive action.  See 21 C.F.R. § 820.100.  These procedures must include an investigation of the cause of the issue, actions to correct and prevent recurrence of the issue, validation to ensure the actions are effective, and management oversight and review.  Similar requirements are imposed on drug manufacturers as part of complaint handling and adverse event reporting.  See, e.g., 21 C.F.R. §§ 211.198, 314.80.  Thus, a framework for addressing compliance issues should be very familiar to pharma and device companies.

Ironically, DOJ issued this guidance in the shadow of another DOJ policy that prohibits its lawyers from basing enforcement on violations of requirements set forth in guidance documents.  Nevertheless, this 18-page guidance document is worth close review by compliance officers.

Last week FDA issued a final guidance, Unique Device Identification: Convenience Kits, which clarifies FDA’s interpretation of a convenience kit for purposes of UDI labeling requirements.  We previously blogged on the draft version here.   As our readers know, the unique device identification system regulations require that the label and device package of a device must bear a UDI, unless an exception or alternative applies.  One such exception is for devices packaged within the immediate container of a convenience kit if the label of the convenience kit bears a UDI.  21 C.F.R. § 801.30(a)(11).

Unchanged from the draft guidance is FDA’s definition of a convenience kit: A convenience kit is “two or more different medical devices packaged together for the convenience of the user” (21 CFR 801.3).  FDA interprets this to mean a device that contains two or more different medical devices packaged together and intended to remain packaged together and not to be replaced, substituted, repackaged, sterilized, or otherwise processed or modified before being used by an end user.  FDA clarifies that “packaged together” means packed (e.g., wrapped or sealed) in a single container that is not intended to be unwrapped or unsealed before it is used by an end user.  Notably, the guidance does not apply to kits that contain devices co-packaged with drugs.

Kits that meet the definition of a “convenience kit” must include a UDI on the kit label and the individual devices within the kit are exempt from the requirement to bear a UDI.  21 C.F.R. § 801.30(a)(11).  Medical devices that are a part of kits that do not meet this definition must be individually labeled in accordance with applicable UDI requirements.

The final guidance includes additional examples and clarifications:

• First aid kits

Like the draft, the final guidance concludes that a first aid kit meets the definition of a convenience kit because the bandages, scissors, etc., are sealed in a single package and are not unpackaged until they are used by the end user.  Those components would not need to be individually labeled with a UDI, as long as a UDI is affixed to the immediate container of the kit.  The final guidance adds that end users may wish to replenish components of the first aid kit, rather than purchasing a new one as supplies run out.  In that case, the individual devices used to replenish or augment the first aid kit must bear a UDI because they were not part of the original convenience kit.

• Non-sterile orthopedic device set

This example is largely the same, with only stylistic differences from the draft.  As before, a collection of orthopedic implants and reusable instruments that are all supplied as non-sterile would not meet the definition of a convenience kit for UDI purposes.  Each of these devices is removed from its packaging and placed into a sterilization tray for cleaning and sterilization at some point prior to use.  Potentially unused components, which may be used later, will not remain packaged with the other components prior to use.  Therefore, each device in the set must comply with all applicable UDI labeling, data submission, and direct mark requirements.

• Single use disposable medical procedure kit

This example is also largely unchanged.  A sterile procedure kit consisting of various instruments, guide wires, graft passers, etc. would meet the definition of a convenience kit because the components all remain packaged together up until the point in time when the surgeon opens the tray for use on the patient.  The final guidance adds that this example is distinguishable from Example 2, in which the devices are intended to be sterilized prior to use and intended to be reassembled and restocked between uses.

• Sterile kit containing both single-use and reusable medical devices packaged together

This is a new example in the final guidance.  In this example, FDA describes a suture kit which contains single-use sutures and reusable stainless steel instruments, including forceps, needle holders, and scissors.  The kit is supplied sterile, but after the initial procedure in which the single use device (suture) is consumed, the labeler intends that the instruments may be reused on different patients, which requires reprocessing before each subsequent use.  FDA would consider this a convenience kit because the individual devices within the device are packaged together for the convenience of the user and not intended to be replaced, substituted, repackaged, sterilized, or otherwise processed or modified before the devices are used by an end user.  FDA notes, however, that because some devices in the kit are intended to be reprocessed and reused, those devices would be subject to direct mark requirements under 21 C.F.R. § 801.45.

• Different devices packaged together for the convenience of the user but the collection of devices is not itself a device

This is also a new example in the final guidance.  In this example, a labeler manufactures fluid-filled teething rings in a variety of shapes.  The labeler packages one teething ring of each shape together as a fixed quantity to create an item for retail with a higher profit margin and/or to allow each end user to select and use a particular model of teething ring according to preference.  This is not considered a convenience kit for UDI purposes because the devices packaged together are not collectively a device.

A few key points regarding this final guidance:

These additional examples help to clarify some of the takeaways we previously reported.  For example, the draft guidance implied that if any devices in a kit required sterilization prior to use, it could not be considered a convenience kit.  Based on the fourth example in the final guidance, however, there is a noteworthy exemption from this general rule.  If the product is initially provided as sterile, but requires sterilization after its first use, FDA would consider this a convenience kit.

We also note, as we did in our previous post, that the intent of the labeler informs the determination of whether a kit is a convenience kit for UDI purposes.  How the product is used has no bearing on the analysis.