FDA issued its final Guidance on Data Integrity on December 12.  The federal government has sworn off regulating by guidance (see blogpost here about Brand memo).  In fact, at the Food and Drug Law Institute (FDLI) Enforcement and Litigation Conference that was occurring simultaneously with release of the guidance,FDA Chief Counsel Stacy Kline Amin repeated the principle that the government does not regulate by guidance, and cited the “Brand Memo” as authority.  Despite those assurances, it would be hard to argue that the data integrity guidance does not represent an attempt to regulate by guidance.

To begin with, the guidance cites as support for its propositions (you guessed it!) ten other FDA Guidances; some of them are cited multiple times.  Perhaps more importantly, the final guidance, which governs manufacturing of finished dosage form drugs and by extension Active Pharmaceutical Ingredients (the guidance said that it is “consistent with CGMP for active pharmaceutical ingredients”), imposes onerous regulatory burdens.  In particular, one section jumps out at the authors of this article.

Written in Question and Answer Format, Question 8 of the final guidance asks, “How often should audit trails be reviewed?”  (Audit trails are records showing when and how electronic manufacturing and testing data were created, whether data have been altered or deleted, and other important information.)  The answer is startling.  Answer 8 states that “[i]f the review frequency for the data is specified in CGMP regulations, adhere to that frequency for the audit trail review.  For example, 211.188(b) requires review after each significant step in manufacture, processing, packing, or holding, and 211.22 requires data review before batch release.  In these cases, you would apply the same review frequency for the audit trail”.  In other words, in these instances, the audit trails must be reviewed for each batch before the batch can be released for distribution, despite there being no regulatory authority for this requirement.

This is a significant regulatory burden: in addition to reviewing entries on either the electronic or paper batch records to ensure all proper manufacturing steps have been performed, critical manufacturing checks have been reviewed and confirmed by a second individual, ingredients have been properly weighed and added, labels are accurate, all printed labels have been accounted for, and finished product meets required specifications (all of which are long-standing and well-understood requirements), Quality Control reviewers will now be compelled to review records maintained on electronic recording equipment (such as weight scales, laboratory testing and analysis equipment including High Performance Liquid Chromatographic equipment, and meters establishing density or acidity of finished product or in-process samples) for every batch.  This is a requirement that hardly springs naturally from the relevant regulations, 21 C.F.R. §§ 211.88(b) and 211.22.

Even more curiously, the apparent requirement that audit trail data integrity be reviewed for every batch before the batch can be released appears to be more stringent than the answer to the same question in the draft of this guidance that was issued only a couple of years ago.  We previously blogged about the draft guidance here and here.  That draft guidance answered the same question (although it was Question 7) as follows: “FDA recommends that audit trails that capture changes to critical data be reviewed with each record and before final approval of the record.”  So, in the draft guidance it was a mere “recommendation,” and now it appears to be a requirement (“adhere to that frequency for the audit trail review” instead of “FDA recommends that you adhere to that frequency for audit trail review”).

What has changed?  Certainly not the Federal Food, Drug, and Cosmetic Act in this regard. Not the regulations at 21 C.F.R. Part 211 on this issue.  This seems like more regulation by guidance to us.  And, although the guidance states (as do all guidance) that it does not establish legally enforceable responsibilities unless specific regulatory or statutory requirements are cited (note that none of the regulations FDA cites to make any reference, express or implied, to audit trail review), woe to the quality unit that even dares to claim that audit trail review is consistent with cGMP if done under another standard.

Nor is this the only example of regulation by guidance in the document.  Question 15 asks: “Can an internal tip or information regarding a quality issue, such as potential data falsification, be handled informally outside of the documented CGMP quality system?”

FDA’s response to this question is: “No. Regardless of intent or how or from whom the information was received, suspected or known falsification or alteration of records required under parts 210, 211, and 212 must be fully investigated under the CGMP quality system to determine the effect of the event on patient safety, product quality, and data reliability; to determine the root cause; and to ensure the necessary corrective actions are taken (see §§ 211.22(a), 211.125(c), 211.192, 211.198, 211.204, and 212.100).”

Yet none of these regulatory provisions actually require that firms investigate an internal tip or information regarding a quality issue within the cGMP quality system.

Another example is question 1(a), in which the agency asks “what is data integrity?” The answer states that “[f]or the purposes of this guidance, data integrity refers to the completeness, consistency, and accuracy of data. Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA).”  Under footnote 5, the agency’s stated support for the proposition that ALL data for drug manufacturing should be “contemporaneously recorded” is the regulatory requirements at 21 CFR 211.100(b) and 21 CFR 211.160(a), which granted, do provide that documentation take place “…at the time of performance…”.

However, these regulatory provisions are very narrowly tailored and refer specifically to, in the first instance, production and process control functions and, in the second instance, laboratory controls.  The agency does not cite to any additional regulatory authority for the general notion enunciated in the answer to question 1(a) that ALL data must be contemporaneously recorded.

Later in the document, in response to question 1(c) the guidance states: “CGMP-compliant record-keeping practices prevent data from being lost or obscured and ensure that activities are documented at the time of performance (see §§ 211.68, 211.100, 211.160(a), 211.188, and 211.194)” [Emphasis added], and yet none of these additional regulatory citations speak to the requirement that all data must be contemporaneously recorded.

Another example is the requirement that ALL data generated and recorded in all drug facilities be “attributable” (meaning ascribed to a particular individual in the facility) as described by answer 1(a) and footnote 5.  Yet, again the regulatory citations for this requirement are sorely lacking.  Of the ones cited in the guidance (§§ 211.101(d), 211.122, 211.186, 211.188(b)(11), and 212.50(c)(10)) only the last three regulatory provisions speak directly to the “attribution” issue, and again they are very narrowly tailored and only speak to, in the first instance, master production and control records, in the second instance, batch production and control records and, in the third instance, Positron Emission Tomography drug production and process control records!

We could go on and on but suffice it to say that the guidance on data integrity is replete with instances of regulation by guidance.  We had hoped that an administration that claims to be concerned about over-regulation would make sure to prevent this, whether it is the result of notice and comment rulemaking, or the result of the more pernicious “regulation by guidance.”

On December 4, 2018, FDA issued a proposed rule that would govern the de novo classification process.  After a comment period, it may be re‑issued as a final rule to take affect 90 days after publication.   While we agree with FDA’s goal of creating greater consistency and predictability in the de novo process, the proposed rule appears in some respects to unduly increase the burden on applicants.  In this regard, the proposed rule would make the de novo process look more like review of a premarket approval (PMA) application than a 510(k) submission.  It is also not clear if FDA has statutory authority to implement certain features of the proposed rule.

As a reminder, de novo classification allows the placement of novel device types into Class I and Class II, rather than burdening them with the Class III, PMA approval process that applies by statutory default to all new device types.  After a new device type is classified in Class I or Class II via de novo classification, similar devices within the same generic type can proceed to market based upon 510(k) clearance.

Most of FDA’s classification regulations were adopted for devices on the market in the 1970s and 1980s.  As time has passed, more novel device types have been developed.  The de novo process is an important way to expand the classification regulations to incorporate new Class I and Class II device types.

Until recently, there was little written guidance from FDA as to how de novo reviews would be conducted.  In recent years, FDA has issued several guidance documents on various aspects of the de novo program (for example: here, here and here).  A regulation would harden “recommendations” in a guidance document into “requirements” that must be followed.  A regulation gives both industry and FDA less flexibility, but it also gives greater certainty about the rules of the road.

In general, the proposed rule is consistent with FDA’s current administrative practice in processing de novo submissions.  The proposed rule appears structurally similar to the 510(k) regulation (21 C.F.R. Part 807, Subpart E) and the PMA regulation (21 C.F.R. Part 814), in setting forth requirements for (i) the format and content of a de novo submission, (ii) the procedures governing FDA’s review, and (iii) grounds for denial.

The proposed content requirements are nearly the same as those FDA proposed in its draft guidance, Acceptance Review for De Novo Classification Requests (Nov. 2017) (see our blog post here).  But, there are several additions that will likely increase the burden on applicants.  For example, de novo sponsors will be required to submit:

• a bibliography of all published and unpublished reports on the device and any other information relevant to a device’s safety or effectiveness;
• samples of the device and its components, if requested by FDA; and
• advertisements for the device.

These requirements are elements of a PMA application, not the 510(k) submission.  21 C.F.R. § 814.20(b)(8)‑(10).  With regard to advertisements, in particular, the PMA regulation is limited to “advertising that constitutes labeling under section 201(m) of the act.”  Id., § 814.20(b)(10).  In contrast, this proposal is broader.  It is not clear what the justification is, since FDA does not have authority to over the advertising of devices classified into Class I or II.  Perhaps they would justify this request based on the need to determine the intended use.  See id., § 801.4 (defining intended use to include labeling and advertising).

Unlike the 510(k) regulations, and more like the PMA regulations, the proposed de novo rule specifies the types of information required in a submission, including various types of non‑clinical data.  Compare 21 C.F.R. § 807.92(b)(1) with id. § 814.20(b)(6)(i).  This specification will at least provide greater certainty about what is required.  One potential omission is acknowledgement of the types of tests done for in vitro diagnostic devices, which have been a significant percentage of de novo clearances.

The procedure for review of submissions in the proposed rule generally follows FDA’s current administrative approach.  Interestingly, the proposed regulation states that a de novo request can be refused for filing if “the requester has not responded to, or has failed to provide a rationale for not responding to, deficiencies identified by FDA in previous submissions for the same device.”  In the preamble to the proposed rule, FDA states that a de novo can be refused for filing if a requester has not provided “a complete response” to such deficiencies.

The completeness of a response is, of course, in the eye of the beholder.  We hope that FDA will clarify in the final rule that a submission will be accepted if there is a response to prior deficiencies, with evaluation of the completeness and adequacy of the response occurring during the review on the merits.  This issue is of particular concern in light of problems in the 510(k) Refuse‑to‑Accept (RTA) process in the early days of its implementation, in which substantive questions were improperly raised.

The proposal sets forth 11 grounds on which the Agency may deny a de novo request.  In the PMA context, the grounds for denial are set forth in the Federal Food, Drug, and Cosmetic Act (FDCA) and are mirrored in the implementing regulation.  In the 510(k) context, the statute defines “substantial equivalence” and the implementing regulation provides that failure to establish substantial equivalence in accordance with this definition is grounds for denial.  In the de novo context, the statute authorizes only two potential grounds for denial:  (i) existence of a predicate device that provides a reasonable basis for a substantial equivalence review; or (ii) a determination by FDA that “the device submitted is not of low‑moderate risk or that general controls would be inadequate to control the risks and special controls to mitigate the risks cannot be developed.”  It seems potentially unauthorized for the implementing regulation to exceed the FDCA by specifying, as it does, nine additional grounds for denial.

Currently, FDA promptly posts letters granting de novo authorization in its de novo database.  Unfortunately, FDA takes considerably longer to post decision summaries, and it has taken months (and sometimes years) before new classification regulations are published in the Federal Register.  For example, the classification regulation for 23andMe’s DEN140044 was published nearly three years after the de novo classification was granted.

More recently, FDA has been posting decision summaries more promptly in the de novo database.  FDA should add a provision to the proposed rule establishing a definite timeline for posting both decision summaries and issuing Federal Register notices.  FDA publishes 510(k) Summaries (and decision summaries for 510(k)s for IVDs) within 30 days of clearance.  That would be a reasonable timeline for publishing the results of de novo classification decisions.

We found it interesting that the proposed rule states that FDA will decide a de novo request within 120 days.  That deadline is already in the statute, so FDA had to adopt the same timeline in the proposed rule.  In actuality, though, FDA routinely misses this deadline.  In the MDUFA IV Commitment Letter, FDA publicly agreed only to approve/deny 50% of de novo requests within 150 days (i.e., 30 days beyond the statutory deadline), with the other 50% presumably being decided somewhere north of 150 days.  In conjunction with the proposed rule, FDA should request appropriate funding from Congress to staff the de novo program to meet the 120‑day statutory requirement.  All parties would benefit.

Possibly the most controversial feature of the proposed rule is that it would give FDA authority to inspect submitter’s manufacturing facilities and clinical trial sites.  Here is the proposed regulatory provision (§ 860.256(c)):

(c) Prior to granting or declining a De Novo request, FDA may inspect relevant facilities to help determine:

(1) That clinical or nonclinical data were collected in a manner that ensures that the data accurately represents the benefits and risks of the device; or

(2) That implementation of Quality System Regulation (part 820 of this chapter) requirements, in addition to other general controls and any specified special controls, provide adequate assurance that critical and/or novel manufacturing processes produce devices that meet specifications necessary to ensure reasonable assurance of safety and effectiveness.

Start with manufacturing inspections:  In the 510(k) context, the FDCA expressly forbids FDA from conducting inspections for Quality System Regulation (QSR) compliance, unless “there is a substantial likelihood that the failure to comply with such regulations will potentially present a serious risk to human health.”  FDCA § 513(f)(5).  FDA has declared that it may conduct preclearance inspections for a few device types, e.g., infusion pumps.  Most device types do not meet this standard and preclearance manufacturing inspections are rare.

In the PMA context, the statute permits FDA to withhold approval if manufacturing facilities do not conform to QSR requirements.  FDCA § 515(d)(2)(C)).  The implementing regulation expressly authorizes conditioning approval on a successful manufacturing inspection.  21 C.F.R. § 814.44(e)(1)(iii).  As a matter of administrative practice, FDA routinely performs QSR inspections prior to granting PMA approval.

As to de novo classification, the FDCA is silent on whether preclearance inspections are authorized.  Yet, in the proposed rule, FDA grants itself authority to conduct manufacturing inspections when deciding de novo classification requests.  Perhaps recognizing this legal weakness, FDA’s proposal is not a straight‑up right to inspect for QSR compliance.  Rather, FDA purports to authorize itself to inspect whether the applicant’s “implementation” of the QSR “in addition to other . . . controls” (whatever that means) will “provide adequate assurance that critical and/or novel manufacturing processes” will “produce devices that meet specifications necessary to ensure reasonable safety and effectiveness” (proposed § 860.256(c)).

The actual meaning of this convoluted language is anybody’s guess.  It seems like a questionable effort to tie QSR compliance to device classification.  There is no support in the FDCA for doing so.  On the contrary, the statutory provision that authorizes all the various classification proceedings (FDCA § 513) does not authorize manufacturing inspections, with an express limited exception in the 510(k) context (discussed above).  In practice, none of the classification regulations promulgated in the 1970s and 1980s were associated with manufacturing inspections.  Since a de novo review is in fact the promulgation of a new classification regulation, it would seem that likewise a manufacturing inspection is not authorized for de novo review.  Certainly, there is no express statement anywhere in § 513 that FDA may conduct manufacturing inspections in conjunction with de novo classification proceedings (in contrast to the express authorization in § 515 in connection with PMA approval).

Apart from the uncertain statutory grounds, this process of inspecting de novo applicants for QSR compliance would create an undue burden on a first comer.  After a de novo is granted, subsequent applicants will proceed through the 510(k) process (for non-exempt devices).  As noted above, FDA is expressly prohibited from inspecting 510(k) applicants for QSR compliance, unless there is a serious risk to health.  Therefore, these second comers will have a lower bar to clearance than the de novo applicant, creating an unevenly applied regulatory scheme.

The proposed rule is on more solid ground with clinical study site inspections.  FDA has authority to inspect data and information related to investigational devices, including the results of clinical studies evaluating such devices.  E.g., 21 C.F.R. § 812.145.  The statutory authority underlying that regulation is not open to question.

One wonders also how practical is will be for FDA to routinely conduct clinical and/or manufacturing inspections in a 120‑day time frame for de novo review?  It would be resource‑intensive to complete inspections in this time frame, possibly detracting from the ability to conduct routine inspections or causing FDA to frequently miss the deadline for completing de novo reviews.  With regard to manufacturing, there will also be a substantial burden on companies that have developed novel device types.  These firms are frequently start‑ups that have not completed building out their manufacturing facilities and procedures.  It might be better to conduct an early inspection once they are engaged in actual commercial distribution.

As to clinical data, although we do not question FDA’s authority or even the need in some cases to conduct inspections, we are already aware of two past de novo requests for which FDA has inspected clinical data and the review time significantly exceeded the 120-day statutory decision deadline.  It is not clear how routine clinical inspections would work as a practical matter or whether FDA envisions such inspections taking place only if there are “for cause” concerns about the integrity or validity of the clinical data.  This point at least needs to be clarified.

Overall, in our view, the proposed rule is a good idea to bring greater certainty to the de novo process.  If the proposed rule is finalized as‑is, though, it will materially increase the burden on applicants seeking de novo marketing authorization for a low‑risk novel device.  That potential impact is concerning, especially in light of FDA’s recent statements about an intent to increase utilization of the de novo pathway.

Those in industry who would be subject to the proposed rule may wish to submit comments on the legalities and burdens associated with the proposed rule.  Comments are due by March 7, 2019.

On December 11, 2018, the authors of this blog post attended the oral argument in Federal Trade Commission v. Shire ViroPharma, Inc., No. 18-1807 (3d Cir. filed Apr. 12, 2018).  We have previously blogged about the case here, here, and here. In a nutshell, Shire examines the FTC’s statutory authority to bring suit in federal court seeking injunctive and equitable relief where the alleged statutory violations at issue have long since ceased. Section 13(b) of the Federal Trade Commission Act (“FTC Act”) (15 U.S.C. § 53(b)) gives the FTC authority to file a case only when the FTC has reason to believe that a defendant “is violating” or “is about to violate” the FTC Act.

Although it is often hard to predict the outcome of an appeal after hearing the questions and comments of the three-judge court, in this case the Court’s questions and comments suggested that odds are leaning heavily against the FTC winning.  If the FTC does lose, the question will then be how severe an effect the Court’s ruling will have on other FTC enforcement cases. And this is not the only recent court case that poses significant litigation concerns for the FTC.  Two other recent court rulings suggest that courts are revisiting the FTC’s authority to seek equitable relief (including restitution and disgorgement) under the FTC Act § 13(b).  These rulings also may raise an issue that our firm opined on fifteen years ago, namely whether FDA has the authority to seek equitable remedies when it pursues injunctive relief in court.

What Will an FTC Loss in Shire Mean for FTC Act Enforcement?

The questions presented to the Third Circuit panel (Smith, J., McKee, J., and Fisher, J.) in Shire centered on what legal standard the FTC must meet in order to adequately allege reason to believe that a defendant “is violating, or is about to violate” the FTC Act under Section 13(b), and whether the FTC met its burden in this case. The judges’ questioning at oral argument strongly suggested that the answer to the latter question will be “no.” The answer to the former question is less clear.

The FTC’s primary argument in Shire is that the “about to violate” language must be analogized to the standard applied for injunctive relief under other statutes, which would only require the FTC to adequately plead that an alleged violation was reasonably likely to recur. The FTC cited the Third Circuit case of SEC v. Bonastia, 614 F.2d 908 (3d Cir. 1980) for the factors used to determine likelihood of recurrence – factors that do not include a temporal element. The panel appeared to reject the FTC’s proposed standard, with at least Judges Smith and McKee indicating their belief that some temporal consideration must be involved in a determination of whether someone is “about to violate” the law. Chief Judge Smith, in particular, emphasized that the plain language “about to” seems to reflect a degree of imminence.

The Third Circuit Court’s emphasis on the relatively extreme facts of the Shire case – a five-year delay between the alleged violative conduct and initiation of the FTC’s suit, and no allegations of future circumstances in which Shire could be expected to repeat the alleged misconduct – suggest that the court could simply hold that the FTC had failed to adequately plead even a reasonable likelihood of recurrence and leave the matter there. However, the FTC’s position that the “likelihood of recurrence” includes no explicit consideration of timing may make it difficult for the Court to rule under that standard without altering it to include a temporal factor.

Assuming that the Court does rule against the FTC with respect to the applicable legal standard under Section 13(b), of course the Commission may seek rehearing or rehearing en banc, and may ultimately seek Supreme Court review. Moreover, a loss in the Third Circuit would still permit the FTC to seek a different result in any state other than New Jersey, Pennsylvania, and Delaware (in those three states, the FTC will have to follow an adverse Third Circuit ruling unless and until it is overturned by the Supreme Court).

Still, an ultimate loss for the FTC on this issue, particularly if the Court’s reasoning is adopted by courts outside the Third Circuit, would likely result in a longer process to resolve many FTC Act violations. As Shire’s counsel pointed out at oral argument, the FTC clearly has authority to bring an administrative action for violations of the FTC Act without any statutorily imposed temporal limitation (See 15 U.S.C. § 45(b); 16 C.F.R. Part 3). However, the Commission cannot obtain consumer redress through an administrative proceeding. To obtain recompense for consumers in consumer protection cases, the FTC would have to bring and successfully complete an administrative case, overcome a court challenge to a final order, and then file and win a court case seeking equitable relief pursuant to 15 U.S.C. § 57b. Even that process is inapplicable in “competition” cases such as Shire, because 15 U.S.C. § 57b is focused on consumer protection cases. This means that, practically speaking, in a case of harm to consumers where the FTC cannot make a showing of “imminent” future violation, the FTC may well be unable to provide relief to affected consumers.

The delay associated with pursuing an administrative cease and desist order is one of the reasons that the FTC has filed hundreds if not thousands of cases where the FTC bypasses the administrative process and goes straight to court seeking an injunction.  In consumer protection cases, the FTC seeks relief such as restitution and disgorgement of profits in most such cases.  In many cases, the FTC also seeks and obtains “emergency” relief such as a total freeze of the defendants’ assets. All of this authority would be in jeopardy if the FTC cannot seek and obtain such relief at all, or only after a long administrative process and later court case.

Of course, even if the FTC loses this case, it can collaborate with other government agencies with consumer protection and antitrust authorities, including the U.S. Department of Justice and State Attorneys General. Such coordination takes additional time, as well as the balancing of agency investigative and enforcement resources. Additionally, the FTC would lose its independence to bring these actions without needing to go through another federal or state agency — the FTC has been fiercely fighting to obtain and retain independent litigating authority for almost fifty years.

Does Shire Affect the FTC’s (and FDA’s) Pursuit of Equitable Remedies?

In Shire, the FTC’s brief argued in the alternative that even if the FTC had not adequately alleged a likelihood of recurring violations, the FTC should nevertheless be permitted to go forward with its claim for restitution to consumers who presumably overpaid for one of Shire/ViroPharma’s drugs.  Shire’s brief countered that the FTC failed to adequately plead the statutory prerequisites to bring suit under Section 13(b), thus, the Commission had no right to alternatively seek monetary relief. Shire also noted the Supreme Court’s 2017 ruling in Kokesh v. SEC, 137 S. Ct. 1635, that cast doubt upon agencies’ authority to seek equitable remedies not expressly referenced by the applicable statute.

This week’s oral argument did not address the question of alternative equitable remedies.  Thus, it is quite possible that the Court will simply rule that the entire case must be dismissed because it was brought too late, without reaching the question of whether the FTC has the right under Section 13(b) to seek restitution and other equitable relief such as disgorgement of profits.

However, in many respects, the issue of the FTC’s right to obtain equitable remedies in a Section 13(b) suit is of greater importance to the FTC than the standard for determining whether the FTC has satisfactorily alleged that it has reason to believe that the defendant is about to violate the FTC Act.  That issue is largely a timing question, and the FTC usually brings suit much closer to the violative events than it did in Shire.  In contrast, if the courts definitively rule that the FTC has no authority to seek equitable relief in Section 13(b) cases, that result would severely damage most of the FTC’s consumer protection 13(b) cases, where the Commission typically seeks such remedies.

The question is one of statutory interpretation:  Does Section 13(b) authorize the FTC to seek all forms of equitable relief assuming the court has power to grant any relief at all?  The statute itself specifically authorizes a court to issue a temporary restraining order, a preliminary injunction, or a permanent injunction, but is silent on other forms of equitable relief.  Although the FTC has been successful in arguing to many courts that once a court has jurisdiction over a case seeking injunctive relief, that court has the authority to award equitable relief such as asset freezes, the payment of restitution, and/or the payment of disgorgement of profits, this previously established authority is now being reexamined by the courts.

Aside from the Third Circuit in Shire, other courts have recently looked at the FTC Act and questioned the FTC’s authority to seek and obtain equitable relief not expressly referenced by Section 13(b). FTC v. Hornbeam Special Situations, an October 2018 decision in the Northern District of Georgia, is a similar case we have blogged about.  More recent is the December 3, 2018 Ninth Circuit ruling in FTC v. AMG Capital Mgmt., LLC.  There, the court ruled in favor of the FTC’s pursuit of equitable remedies: The court conceded that defendant’s argument regarding the FTC’s lack of statutory authority “has some force but it is foreclosed by our precedent.”  However, one Ninth Circuit judge (O’Scannlain) also filed a concurring opinion arguing that the Ninth Circuit’s earlier rulings authorizing the FTC to obtain equitable remedies under Section 13(b), while binding, were “no longer tenable.”  Judge O’Scannlain’s opinion suggested that the Ninth Circuit should hear the case en banc to reconsider its precedent on the issue.  He specifically noted that a separate provision of the FTC Act (15 U.S.C. § 57b), applicable in different circumstances, expressly authorizes alternative equitable relief in certain consumer protection cases, while Section 13(b) is tellingly silent on those remedies. Although the ultimate disposition of the AMG Capital case is not yet clear, Judge O’Scannlain’s concurring opinion should give the FTC reason to worry.

In light of the developing case law, FDA may also need to be more circumspect in seeking equitable relief when it (through the Department of Justice) files an injunction action under 21 U.S.C. § 332.  That provision authorizes courts to “restrain violations” of the Federal Food, Drug, and Cosmetic Act, but is silent on the court awarding equitable relief as part of the injunction.  The issue of FDA’s authority to seek restitution or disgorgement in a Section 332 action was hotly debated fifteen years ago, when our firm argued in a law review article that FDA lacks this authority.  See Jeffrey N. Gibbs and John R. Fleder, Can FDA Seek Restitution or Disgorgement?, 58(2) Food & Drug L.J. 129 (2003).  FDA disagreed, and in several subsequent court rulings FDA’s position was adopted.  See United States v. Kaminski, 501 F.3d 655, 670 (6th Cir. 2007); United States v. Rx Depot, Inc., 438 F.3d 1052, 1063 (10th Cir. 2006); United States v. Lane Labs-USA, Inc., 427 F.3d 219, 236 (3d Cir. 2005).  FDA has also successfully received such equitable relief via consent decrees.  See, e.g., FDA: Michigan Heart-Lung Bypass Machine Manufacturer (disgorgement of $35 million, E.D. Mich. 2011, link); Bristol-Myers Squibb to Pay More than $515 Million to Resolve Allegations of Illegal Drug Marketing and Pricing (disgorgement of over $25 million, D. Mass. 2007, link). Nevertheless, FDA’s authority to obtain equitable remedies in an injunction suit may now be in as much in jeopardy as the authority of the FTC.

We will continue to monitor this area of developing case law, and keep readers informed.

Duodenoscopes are flexible, lighted tubes that are threaded through the body into the top of the small intestine (duodenum) and allow doctors to see potential problems in the pancreas and bile ducts. Because duodenoscopes are reusable devices, they must be reprocessed (cleaned) after each use to ensure that tissue or fluid from one patient is not transferred when used on a subsequent patient.

For several years, FDA has been concerned about the reprocessing of duodenoscopes. In 2015, FDA required all manufacturers who make and sell duodenoscopes in the United States to conduct postmarket studies to allow FDA to better understand how duodenoscopes are reprocessed in real-world settings; in March of this year, FDA issued Warning Letters to all U.S. duodenoscope manufacturers for failing to meet their postmarket surveillance study requirements; and just this week, FDA provided interim results of the reprocessing studies and its recommendations.

Despite all this scrutiny, or maybe because it was already on the government’s radar, one of the manufacturers, Olympus Medical Systems Corporation, and its former quality manager were targeted for their failure to file reports related to known adverse events associated with its duodenoscopes. FDA requires medical device manufacturers to submit Medical Device Reports (MDRs) under 21 C.F.R. Part 803 for an event when they “become aware of that reasonably suggests that one of their marketed devices”:

(i) May have caused or contributed to a death or serious injury, or

(ii) Has malfunctioned and that the device or a similar device marketed by the manufacturer [or importer] would be likely to cause or contribute to a death or serious injury if the malfunction were to recur.

A failure to submit an MDR renders a medical device “misbranded,” and the FDC Act prohibits the introduction of a misbranded medical device into interstate commerce.

On December 10, 2018, Olympus agreed to plead guilty to three misdemeanor counts of introducing misbranded duodenoscopes into interstate commerce. The plea agreement contains a stipulation of facts describing Olympus’ receipt of information requiring submission of an initial or supplemental MDR, and requires the company to distribute to its U.S. customers a notice about the plea agreement. The company also is required to undertake certain compliance measures specific to MDR processes, akin to those contained in FDA civil consent decrees:

• Retain an independent MDR expert to inspect and review the company’s policies and procedures;
• Have the MDR expert conduct periodic reviews of the company’s continued compliance with MDR requirements;
• Report to FDA and DOJ periodically for 3 years; and
• Require the President and Board of Directors to periodically review MDR compliance measures and provide certifications to FDA and DOJ regarding those reviews.

The global settlement was authorized by DOJ’s Assistant Attorney General Joseph Hunt, which permitted the lead prosecutor from the U.S. Attorney’s Office in New Jersey to bind “the United States Attorney’s Offices for each of the other 93 judicial districts of the United States,” a provision that assures the company that another aggressive prosecutor will not bring follow-on charges against the company.

Hisao Yabe, the former Division Manager for the Quality Assurance and Environment Division, agreed to plead guilty to one count for the same conduct. He stipulated that he was aware of the obligation to file and supplement MDRs, and that he failed to make such submissions even when required. Interestingly, the stipulation notes that he considered whether to submit a supplemental MDR in 2013, but did not file it until 2015. In reviewing the underlying Information, it appears Yabe was in the process of evaluating whether the information it received in 2013 required reporting (e.g., whether the methodology and conclusions of the information were appropriate), and agreed that if a supplemental MDR was required, the company should file it. It is unclear, however, why the company waited until 2015 and what ultimately motivated the filing decision at that time. One can only speculate that the coincident timing of FDA scrutiny resulted in the MDR filing, which three years later, now forms the basis for the criminal charge.

In addition to the mandatory compliance measures, the company agreed to pay an $80 million criminal fine (which was 2.5 times the profit earned from the duodenoscopes sold during the time period), and a $5 million forfeiture. Yabe faces up to a year in prison and a $100,000 fine; he will be sentenced in March 2019.

On Friday, the Yale Law School Media Freedom and Information Access law clinic filed a complaint against FDA, HHS, and NIH alleging violations of the Administrative Procedure Act based on Section 801 of the FDA Amendment Act (FDAAA), which requires results reporting of clinical trials to the defendant agencies. Filed on behalf of a journalism professor and reporter, Charles Seife, and a physician, the President of the Center for Science in the Public Interest, and former FDA official, Peter Lurie, the suit alleges that defendants acted arbitrarily and capriciously in their interpretation of FDAAA 801 to apply only to trials completed after January 18, 2017 and in their application of FDAAA 801 by failing to issue statutorily-required notices of noncompliance and post them on ClinicalTrials.gov.

As we explained when the final rule implementing FDAAA 801 was published in October 2016, FDAAA 801 requires the submission and posting of registration and results information of applicable clinical trials, including both approved, licensed or cleared products and unapproved, unlicensed, or uncleared products. If the product has not been approved, licensed or cleared at the time of a trial completion, basic results information must be reported within 30 days of approval. The final rule added a de facto exemption for clinical trials of unapproved products with a primary completion date before the rule’s effective date; as such, products with a primary completion date prior to January 18, 2017 were exempted from the reporting requirement. The rule also required the agency defendants to maintain a registry and results data bank, which they did via the ClinicalTrials.gov website, along with public notices of violations of these reporting requirements.

Plaintiffs raise the argument that the de facto reporting exemption for studies with a primary completion date prior to January 18, 2017 exceeds the statutory authority set forth in FDAAA 801. Without basic results information, Plaintiffs argue that their efforts to characterize the integrity of clinical trial enterprise and complete research into evidence development and dissemination are harmed by this arbitrary and capricious interpretation.

Additionally, plaintiffs allege that the agency defendants have failed to comply with their congressionally-mandated obligation to issue and publicly post notices of FDAAA violations. Despite public knowledge of widespread noncompliance with the statute, defendants have not issued a single public notice of noncompliance on ClincialTrials.gov, as required by statute. Nor have defendants implemented a public search function for notices of noncompliance on ClincialTrials.gov, as required by statute. Plaintiffs allege that this failure to comply with the FDAAA 801 requirements “constitutes agency action unlawfully withheld and/or unreasonably delayed, in violation of 5 U.S.C. § 709(a).” Plaintiffs cite, amongst other studies, AllTrials data stating that that only 60.8% of applicable clinical trials with completion dates on or after the FDAAA Final Rule effective date, January 18, 2017, have publicly reported results on ClinicalTrials.gov.

Plaintiffs request that the U.S. District Court for the Southern District of New York (SDNY) strike down portions of the final rule exempting studies with primary completion dates prior to January 18, 2017 from mandatory reporting obligations. Further, Plaintiffs ask that SDNY compel defendants to issue noncompliance notices and provide them in an easily-searchable database on ClinicalTrials.gov.

To the best of our knowledge, this is the first litigation arising from FDAAA 801. It’s an interesting tactic, reminiscent of suits brought under FOIA to require agencies and officials to enforce the law (i.e., the FOIA project, EPIC). Because of the strong statutory language with respect to notice of violations in 42 U.S.C. § 282(j)(5)(E)(i)–(ii), plaintiffs do have a persuasive argument that, in this instance, Congress explicitly intended to curtail agency enforcement discretion, and perhaps it will survive a motion to dismiss. But given the extent of Chevron deference and an agency’s discretion to enforce, there is a good possibility that this case will be dismissed.

Nevertheless, the case highlights the lack of transparency in the federal government. While this action is obviously limited to only the three relevant agencies, the overarching issues surrounding transparency seem to be par for the course across all of government right now. FDAAA was clearly passed to provide transparency for the purposes of research integrity, scientific progress, and prevent duplication of unsafe and unsuccessful trials.

Yet here we are, 11 years later, plaintiffs still need to sue to get access to information statutorily-mandated clinical trial information disclosed to the public.

On Dec. 6, FDA announced that it is formally seeking data, comments and information related to the assessment of safety and effectiveness of food handler antiseptic drug products (rubs and washes) for over-the-counter (OTC) use. Although this is a positive development, judging from the questions FDA poses, it is only the first step in what likely will be a long journey.

As detailed in the Federal Register notice, the road to this notice has been long. Since 1994, industry repeatedly has called for regulation of antiseptics for food handlers as a separate category of antiseptics under the monograph.

As readers of this blog know, antiseptic washes and rubs for use by consumers and in health care have been subject to review, and monographs for these products have been finalized. On every occasion, industry has submitted comments requesting that FDA treat food handler products separately. FDA recognizes that a separate category for this type of product is warranted. However, the Agency seems uncertain about a significant number of issues. In the notice, FDA discusses several issues for consideration, including:

• The broad spectrum of uses. Food handling occurs in commercial settings from farm to table, including where food is grown, harvested, manufactured, packed, held, transported, prepared, served and consumed.
• The variety of conditions. Not all food handler conditions are the same and they pose different challenges to effectiveness. For example, in some situations, hands are heavily soiled with organic matter such as grease and dirt.
• The length of contact time. The Model Food Code, which addresses the safety at retail and food service establishments, specifies that a cleaning regime should last at least 20 sec. using a cleaning compound in a hand washing sink. In contrast, in vivo testing for health care antiseptics requires 30 sec. contact.
• Causes of food borne illnesses include viruses and parasites. In fact, according to the CDC, only 51 percent of foodborne disease outbreaks are ascribed to bacteria. This raises the question whether food handler antiseptics should be tested for effectiveness against viruses and possibly parasites as well. FDA has resisted allowing viral claims for other OTC antiseptics.
• The potential risk of indirect exposure to antiseptics by consumers due to transfer from the hands from food handlers to food raises questions also.

FDA has established a docket to obtain data, information and comments related to the assessment of the safety and effectiveness of food handler antiseptics. Questions range from determination of eligibility, current conditions of use, and safety and effectiveness criteria and evaluation.

Particularly, the eligibility of active ingredients for the OTC Drug Review may become a hurdle. A product is eligible for the OTC Drug Review if its conditions of use existed in the OTC drug marketplace on or before May 11, 1972, or if drug products with the same conditions of use have been marketed for a material time and extent such that they meet the requirements for eligibility under FDA’s time and extent application (TEA) regulation. FDA indicates that it anticipates that few if any products are eligible based on marketing before May 11, 1972. Thus, evidence of marketing for a material time and extent will be needed. Because no call for data or information about food handler antiseptics then on the market was issued in the 1970s at the inception of the OTC drug review, it may be nearly impossible to identify what products are eligible. Perhaps OTC monograph review will allow FDA and the industry to sidestep this thorny issue.

Comments must be submitted by Feb. 5, 2019.

Hard to believe that just two years ago, ev3, Inc. scored a resounding victory after the First Circuit affirmed the dismissal of a qui tam action against it (we reported it here). This week, DOJ announced that the same company has agreed to a criminal plea on what, at first blush, appears to be the same basic set of facts. The plea includes a misdemeanor count for violation of the Federal Food, Drug, and Cosmetic Act (FDC Act), and payment of $11.9 million in criminal penalties along with a $6 million forfeiture.

The original action involved a qui tam whistleblower who alleged the company was liable under the False Claims Act for misrepresentations it made to FDA when seeking approval of the Onyx liquid embolization device. The government declined to intervene in the case, but the relator pressed his arguments through four amendments to his complaint.

According to the relator, during the approval process for Onyx, ev3 agreed to a very narrow indication for Onyx, and also represented that it would provide significant training to physicians on the proper on-label use of Onyx. Indeed, the approved product labeling restricted its use to “physicians with neurointerventional training and a thorough knowledge of the pathology to be treated, angiographic techniques, and super-selective embolization.” ev3 allegedly also concealed safety issues with the Onyx product from FDA. The relator argued that if FDA had known ev3 had no intention to restrict its marketing to the on-label indication, or adequately train physicians, and if FDA had known about safety issues with the Onyx product, it would not have approved the product (i.e., that the company had fraudulently induced FDA to approve the drug).

The First Circuit rejected the relator’s theory using strong language: “The FDA’s failure actually to withdraw its approval of Onyx in the face of D’Agostino’s allegations precludes D’Agostino from resting his claims on a contention that the FDA’s approval was fraudulently obtained.” In the absence of such official agency action by FDA, the court held that it was impossible to determine that FDA would not have approved the Onyx device without the alleged fraudulent representations. The court also concluded that the relator could not demonstrate materiality where CMS had continued to reimburse for Onyx, stating that “[t]he fact that CMS has not denied reimbursement for Onyx in the wake of D’Agostino’s allegations casts serious doubt on the materiality.”

The December 4 criminal plea, however, demonstrates that the government did take serious issue with ev3’s marketing of its Onyx product, although not necessarily because it evinced the alleged fraud posited by the relator in his FCA claim. The criminal information does not explicitly discuss the company’s communications with FDA during the approval process for the device, but does refer to post-marketing statements by FDA that made clear the company needed additional data to support an expanded indication for Onyx – statements that the company apparently disregarded. Thus, the pleading seems to describe a straightforward off-label promotion violation rather than any “fraudulent inducement” of FDA approval in the first instance.

In sum, while the relator may have “lost,” the government still won. This case showcases the power of the government based on the plethora of statutes at its disposal. It is likely the government saw the flaws in the qui tam case early on (thus choosing to decline the matter) but sought to prosecute the company’s activity and chose the more straightforward FDC Act violation as its tool. Defendants can still appreciate the strong language in the First Circuit opinion, but that may be of little solace to ev3 considering the ultimate end of its story.

While riding out the end of this term, the Government Accountability Office (GAO) delivered to our lame duck Congress some light reading on orphan drug designations and marketing. In a report titled “FDA Could Improve Designation Review Consistency; Rare Disease Drug Development Challenges Continue,” the GAO examined the orphan drug designation process, including the increase in demand for orphan drug designations and FDA’s review of orphan drug designation requests. Arising in response to a congressional request on orphan designations and marketing approvals, the report examines:

• The actions FDA has taken to address the growing demand for orphan designations;
• The extent to which FDA has used consistent criteria and complete information to review applications for orphan designation, and the characteristics of drugs seeking orphan designation;
• The orphan drugs FDA has approved for marketing; and
• The steps FDA has taken to address challenges in rare disease drug development.

The GAO reviewed FDA documents, data, and review templates for orphan drug designation requests from October to December 2017 and interviewed agency officials and stakeholders.

The GAO investigation and Report come on the heels of FDA’s June 2017 Orphan Drug Modernization Plan designed to eliminate the designation application backlog. As part of the plan, FDA introduced collaboration between different review divisions, reduced other regulatory and discretionary burdens on Office of Orphan Products Development (OOPD) (like FOIA requests), and developed the standard designation template to facilitate consistent and efficient review of new designation applications.

The major focus of the GAO Report seems to be the OOPD review templates. The report explains that OOPD reviewers record information from orphan drug designation requests in a five-section review template, which is then used to assess the request. The GAO noted that of the 148 review templates assessed, at least 102 were missing information. FDA officials explained that the background information in the review template provides context for making designation determinations, but there are no instructions provided to reviewers for using this information in evaluating the applications. Further, the GAO report indicated that OOPD did not independently verify data to ensure accuracy and completeness in designation requests.

While the GAO Report seems fairly critical of the OOPD review process, the Report offered only one recommendation: FDA should improve the consistency of the information inputted into its review templates. (Those of you who have had the pleasure of reviewing FDA’s Summary Basis of Approval in any depth know that a lack of consistency in FDA review templates is not limited to OOPD.) While the recommendation focuses specifically on the templates for some reason, the Report points out some big holes in FDA’s orphan drug designation review process in its entirety. A lack of instructions combined with a lack of data verification implies that OOPD is not doing a thorough review of these designation requests.

The report also noted that concerns with the adequacy of a manufacturer’s scientific rationale was the most common reason that orphan designation was not granted. Concerns include that the manufacturer did not provide sufficient or adequate data to support the scientific rationale, or that the manufacturer did not provide data from the strongest available model for testing the drug. Some other interesting facts from the report: FDA’s orphan drug marketing approvals increased from 2008 to 2017, focused primarily on therapeutic areas of oncology and hematology, and took approximately 9 months for agency review.

FDA approved 77 orphan drugs for marketing in 2017. But as the number of orphan designation and marketing approvals has grown, questions about potential challenges in drug development have arisen. The GAO Report cites as the biggest barriers to rare disease drug development the need for more basic scientific research and difficult recruiting small populations for clinical trials. And while the report explained that OOPD has some grant programs that may help manufacturers, it provided no recommendations or analyses for FDA on this issue.

However, HP&M’s James E. Valentine and Frank J. Sasinowski previously co-authored a proposal for an FDA Rare Disease Center of Excellence that would help overcome these barriers and others in orphan drug development and review (see previous coverage here).

Last week, DOJ announced that it had concluded a year-long review of its individual accountability policy and that it had made changes to reflect a more efficient and practical position in its investigations of companies. As you may recall, in 2015, then-Deputy Attorney General Sally Yates issued a memorandum (“Yates memo”) directing DOJ prosecutors to pursue culpable individuals in all civil and criminal investigations involving corporate misconduct.  We reported here on the initial issuance of the policy and clarifying statements. The latest changes, described by DAG Rod Rosenstein, reform DOJ policy to provide more potential for companies to earn cooperation credit and to resolve cases more quickly.  FDA-regulated companies should welcome these developments, although some additional clarity still is necessary.

For criminal cases, the revised DOJ policy takes into account the problem companies face when it is difficult, if not impossible, to identify every individual who was “substantially involved in or responsible for” the criminal conduct regardless of relative culpability, like in cases in which there was corporate-wide direction that was routinely followed.  DOJ recognizes that the former policy was not practical and potentially could result in a waste of limited government resources.  Thus, DOJ policy now makes clear that investigations should not be delayed merely to collect information about individuals whose involvement was not substantial or not likely to be prosecuted.  DOJ encourages companies to engage in dialogue with the government, and puts the burden on the company seeking cooperation credit to explain any restrictions it faces from providing full information.

In civil matters, in which the primary goal is to recover money to the government fisc, DOJ policy is even more flexible and returns more discretion to the civil attorneys to resolve matters without having to pursue individual liability. As Rosenstein explained, “[DOJ] civil litigators simply cannot take the time to pursue civil cases against every individual employee who may be liable for misconduct, and we cannot afford to delay corporate resolutions because a bureaucratic rule suggests that companies need to continue investigating until they identify all involved employees and reach an agreement with the government about their roles.”  Thus, the revised policy permits DOJ civil attorneys to award gradations of cooperation credit rather than have to select between a binary choice of no credit or full credit. The policy also permits civil attorneys to consider an individual’s ability-to-pay in deciding whether to pursue a civil case, which makes sense to conserve investigative (and judicial resources) in cases that are unlikely to yield any monetary recovery.

The Justice Manual (“JM”), formerly known as the U.S. Attorney’s Manual, reflects these changes in sections related to civil and criminal investigations.  Although the JM contains examples of circumstances in which cooperation credit can be awarded despite full information about individual culpability, it remains to be seen how these changes are implemented by the various AUSAs throughout the country.  Overall, the revised policy leans toward facilitating corporate resolutions more quickly and efficiently, which is a goal both sides of an investigation typically can share.

On November 30, CMS published in the Federal Register a proposed rule on Modernizing Part D and Medicare Advantage to Lower Drug Prices and Reduce Out-of-Pocket Expenses. This proposal is the latest in a series of CMS actions to implement the HHS Blueprint to Lower Drug Prices and Reduce Out-of-Pocket Costs, which was issued in May of this year. The Proposed Rule addresses five subjects:

1. Providing Plan Flexibility to Manage Protected Classes
2. Medicare Advantage and Step Therapy for Part B Drugs
3. Pharmacy Price Concessions to Drug Prices at the Point of Sale
4. Prohibition Against Gag Clauses in Pharmacy Contracts
5. E-Prescribing and the Part D Prescription Drug Program

We discuss the first three of these subjects below, because these are the provisions that relate most closely to drug cost reduction. CMS is accepting public comments on the Proposed Rule until January 25, 2019.

Providing Plan Flexibility to Manage Protected Classes

Current Part D policy requires that Part D plan sponsors include on their formularies, with limited exceptions, all drugs in six categories or classes: antidepressants, antipsychotics, anticonvulsants, immunosuppressants for treatment of transplant rejection, antiretrovirals, and antineoplastics. Theses six categories are commonly referred to as “protected” therapeutic classes. While Part D plan sponsors may use utilization management tools like prior authorization and step therapy for other Part D drugs, they have limited authority to use these tools for drugs in the protected classes and may not exclude such drugs from their formularies. The Proposed Rule would not change the six protected classes, but would provide Part D plans with greater leverage to negotiate discounts for drugs in protected therapeutic classes.

The Proposed Rule would create three exceptions that would allow Part D sponsors to impose formulary actions on drugs in protected classes. First, sponsors would be able to impose prior authorization and step therapy requirements to ensure clinically appropriate use, promote utilization of preferred formulary alternatives, confirm that the intended use is for a protected class indication, or a combination of these three purposes. The prior authorization and step therapy procedures would have to be reviewed and approved by CMS.

Second, a Part D sponsor could exclude from a formulary a new formulation of a single source protected class drug or biological that has the same active ingredient or moiety as the original version and that does not provide a unique route of administration – even if the original drug is withdrawn from the market. The preamble explains that this is intended to discourage manufacturers from introducing a more expensive formulation of a protected class drug while discontinuing the original version. Unfortunately, the proposed rule does not define a new formulation, a term whose meaning is not self-evident. For example, does a new formulation include a new strength? What about new formulations that further an important public policy objective, such as abuse deterrent formulations of opioids – are they to be equally discouraged? Readers familiar with the Medicaid Drug Rebate Program (MDRP) will recall that CMS proposed then later withdrew a convoluted definition of this term under the MDRP, and has not attempted to define it since.

Third, CMS proposes, beginning on or after January 1, 2020, to permit Part D sponsors to exclude from a formulary a protected class single source drug or biological if its WAC has increased, compared to a defined baseline month and year, at a rate greater than the rate of inflation as measured by the Consumer Price Index for all Urban Consumers (CPI‑U). If one NDC for any strength, dosage form, or route of administration of a drug exceeded the price increase limit, all NDCs assigned to the drug could be excluded. Part D sponsors would be responsible for monitoring WAC increases and deciding whether to adopt such an exclusion policy, which would have to be approved by CMS. CMS notes that Part D sponsors would not be required to exclude such drugs from their formularies, but instead could use the threat of exclusion to negotiate rebates for formulary placement.

Step Therapy for Part B Drugs Covered Under Medicare Advantage Plans

The Proposed Rule also would permit Medicare Advantage plans to apply step therapy as a utilization management tool for Part B drugs. This proposal is consistent with an August 2018 memo that rescinded a 2012 prohibition on imposing mandatory step therapy for access to Part B drugs. See Prior Authorization and Step Therapy for Part B Drugs in Medicare Advantage (August 2018). Under the Proposed Rule, Medicare Advantage plans would be required to disclose that Part B drugs may be subject to step therapy requirements in the plan’s Annual Notice of Change and Evidence of Coverage documents. Step therapy would not apply to preferred providers organization plans (PPOs) because PPOs are required to reimburse or cover benefits provided out of network and are prohibited from using prior authorization or preferred items restrictions in connection with out of network coverage. 42 U.S.C. § 1395w–22(e)(3)(iv)(II).

Pharmacy Price Concessions in the “Negotiated Price”

Under Part D the negotiated price is the price that a Part D plan negotiates with a pharmacy as the amount the pharmacy will receive, in total, for a Part D drug, and it is also the pharmacy’s price to the enrollee, upon which the enrollee’s co-insurance is based. The negotiated price is net of price concessions from network pharmacies, except for contingent price concessions that cannot “reasonably be determined” at the point-of-sale. 42 C.F.R. 423.100. Because most pharmacy price concessions cannot be determined at the point of sale, negotiated prices typically do not reflect any performance-based pharmacy price concessions that would otherwise lower the amount a sponsor, and the enrollee, ultimately pays for a drug. CMS is considering eliminating this exception for contingent pharmacy price concessions as soon as 2020 and revising the definition of “negotiated price” to mean the lowest amount a pharmacy could receive as reimbursement for a covered Part D drug under its contract with the Part D plan. In other words, the greatest possible pharmacy price concession would be assumed in the negotiated price, so that the enrollee’s co-insurance would be reduced. Any difference between the negotiated price and the amount the pharmacy was ultimately paid would be captured in “direct and indirect remuneration” (DIR) reporting at the end of the plan year.

This proposal is reminiscent of CMS’ November 2017 request for comments on a proposal to require Part D sponsors, through a future rulemaking, to include in negotiated prices a specified percentage of manufacturer rebates as a point-of-sale rebate. See 82 Fed. Reg. 56336, 56421 (Nov. 28, 2017). Apparently, CMS does not consider that concept to be ripe for a rulemaking, because the new proposed rule makes no mention of it.

*   *   *

This Proposed Rule is the latest in a series of CMS actions under the Trump Administration intended to reduce drug costs under Medicare. Though this Proposed Rule and the November 2017 request for comments on point-of-sale rebates involved Part D, most of the initiatives have addressed drug costs under Medicare Part B, including:

• A November 2017 final rule reducing the Part B payment to hospital outpatient departments for separately payable drugs purchased under the 340B Drug Discount Program from ASP plus 6% to ASP minus 22.5%.
• A July 2018 request for information on a proposal to establish a competitive acquisition program for Part B drugs, which would incorporate formulary tools, indication-based pricing, outcomes based agreements, and other cost-reduction features
• An October 2018 proposed rule requiring direct-to-consumer TV ads for drugs covered under Medicare or Medicaid to contain WAC pricing information (see our blog post here)
• An October 2018 advance notice of proposed rulemaking on using an international pricing index as a benchmark for Part B drug payment (see our post here)
• Two November 2018 final rules (hospital outpatient prospective payment system and physician fee schedule) reducing the Part B drug payment rate for drugs for which no ASP data are available from ASP + 6% to ASP + 3%.

Although these Medicare initiatives began before the HHS Blueprint was issued in May, they have clearly been accelerating since the Blueprint. We will be following these CMS initiatives in this blog.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Anne Walsh will again participate in the Food and Drug Law Institute’s (“FDLI”) Enforcement, Litigation and Compliance Conference this year.  The conference will be held in Washington, DC on December 12-13, 2018.  As a member of the Conference Planning Committee, Ms. Walsh helped set the topics and propose speakers for this year’s conference, and FDLI is excited that keynote speakers will include Scott Gottlieb, FDA Commissioner; James Burnham, DOJ Deputy Assistant Attorney General, Consumer Protection Branch; Stacy Cline Amin, FDA Chief Counsel; and Elizabeth Dickinson, FDA Senior Deputy Chief Counsel and former FDA Chief Counsel.

This conference is attended by experienced professionals in the fields of regulatory, legal, public relations, marketing and management who work in the pharmaceutical, medical device, diagnostic, biologics and veterinary medicine industries. The conference is also beneficial for consultants in the areas of advertising, public relations, law and marketing communications.

FDA Law Blog readers can receive a 15% discount off the conference registration price. To receive the discount, use the following promotional code: Enforcement15.  For more information and to register, click here.

In light of recent criticism of FDA’s oversight of medical devices, it is curious why FDA did not release a report touting the success of its enforcement activities with the same fanfare as its report on its plan to modernize the 510(k) program, which we reported on here. The Medical Device Enforcement and Quality Report (Report), available here, claims FDA’s increased inspections have led to improved compliance by industry. The Report provides five conclusions:

1. The FDA has increased its oversight through additional device inspections.
2. The FDA has taken a targeted, risk-based enforcement approach to address specific device areas of concern.
3. The FDA’s focus on violative products and adverse event reporting during inspections has led to an increase in voluntary recalls and adverse event reporting.
4. Most firms have corrected violations on follow-up inspection.
5. The FDA has taken steps to promote device quality, not just compliance with regulations.

In the first section of the Report, FDA notes that since 2007 there has been a “46% increase in the annual number of device inspections” (from ~2000 inspections in 2007 to 2952 in 2017) and a “243% increase in the annual number of foreign device inspections” during the same time period. Report at 2. FDA also gives itself credit for implementing the Medical Device Single Audit Program (MDSAP), which permits FDA to accept regulatory audits by other jurisdictions. It is unclear how this increased number of inspections corresponds to the total number of registered medical device facilities (i.e., whether FDA is inspecting a greater percentage of registered medical device facilities now than in 2007).

The second section of the Report describes how FDA uses a targeted, risk-based enforcement approach to address issues that FDA identifies through reported malfunctions, industry compliance trends and public health concerns. The report provides three case studies as examples of success stories: infusion pumps, automated external defibrillators (AEDs) and radiation therapy devices. Each case study identifies the numbers of inspections conducted, facilities inspected, and warning letters issued, and highlights improvements in reductions of recalls and adverse events as a result of these actions.

Next, the Report notes that FDA has focused on reporting of recalls as required in 21 C.F.R. Part 806 and reporting of adverse events as required in 21 C.F.R. Part 803 during inspections. FDA concludes that firms are more likely to report recalls and adverse events after receiving inspectional findings. This seems to be an obvious result. The open question remains whether the public is better served by compliance with reporting obligations.

Similarly, the fourth section reports that firms tend to have corrected violations on follow-up inspections. FDA notes that through their increased number of inspections and focus on higher risk device types, “the annual number of Official Action Indicated inspections has increased 59%” and that the number of Warning Letters also increased between 2008 and 2012. Id. at 7. Interestingly, despite seeing positive outcomes from their increased scrutiny, the report indicates that more recently there has been a decrease in the number of Warning Letters issued as FDA is taking a more interactive approach with violative firms. Indeed, FDA issued just 32 Warning Letters to device companies in FY2018; compared to 213 letters issued at the peak in FY2012.

The final section provides an overview of the Case for Quality initiative launched in 2011 to elevate industry’s focus from “baseline regulatory compliance to sustained practices that advance medical device quality and safety to achieve better patient outcomes.” Id. at 8. According to FDA, reports coming out of the pilot program, specifically related to use of a voluntary quality maturity appraisal model, suggest positive outcomes.

Overall, the Report’s message is that enforcement actions are robust and effective. It is unclear whether FDA intends to update this report annually, using other case studies to support effectiveness of its efforts. Firms should continue to be diligent in ensuring compliance and inspection readiness and may also benefit by looking beyond regulatory compliance to further promote device quality.

On November 6, we reported that the Health Resources and Services Administration of the Department of Health and Human Services (HHS) had proposed to move up the effective date of its 340B program ceiling price and civil monetary penalties regulation from July 1 to January 1, 2019. After reviewing comments on the proposal, many of which were critical of the acceleration, HHS has stuck to its guns, finalizing the January 1 date today.

HHS has subjected manufacturers to regulatory whiplash. After delaying the effective date of this January 5, 2017 rule five times over the past two years for vague reasons, the department is suddenly in a rush to make it effective – possibly prompted by a lawsuit brought by hospitals and hospital associations. January 1 is only 33 days away. Some manufacturers asked for a delay of two quarters because the abrupt acceleration of the effective date makes it difficult for companies – especially smaller ones – to upgrade their operational systems in time for January 1 compliance. Others commented that HRSA itself is not ready – the agency has not yet operationalized its on-line reporting system so that manufacturers will be able to report 340B ceiling prices, as required by the regulation, by January 1. To the first point, HHS responded that the two-year period since the rule was finalized has given stakeholders sufficient time to adjust their systems. To the second, HHS notes that it “plans to release the 340B ceiling pricing reporting system shortly and HHS will communicate further information through its website.”

On November 7, the FDA announced that it is seeking approval for a web-based pilot survey about allergens in cosmetics, including fragrances, hair products, makeup, nail products and skin care products.  The federal register notice was published on Nov. 8, 2018.

The survey is part of FDA’s efforts to learn more about allergens in cosmetics. Although FDA receives information about adverse reactions to cosmetics via the voluntary reporting to Center for Food Safety and Applied Nutrition (CFSAN) Adverse Events Reporting System (CAERS), the Agency believes these reports are an underestimate of the incidence of allergic and other reactions to cosmetics. The objective of the proposed survey is to collect information needed for a more current understanding of the prevalence of adverse reactions to cosmetics, consumer awareness of the problem, and actions (if any) consumers take to avoid allergens, e.g., purchasing hypoallergenic cosmetics, avoidance of cosmetics containing fragrances.  The survey is a pilot scheduled to cover 1000 adult consumers.  The proposed survey is available in the docket.  FDA requests feedback on four topics:

1. whether the proposed collection of information is necessary for the proper performance of FDA’s functions, including whether the information will have practical utility;
2. the accuracy of FDA’s estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used;
3. ways to enhance the quality, utility, and clarity of the information to be collected;
4. ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology.

Comments must be submitted by Jan. 7, 2019.

On November 5, 2018, FDA issued its latest UDI policy “Unique Device Identification: Policy Regarding Compliance Dates for Class I and Unclassified Devices and Certain Devices Requiring Direct Marking,” deferring enforcement of direct marking deadlines. The new guidance, effective immediately, supersedes the guidance issued in January, previously discussed here.  The guidance document is largely unchanged, other than with respect to direct marking deadlines, as noted below.

Despite the best intentions, and unsurprisingly for industry, the implementation of FDA’s UDI system has been exceedingly complex. As a result, FDA is prioritizing its enforcement of various deadlines.  Specifically, FDA does not intend to enforce UDI direct mark requirements for Class III, life-saving or life sustaining, and Class II non-sterile devices that were manufactured and labeled prior to the UDI compliance deadline and remain in inventory, as long as the UDI can be derived from other information on the device.  This can be through a catalog number, lot number, serial number, or something similar.  FDA expects this information to be documented in the Global UDI Database (GUDID), which will be updated to include new fields to capture this information.

Although the direct mark compliance deadline for Class I and unclassified devices is September 24, 2020, FDA likewise does not intend to enforce UDI direct mark requirements for those devices until September 24, 2022. Moreover, as with the higher classification devices, FDA will not enforce UDI direct mark requirements for devices that are manufactured and labeled prior to the compliance deadline and remain in inventory, where the UDI can be derived from other information on the device.

With this enforcement policy, FDA has acknowledged that some devices can remain in inventory for relatively extensive periods of time, and has adjusted its enforcement expectations accordingly. The new guidance is effective immediately.  Although FDA will accept comments through electronic submission at www.regulations.gov, there is no official comment period, and FDA is not required to address them.