A week before Christmas, CDRH issued a revised draft of the Replacement Reagent policy. When finalized, the revised draft guidance will replace the 2003 final guidance. According to FDA, the revised guidance “is intended to update and provide clarity on” the existing policy. FDA has long commented that the 2003 guidance was overused and often misunderstood. As discussed below, the draft guidance that will replace the existing Replacement Reagent policy takes a more limited view of the replacement reagent policy. This means that fewer reagent instrument combinations will be able to enter the market via this approach. It is somewhat ironic then that the guidance states, in its introduction, that this revised policy “is important for public health as it promotes more timely availability of a wider array of clinical laboratory tests for patient benefit.” In fact, it appears likely to have the opposite effect.

At a high-level the policy is unchanged, 510(k)-cleared reagents can be used on certain additional instruments that were not included in the reagent 510(k) without the need for a new 510(k).  Specifically, the additional instruments can include:

1. 510(k)-cleared instruments that were not included in the reagents 510(k) clearance; and
2. instruments in the same instrument family as the instruments on which the reagents were validated in their 510(k).

The guidance does not apply to certain assays, including Class III devices, point-of-care devices, and prescription home use devices, among others.  The new policy notes that certain assay-specific guidances exclude application of the Replacement Reagent policy, for example, the clinical multiplex test system guidance.  The revised draft guidance also excludes “modifications other than application of a cleared assay to a new instrument.”  This exclusion is modified from the 2003 policy, which stated “changes in the intended use of a cleared product.”  The exclusion in the proposed policy is significantly broader and could exclude minor modifications that would not otherwise require a 510(k) clearance (e.g., a minor change to the 510(k) cleared reagents that is unrelated to the application of the reagents to the new instrument platform).  Thus, at the outset, the policy appears to be more limited in scope than the original guidance meaning that fewer assays will be eligible.

In addition, the revised draft guidance notes that the policy has been historically applied to traditional laboratory automated chemistry systems and immunoassays.  The guidance indicates that manufacturers can contact FDA regarding the policy’s applicability to “evolving technology” (e.g., via the pre-sub process).  It is unclear, however, how FDA defines an “evolving technology.”  Is it any technology other than traditional laboratory automated chemistry systems and immunoassays?  There are many well-known technologies in this category, for example, liquid chromatography and mass spectrometry.  Or something truly new and not yet known?  In short, the revised draft guidance may apply to a narrower subset of the universe of instruments than its erstwhile predecessor.  This exclusion for “evolving technology” appears to even further limit the scope of the guidance.

While the broad objective of the draft policy is fundamentally the same as the 2003 version, the revised draft does include a new recommendation that the manufacturer seeking to apply the policy perform a risk assessment of the change.  The risk assessment is intended to identify the risks associated with applying the 510(k)-cleared reagents to a new instrument.  These risks and associated verification and validation results will be used to determine whether the proposed change fits within the Replacement Reagent policy or if a new 510(k) is required.  This approach is consistent with the new, final guidance “Deciding When to Submit a 510(k) for a Change to an Existing Device,” but adds a layer not found in the current policy.

The revised draft policy also provides specific suggested tests to be performed as part of the verification and validation of the cleared assay on a new instrument.  The guidance also notes, “if an updated, FDA-recognized standard or guidance has been published since the time of assay clearance, it is preferable that the manufacturer follow this; however, it is also acceptable to use the same standard or guidance that was followed to support the cleared 510(k).”  This could be a dangerous suggestion – what if an assay does not pass the updated standard but does pass the original standard?  Will the policy still apply?  It is unclear and could become a problem for companies seeking to utilize this policy for their assays.

For the Instrument Family Policy to apply, an instrument must be in the same family as the cleared instrument, including sharing a common design history file.  The revised draft guidance makes clear that instruments in the same family are essentially just iterations of the same original instrument. The guidance “encourages” communication between the reagent and instrument manufacturers, when they are not the same company.  However, without a formal relationship, the reagent manufacturer may have trouble knowing if one instrument is in the same family as another.  We anticipate that, particularly for assay-only manufacturers, that this will further limit the ability for companies to utilize this policy.

The new draft guidance replaces the flowcharts in the 2003 guidance with numerous examples.  The guidance also provides additional recommendations as to how to present information in a CLIA categorization request when an assay and instrument combination enter the market through this policy.  While the guidance does provide some additional useful information, the scopes appears to be so much more limited and the requirements more burdensome now that its utility will yet to be seen.

As stated in our blogpost discussing FDA’s announcement of 2018 Compounding Policy Priorities (here). FDA also released its Final Guidance on Compounding “essentially copies” of commercially available drugs.  This long-anticipated guidance discusses how FDA intends to determine whether a compounded drug is essentially a copy of a commercially available drug product.  We discuss each Final Guidance separately below.

Essentially Copies Under Section 503A

FDA’s Final Guidance for traditional, Section 503A pharmacy compounders does not read that differently from the draft guidance, which we blogged about here.

The Final Guidance does, however, contain a handy flow chart (similar to the chart FDA included in the 503B draft guidance) that enables the reader easily to review FDA’s criteria for what it considers is essentially a copy and make a determination whether a compounded product meets the guidance’s criteria. FDA states in a footnote that it also considering “the applicability” of the guidance to hospitals and health systems, and will address that issue in a separate guidance or rulemaking, thus telegraphing that the Agency will potentially adopt a different “essentially copies” analysis for compounding for those entities.

The Final Guidance does not change the definition of what it considers a “commercially available drug product” (i.e., considering whether a product is no longer commercially marketed (excluding for reasons of safety or effectiveness) and Section 506E shortage drugs).  It also does not change what it considers “essentially a copy” of a commercially available drug product, using the same test set forth in the draft guidance:

• the compounded drug product has the same active pharmaceutical ingredient (API);
• the APIs have the “same, similar or easily substitutable strength”; and
• the products can be used by the same “route of administration.”

If the compounded formulation meets ALL three of these criteria, then the compounded product is “essentially a copy” of a commercially available product and can only be compounded in small amounts as described in the Final Guidance.  Concerning similar dosage strengths, and despite several comments addressing the issue, FDA left in the Final Guidance its “10% statement:” “FDA generally intends to consider two drugs to have a similar dosage strength if the dosage strength of the compounded drug product is within 10% of the dosage strength of the commercially available drug product.”  And, notably, if the commercially available drug has to be “split” and the tablet is not suitable for splitting, FDA would not consider the compound made to the prescribed dosage strength to be “easily substitutable.”  FDA also maintained its limitations in the Final Guidance concerning compounds that have the same characteristics as two or more commercially available drug products, notwithstanding some industry confusion concerning permissible conduct when compounding multiple ingredients in the same, similar or easily substitutable strength that are also separately commercially available.  The Guidance also again makes clear that price alone is not sufficient to render a product outside the essentially copies prohibition.

The Final Guidance also does not substantively differ from the draft concerning the required “statement of significant difference” when copying commercially available drug products. With respect to whether a compounder is compounding “regularly or in inordinate amounts,” FDA’s final position is also consistent with statements in the draft guidance, including considering permissible compounding “four or fewer” prescriptions of essentially copies in a calendar month.  FDA does not consider any prescription that notes a “significant difference” to be essentially a copy; thus those prescriptions would not be counted in the four-prescription limit.  FDA recommends that pharmacies maintain records documenting statements of significant difference for a period of at least three years.

Essentially Copies Under Section 503B

Notwithstanding dozens of comments from industry, like the Section 503A essentially copies Final Guidance, the Section 503B Final Guidance is not substantially different from the draft guidance that FDA released in 2017, and blogged about here.   FDA adds that it does not intend to take enforcement action against an outsourcing facility for failing to compound in accordance with section 503B(a)(5) if it fills orders for a compounded drug that is essentially a copy of an approved drug that has been discontinued and is no longer marketed.  FDA does not clarify whether these compounds would be limited to those drugs made with substances on FDA’s bulks list 1 (or the bulks list FDA intends to finalize through regulations), however.

FDA is considering the same factors to determine whether the compounded product is identical or nearly identical to the approved drug where ALL of the following are the same:

• active ingredients;
• route of administration;
• dosage form;
• dosage strength; and
• excipients.

Unlike the draft, the Final Guidance adds the following concerning “route of administration:” If the approved drug can be used (regardless of how it is labeled) by the same route of administration prescribed for the compounded drug, FDA intends to treat the “compounded drug as though it has the same route of administration for purposes of this analysis.  For example, if the approved drug is an injectable drug sold in a vial that is labeled for intra-muscular use, but this drug can also be drawn from the vial by a smaller needle for subcutaneous administration, a compounded drug product sold in a similar vial and prescribed for sub-cutaneous use would be considered to have the same route of administration under this analysis.”  In contrast to “essentially copies” under Section 503A (where FDA does not define “identical” or “nearly identical”), if a compounded drug product is “identical” or “nearly identical” to the commercially available drug product, the fact that a prescriber makes a determination of significant or clinical difference is of no matter – such a product may not be compounded under Section 503B unless there is a drug shortage. Like Section 503A, however, FDA does include a footnote that seemingly permits compounding drug products have been discontinued (or never marketed) for reasons other than safety or effectiveness.

Other provisions of the Section 503B “essentially copies” guidance have not changed between the draft and the Final Guidance, other than FDA’s recommendation that a facility keep records demonstrating the clinical difference determination for a period of at least three years. Like in the draft guidance, the Section 503B Appendices setting forth how FDA intends to determine whether a compounded drug product is essentially a copy of a commercially available drug product under Section 503B are attached here.

In 2015, FDA proposed to revise the intended use regulations, which describe how the agency determines the intended use of a drug or device, including the types of evidence that may be considered. FDA’s proposed rule would have deleted the infamous “knowledge” sentence, which could be read to say that a firm’s knowledge of off-label use by clinicians can be a basis for FDA to infer intended use. We explained the problem and praised the proposal to delete the sentence in a this blog post.

The seemingly sensible reform in the proposed rule did not take place. Instead, in early 2017, FDA issued a final rule that shockingly did not delete the knowledge sentence. Instead, the final rule amended it to introduce a new and problematic “totality of the evidence” standard. (FDA insisted that the purpose of the amendment was merely to clarify existing administrative practice.) We commented in a blog post here.

Fortunately, the rule was caught up in the new Trump administration’s initial regulatory freeze, and then a further delay until March 19, 2018 was announced. Now, FDA proposes an indefinite delay to re‑evaluate the final rule, and in particular, 13 follow‑on comments and an industry petition. (The press announcement is here.) FDA summarizes the comments as alleging that the amended knowledge sentence: violates the First Amendment, the Fifth Amendment, and the Administrative Procedure Act (APA); is an interference with the practice of medicine; is unsupported by the text or legislative history of the Federal Food, Drug, and Cosmetic Act; and is unsupported by case law or past practice. FDA indicates that it needs more time to fully consider these issues.

We support the delay. These issues are too important for the drug and device industries, and for clinicians and patients. FDA should take the time to get it right. We urge interested parties to comment in support of the proposal. Comments are due by February 5, 2018, and there will be no extensions granted, in order to ensure time to consider the comments before the current March 19, 2018 implementation date.

Ultimately, it would be best if FDA returns to the original proposal and deletes the knowledge sentence. If FDA wishes to go further than that, it might consider our recommendations for an overhaul of the intended use regulations, as described here. But even if the agency simply returns to the more limited 2015 proposal, that would be an important step forward.

Last week FDA announced the release of its 2018 “Compounding Priorities Plan.” FDA also released several guidance documents in the wake of its announcement, such as its final guidance on essentially copies of commercially available drug products for Section 503A and 503B facilities (more on that in another blog post), and guidance on repackaging of biologic products outside of an approved BLA. FDA notes that “Our 2018 compounding policy priorities plan lays out how the agency will implement certain key provisions of DQSA and other provisions of the law relevant to compounders over the course of the coming year. Our policy will be part of a series of draft and final guidance documents, proposed and final rules and a revised draft memorandum of understanding (MOU) between the FDA and the states.” FDA is indeed busy in this area. The priorities include the following:

Risk Based Approach to Manufacturing Standards for Outsourcing Facilities

FDA states its policy goal is to make it more efficient and lower cost for more compounding pharmacies to “voluntarily meet the higher production standards for 503B outsourcing facilities as a way to promoted more patient access to higher quality compounded medications.” Is FDA describing a “503B lite” standard for certain compounders that the Commissioner Gottlieb hinted at last fall? Likely so. FDA states that it plans to issue proposed regulations addressing cGMP requirements for outsourcing facilities. In the meantime, however, it intends to issue revised guidance for cGMP – considering how it should apply quality standards given the differing size and scope of compounding operations. FDA’s stated goal of these new requirements is to cajole more compounders to register as outsourcing facilities. FDA states that the new draft revised cGMP guidance “will address standards critical to producing a high-quality product,” while “balancing appropriate flexibility.”

Restricting Compounding of Drugs that are Essentially Copies of FDA-Approved Drugs

FDA announced the release of two Final Guidance Documents (here and here) on compounding essentially copies of commercially available drugs.

Although the Final Guidance documents do not seem to be materially different than what FDA released in draft form last year, FDA states that, as it moves forward with implementation and enforcement, the Agency “intends to focus its initial efforts on education and outreach” to practitioners and prescribers of compounds, who can determine whether the compounded product produces a significant or clinical difference for the patient than the commercially available product. FDA also states it intends to prioritize review of those situations that will adversely impact the public health “such as compounding a drug using a bulk substance to produce a product than can otherwise be made by diluting an FDA-approved FDA drug according to its labeled instructions.”

Regulating Compounding From Bulk Substances

Not mentioning the litigation that FDA is facing in the D.C. District Court concerning whether its Interim Bulks Policy violates the Administrative Procedure Act, FDA discusses the “temporary” approach it took when implementing the interim bulks list for both 503A and 503B compounding in 2015, pending promulgation of the required final rule setting forth bulk substances that may be used in compounding. FDA again warns that it is exercising enforcement discretion concerning substances on the bulks lists. It also states that it will continue to promulgate regulations under 503A (as it did in December 2016 addressing ten substances). For 503B, FDA will issue (in March 2018), a draft guidance setting forth (for a third time…) criteria for making clinical need determinations for the list. FDA states it intends to address concerning about compounding from bulk substances when the drug can be compounded from FDA-approved drugs. FDA emphasized that bulk drugs will be placed in the 503B bulks list only “when there is a clinical need to compound drugs using these substances.” It will be interesting to see whether FDA will require renominations of substances already on 503B’s Bulks List 1.

Solidifying FDA’s Partnership with State Regulatory Authorities

FDA’s announcement hints that a revised MOU under Section 503A between FDA and states (again in draft form) is forthcoming. FDA states that it will clarify “inordinate amounts” shipped interstate by a compounder if the “number of prescriptions of compounded drugs distributed interstate during any calendar month is greater than 50 percent.” Importantly, instead of that number serving as a “hard limit, for state action,” the 50 percent target will trigger certain reporting requirements. The new MOU will also provide states more time to report to FDA, and flexibility on identifying when amounts are inordinate, considering the size and scope of compounding operations.

Finalization of Biological Products Guidance and Clarifying Other Policies on Activities that Compounders Undertake

FDA’s biological products guidance was the subject of many comments, especially surrounding beyond use dating of these compounded products. FDA announced that the new guidance is a “good example” of FDA’s consideration of feedback in development of policies. The final guidance describes a mechanism for outsourcing facilities to assign beyond use dates (BUDs) to repackaged biological products that exceed the “default” BUDs of 24 hours based on a “science and data-driven policy approach” to “support patients and their clinicians, while also protecting public health.”

Miscellaneous

Last but certainly not least, FDA states that it will issue guidance clarifying its “facility” guidance, and will address whether an outsourcing facility can be co-located with a Section 503A pharmacy (we thought the answer was “no” based on earlier draft guidance, here).  FDA will also soon issue long awaited guidance on repackaging radiopharmaceuticals by a state-licensed pharmacies and outsourcing facilities. FDA will also reissue guidance describing “insanitary” compounding conditions. Importantly, the insanitary conditions guidance will address concerns raised by pharmacies or prescribers that compound small quantities of drugs. FDA plans to “better define the circumstances” under which it believes drugs are being mixed and applied in a manner that creates “a negligible patient risk” (and thus such entities will not be subject to the same compliance policy under FDA’s risk-based enforcement approach). FDA will also update its rule setting forth withdrawn or removed drugs for reasons of safety or effectiveness.

Phew… looks like FDA’s compounding folks are in for an extremely busy 2018.

On December 29th, the Drug Enforcement Administration (“DEA”) published notice of its intent to temporarily control fentanyl-related substances that are not currently regulated under the Controlled Substances Act (“CSA”).  Schedules of Controlled Substances: Temporary Placement of Fentanyl-Related Substances in Schedule I, 82 Fed. Reg. 61700 (Dec. 29, 2017).  DEA has temporarily scheduled other substances fentanyl-related substances over the past four years, including cyclopropyl fentanyl on January 4, 2018. Schedules of Controlled Substances: Temporary Placement of Cyclopropyl Fentanyl in Schedule I, 83 Fed. Reg. 469 (Jan. 4, 2018).  However, as DEA notes these prior scheduling actions have not proven effective because  when it temporarily schedules a fentanyl-related substance, illicit manufacturers abroad structurally modify the substances and smuggle them into the U.S. and distribute them as non-controlled substances.  Also, the alternative of attempting to prosecute these individuals under the controlled substances analogue statute is difficult. Temporary Placement of Fentanyl-Related Substances, 61701 n.3.  This does not affect the scheduling of already approved fentanyl pharmaceutical products that are FDA-approved and currently regulated/scheduled by DEA.

DEA is now attempting to temporarily schedule fentanyl-related products by defining the class of products in such a manner so as to be broad enough to effectively capture any fentanyl-products being illicitly manufactured. Previously, the agency has had to schedule each substance based on its chemical make-up to ensure it met the legal definition of a controlled substance.  In almost all cases, the CSA controls a drug or substance by its specific formulation.  In this case, DEA is attempting to control a substance based on a definition of its potential formulation.

DEA’s notice states that deaths associated with the abuse of substances structurally related to fentanyl in the U.S. have reached an alarming level. DEA asserts that “chief among the causes is the sharp increase in recent years is the availability of illicitly produced, potent substances structurally related to fentanyl.” Fentanyl is about a hundred times more potent than morphine and the substances subject to temporary control are typically manufactured outside the U.S. by clandestine manufacturers and smuggled into the country and are often mixed with heroin, cocaine and methamphetamine or used in counterfeit pharmaceutical prescription drugs.

None of the affected fentanyl-related substances have an accepted medical use in the U.S. nor are they the subject of an exemption or approval under section 505 of the Food, Drug and Cosmetic Act. Fentanyl-related substances subject to exemption or approval will be excluded from the temporary scheduling order.

DEA’s attempt to create a definition for such substances includes the temporary scheduling of any non-controlled substance not assigned a DEA Controlled Substance Code Number that is structurally related to fentanyl by any one or more of the following specific modifications:

1. Replacement of the phenyl portion of the phenethyl group by any monocycle, whether or not further substituted in or on the monocycle;
2. Substitution in or on the phenethyl group with alkyl, alkenyl, alkoxyl, hydroxyl, halo, haloalkyl, amino or nitro groups;
3. Substitution in or on the piperidine ring with alkyl, alkenyl, alkoxyl, ester, ether, hydroxyl, halo, haloalkyl, amino or nitro groups;
4. Replacement of the aniline ring with any aromatic monocycle whether or not further substituted in or on the aromatic monocycle; and/or
5. Replacement of the N-propionyl group by another acyl group.

As noted above, this is a different approach to scheduling and we will see if these definitions can withstand the expected challenges from defense attorneys related to whether this type of scheduling is consistent with the CSA.

DEA will publish the scheduling order in the Federal Register on or after January 29, 2018 and it will be effective immediately. Temporary scheduling will last for two years, but DEA can extend it for an additional year if proceedings to permanently schedule the substances are pending.

As we previously reported, in October 2017, the New Jersey Attorney General and Division of Consumer Affairs issued a proposed rule in response to concerns about the amount of money being paid to prescribers in the state of New Jersey. On December 22, 2017, the Attorney General finalized the rule, which is entitled “Limitations On and Obligations Associated with Acceptance of Compensation from Pharmaceutical Manufacturers by Prescribers” (N.J.A.C. 13:45J). The rule applies to all New Jersey prescribers (i.e., physicians, podiatrists, physician assistants, advanced practice nurses, dentists, and optometrists). It became effective on January 16, 2018, and does not apply to contracts entered into on or before January 15, 2018.

To assist our readers, we provide here the text of the final rule, which is compiled from the proposed rule and the revisions that were published in the New Jersey Register.

Under the final rule, New Jersey prescribers may not accept the following from pharmaceutical manufacturers or manufacturer’s agents:

• Any financial benefit or benefit-in-kind, including, but not limited to, gifts, payments, stock, stock options, grants, scholarships, subsidies, and charitable contributions, except as specifically permitted by the rule.
• Any entertainment or recreational items, such as tickets to theater or sporting events, or leisure or vacation trips.
• Items of value that do not advance disease or treatment education, including, but not limited to,
  • Pens, note pads, clipboards, mugs, or other items with a company or product logo;
  • Items intended for the personal benefit of the prescriber or staff, such as floral arrangements, sporting equipment, artwork;
  • Any payment in cash or cash equivalent; and
  • Items that may have utility in both the professional and non-professional setting, such as electronic devices.
• Any payment or travel expenses for attending an education event or promotional activity as non-faculty.

Under the final rule, New Jersey prescribers may accept the following permitted gifts and payments from pharmaceutical manufacturers or manufacturer’s agents:

• Items designed primarily for educational purposes for the patients or prescriber that have minimal or no value to the prescriber outside of his/her professional responsibilities. Items that may have independent value to the prescriber may only be accepted if the items are used by patients and remain in the common area of the prescriber’s office.
• A subsidized registration fee at an education event, if that fee is available to all participants.
• Modest meals, worth no more than $15 per prescriber, provided by the event organizer at an education event, if the meals facilitate the educational program to maximize prescriber learning.
• Modest meals, worth no more than $15 per prescriber, provided by a manufacturer to non-faculty prescribers at a promotional activity.
• Compensation, based on fair market value, for providing bona fide services as a speaker or faculty organizer or academic program consultant for an education event or promotional activity, or for participation on advisory bodies or under consulting arrangements. A prescriber may also accept reasonable payment for travel, lodging, and other expenses associated with such services.
• Reasonable payment for travel, lodging, and other expenses in connection with research activities.
• Reasonable payment to prospective applicants for travel, lodging, and other expenses in connection with employment recruitment.
• Royalties, licensing fees, or other arrangements regarding the purchase of intellectual property rights from a prescriber.
• Sample medications intended to be used exclusively for the benefit of the prescriber’s patients.

The rule imposes a limit of $10,000 per calendar year on the amount of compensation that a single prescriber may receive in the aggregate from all pharmaceutical manufacturers for speaking at promotional activities, participation on advisory boards, and consulting arrangements. Payment for speaking at education events are not subject to the $10,000 cap but must be fair market value and set forth in a written agreement. In addition, payments for research activities, royalties and licensing fees are not subject to the $10,000 cap. Under the final rule, research includes pre- and post-market activities that study or assess the safety or efficacy of prescribed products as well as scientific advising on the development, testing, and evaluation of prescribed products.

Although many commenters expressed concern about the $15 per prescriber limit for meals, the Attorney General declined to eliminate or revise this limit, and disagreed with the commenters’ assessment that $15 is an unreasonable limitation on the cost of meals provided to prescribers.

As we previously noted, this rule does not impose penalties on, or otherwise increase the state’s authority over, pharmaceutical manufacturers and wholesale distributors (who are included in the definition of pharmaceutical manufacturer). Rather, the rule provides the various New Jersey prescriber licensing boards with authority to take enforcement action against prescribers who accept prohibited gifts or payments from pharmaceutical manufacturers.

Even though the state’s authority over pharmaceutical manufacturers has not expanded, the limitations in the final rule will impact how manufacturers interact with prescribers licensed by New Jersey. Under the rule, prescribers are responsible for independently monitoring their payments from pharmaceutical manufacturers to ensure compliance with the rules. However, prudent manufacturers may want to ensure that the payment limits in the rule are not exceeded in order to prevent their prescriber speakers, advisors, and consultants in New Jersey from incurring sanctions.

For the same reason, pharmaceutical manufacturers will want to ensure that their written agreements with prescribers for bona fide services comply with the rule by:

• Specifying the services to be provided and the dollar value of the prescriber’s compensation based on the fair market value of the services;
• Specifying that meetings held in association with bona fide services occur in venues and under circumstances conducive to the services provided and that the activities related to the services are the primary focus of the meeting; and
• Identifying the following:
  • The legitimate need for services in advance;
  • The connection between the competence, knowledge, and expertise of the prescriber and the purpose of the arrangement;
  • How participation of the prescriber is reasonably related to achieving the identified purpose;
  • The manner by which the prescriber will maintain records concerning the arrangement and the services provided by the prescriber; and
  • An attestation that the prescriber’s decision to render the services is not unduly influenced by a pharmaceutical manufacturer’s agent.

On January 4, the Federal Trade Commission (FTC) announced the release of a new guidance by FTC staff concerning Multi-Level Marketing (MLM). The guidance, in the form of questions and answers, addresses issues relevant for businesses evaluating their compliance with the FTC Act.

Multi-level marketing is a business model used in a wide variety of industries, including the dietary supplement and cosmetic industries. Generally, an MLM distributes products (or services) through a network of individuals.  These individuals essentially comprise the sales force.  They are not employees but independent contractors.  The business model relies on the sales people not only selling product but also recruiting additional individuals who, in turn, want to sell products and also recruit additional sales people.  Thus, the model results in multiple “levels” of distributors/members/participants.

The FTC has a long history of challenging unfair and deceptive MLM practices. Recent actions regarding MLM practices concerning dietary supplement companies include actions against HerbaLife International of America (July 15, 2016), and Vemma Nutrition Comp. (Aug. 26, 2015). The orders in these cases, as well as other  FTC documents, e.g., a 2017 letter by former FTC Chairwomen Edith Ramirez provide insight into FTC’s expectations regarding a lawful MLM business. The newly released Guidance memorializes and expands on the principles set forth in these documents and clarifies the factors that the FTC will consider in assessing whether a company has committed unfair and deceptive acts or practices in violation of the FTC Act.

Whether an MLM is lawful is a fact-specific determination. For FTC, primary issues are the compensation structure (which should be based on actual sales to actual consumers (rather than on purchases by distributors)) and the representations of earning potential by distributors/members/participants.  The guidance addresses specifics such as “internal consumption” (consumption by the distributors themselves), what evidence is needed to validate that sales are indeed retail sales and income and business opportunity claims used to recruit new distributors.  The guidance also addresses compliance programs.  An MLM should develop a compliance program.  The program should include monitoring of distributors/participants to ensure they also comply with applicable policies and procedures, particularly those related to claims, sales validation, and other consumer protection-oriented policies.

The guidance serves as an important reminder for MLM businesses. Companies would be well-served to (re)evaluate their business practices and compliance programs in light of the new guidance and other FTC materials, including the FTC orders.  (Unfortunately, the guidance does not link to that information.)

The guidance is final. It summarizes existing law or FTC cases, and provides tips and advice to consumers and businesses but is not itself binding.

On December 20, FDA issued a new, draft guidance, “Medical Device Accessories – Describing Accessories and Classification Pathways.”  This guidance is the latest chapter in the years-long, and still on-going, story of accessory classification. As you may recall, Congress and FDA have both been working for years to revamp how accessories are classified.  The 21st Century Cures Act (Cures Act), signed into law in December 2016, required that accessories be independently classified from the parent device.  The Food and Drug Administration Reauthorization Act (FDARA), signed into law in August 2017, went a step further, specifying a process for such classification and re-classification or accessories previously classified based on the parent device with which it is used.

It is impressive that after a mere four months, FDA has issued a draft guidance that complies with the new statutory provision. Below, we provide historical perspective on why the accessory classification process needed changing as well as commentary on the draft guidance.

In short, the guidance is a clear restatement of the statutory requirement and lays out a good framework on which industry can comment. In our view, additional clarification and details, beyond the statutory requirements, should be included in the final guidance.

Historical Background

As we have previously discussed in our earlier posts (here, here, and here) regarding the Agency’s classification of accessories, FDA has historically classified accessories in one of two ways: (1) according to the parent device’s classification (either by express inclusion in the classification regulation or by clearance or approval of an accessory under the parent device’s classification regulation); or (2) by establishment of a separate classification regulation specific to the accessory type. This classification scheme led to a number of issues.  With regard to accessories classified according to the parent device’s classification were, in at least some instances, being over-regulated.

The Cures Act and FDA’s 2016 Guidance

The Cures Act has a provision directing the Agency to “classify an accessory . . . based on the intended use of the accessory, notwithstanding the classification of any other device with which such accessory is intended to be used.” FDA finalized the guidance, “Medical Device Accessories – Describing Accessories and Classification Pathway for New Accessory Types,” later in the same month that the Cures Act was passed.  (2016 Guidance)

The 2016 Guidance acknowledged that some accessories present less risk than the parent device with which they are used and should not, accordingly, be automatically placed in the same class as the parent device.  The 2016 Guidance recommended that sponsors utilize the de novo process for new types of accessories (i.e., not yet classified) for which the risk is less than the parent device.

The Cures Act and the 2016 Guidance only addressed new, not yet classified, accessories. Neither addressed the large body of accessories classified prior to passage of the Cures Act.  The only option for reclassification of these accessories would be to submit a petition for reclassification under 21 C.F.R. § 860.123.  Petitions for reclassification are seldom used and the Agency is typically slow to respond.

FDARA and FDA’s 2017 Draft Guidance

FDARA, in part, sought to solve this problem of previously classified accessories. FDARA established an 85-day process for re-classifying accessories based on their risk, separate from the parent device with which they are used.  This is a new submission type not previously implemented at FDA.  In addition, for accessories previously classified according to the parent device with which they are used, by August 2018, and at least once every 5 years thereafter, FDA is now required to publish a list of accessories that it determines are suitable for classification into Class I.

FDARA also created a new streamlined process for classifying new accessories separately from, but concurrently with the parent device. For accessories not previously classified, when a sponsor submits a 510(k) or PMA for a parent device with an accessory, the sponsor may include a request for classification of the accessory based on its risk.  FDA’s clearance or approval letter shall include a granting or denial for the sponsor’s request.

The 2017 draft guidance indicates how FDA will implement the revised statutory provisions in FDARA. Specifically, Section VI of the guidance reiterates the two new accessory classification request pathways created by FDARA.  FDA plans to track both types of requests as pre-submissions.  While pre-submissions by their nature are non-binding, it appears this will simply be for tracking purposes because the output of an accessory classification request will be a classification order.  Administratively, it is not clear how this will work.  At a minimum, under the statute, FDA has authority to issue a classification order in response to an accessory classification request.  We assume this order will be published in the Federal Register, like administrative classification and reclassification orders permitted under FDASIA.  However, the timing for issuance of the public order is unclear.  Pre-Submissions are generally non-public, unlike other premarket submissions, the output of which are made public on FDA’s website.  However, the output of this new type of Pre-Submission will be important to both the applicant as well as the general public.  We hope that the final guidance provides additional clarity regarding how and when it will make publicly available the output of accessory classification requests that are done solely through the pre-submission process.

The guidance also strongly recommends that manufacturers submit a pre-submission prior to seeking reclassification or classification of an accessory through either of the new pathways. Yes, you read that correctly, a pre-submission to a pre-submission.  Everyone loves the pre-submission program!

With regard to reclassification of accessories previously classified under a parent device’s classification, applicants can submit an “Accessory Request” for reclassification under a lower regulatory classification. The draft guidance provides very high level recommendations as to the type of information that should be included in such a request.  FDA has 85 days from receiving an Accessory Request in which to review and approve or deny it, as required by statute.

With regard to new accessories, an applicant can submit a request for classification together with a premarket submission (e.g., 510(k), PMA, de novo) for the parent device for which the accessory is intended for use (a “New Accessory Classification”). The classification request would identify a lower classification than the classification of the parent device under review.  For example, a classification request in a PMA might explain why an accessory used with the parent device that is the subject of the PMA is appropriately classified as Class I or II.  The draft guidance provides very high level recommendations as to the type of information that should be included in such a classification request.  FDA will grant or deny the classification request when it clears or approves the premarket submission.  If the request is denied, the accessory will be considered cleared or approved with the parent device in its same classification.

Because the request must be submitted with the parent device’s premarket submission, it appears this process will only benefit accessories owned or manufactured by the parent device company or those accessory manufacturers with a cooperative relationship with the parent-device manufacturer. Manufacturers of new accessories that do not have a relationship with the parent device manufacturer may utilize the de novo process to seek classification of their accessories.  This may sound like a minor procedural difference; however, there are no user fees associated with the classification request included with the parent device submission and the de novo user fee is $93,229 ($23,307 for a small business).  Thus, there is a significant financial savings by submitting for classification as part of the parent device submission and potentially more expeditious (MDUFA goal of 150 days for a de novo as compared to 90 days for a 510(k) or 180 days for a PMA).  It is unclear as to how difficult the burden of each submission will be because the 2017 draft guidance does not provide great insight into the type of information necessary to support a classification request.

One important clarification that will be needed for the New Accessory Classification requests is what constitutes “the parent device submission.” Does it mean the first time a parent device is submitted to FDA (e.g., an original PMA or 510(k)) or could it be a change to an existing device (e.g., a PMA supplement or Special 510(k))?  If it is the latter, a PMA Supplement that proposes a Class I or Class II classification for a new accessory or a Traditional or Special 510(k) for a Class I accessory would be far less expensive than a de novo.  We think it would be advisable for FDA to clarify this point in their final guidance.  If New Accessory Classification requests can be submitted as changes to a cleared/approved device, accessory manufacturers may seek out relationships with the parent-device manufacturer in order to be able to take advantage of this cost savings.  Such a relationship may also streamline the process for generating data to support such a submission.

There are two other notable changes in the new draft guidance. First, the draft guidance expressly states that it applies to all accessories, whether required or optional.  In addition, the guidance expressly applies to software accessories.  These points arguably were implied in the 2016 guidance, but it is nice that they are now expressly stated.

The draft guidance has a detailed appendix regarding the type of information to be included in a de novo application for a new accessory. It would also be helpful for FDA to consider including appendices detailing the types of information that should be included in a classification request as part of a parent device submission and a reclassification request.

In sum, we think this is a good draft, which closely follows the statutory requirements for the new program. However, additional details should be added before the final guidance is issued to make it more useful for both industry and FDA.

In a thorough and thoughtful 23-page opinion, Judge Steven Merryday of the Middle District of Florida dismissed a $350 million judgment against the defendants, owners and operators of specialized nursing facilities. The court detailed the rigorous materiality and scienter requirements for liability under the False Claims Act that the U.S. Supreme Court “defined unambiguously and required emphatically” in Universal Health Services, Inc. v. Escobar, 136 S. Ct. 1989 (2016):

Escobar necessarily means that if a service is noncompliant with a statute, a rule, or a contract; if the non-compliance is disclosed to, or discovered by, the United States; and if the United States pays notwithstanding the disclosed or discovered non-compliance, the False Claims Act provides a relator no claim for “implied false certification” (although some other claim, maintainable by the United States in its own name, or some regulatory authority, exercisable by the United States, might attach under other law).

In other words, a False Claims Act claim cannot be based on a “minor or unsubstantial” or “garden-variety” regulatory violation; to do so would result in a system of “government traps, zaps, and zingers” that permits the government to retain the benefit of a “substantially conforming” good or service, and to recover under the False Claims Act damages (up to treble times) due to the immaterial regulatory non-compliance.

In United States ex rel. Ruckh v. Salus Rehabilitation, LLC et al., No. 8:11-cv-01303-SDM-TBM (M.D. Fla. Jan. 11, 2018) (Merryday, J.), the relator alleged the nursing facilities violated Medicaid regulations, which rendered fraudulent its claims to the Medicaid program. The alleged non-compliances involved a failure to maintain a comprehensive care plan and a failure to keep proper records of services. After trial, the judgments against defendants totaled $350 million.

In its opinion, the court found compelling the entire absence of evidence of how the government has behaved in comparable circumstances. Given the lack of evidence, the jurors returned “an unwarranted, unjustified, unconscionable, and probably unconstitutional forfeiture – times three – sufficient in proportion and irrationality to deter any prudent business from providing services and products to a government armed with the untethered and hair-trigger artillery of a False Claims Act invoked by a heavily invested relator.”

The court, like many now since Escobar, agreed that Escobar requires that the relator prove “both that the non-compliance was material to the government’s payment decision and that the defendant knew at the moment the defendant sought payment that the non-compliance was material to the government’s payment decision.” Absent this evidence, a False Claims Act cannot stand – whether at a motion to dismiss stage, summary judgment stage, or like in Ruckh, past jury trial and judgment.

It was a somewhat unsettling year for the Drug Enforcement Administration. The Agency faced a barrage of criticism in the press regarding its involvement in passage of the Ensuring Patient Access and Effective Drug Enforcement Act (EPAEDEA), which some criticized as hobbling DEA’s immediate suspension order (ISO) authority (see here). Meanwhile, notwithstanding a D.C. Circuit “win” for the Agency in Masters Pharmaceutical, Inc. v. Drug Enforcement Administration, 861 F.3d 206 (D.C. Cir. 2017), where the court set forth new and significant suspicious order monitoring and reporting requirements, the industry still decried the lack of clarification to DEA’s suspicious order reporting regulations—promulgated by notice-and-comment rulemaking—something the Agency has been promising for years (see post here).

Regardless, DEA’s Diversion Control Division has continued to bring administrative revocation and registration denial cases (see post here for a general description) against DEA registrants (typically practitioner cases). According to DEA, the number of administrative cases brought in 2017 was more than double the number brought in 2014.

Based on our review of the published decisions this year, here are some statistics on DEA’s 2017 administrative docket:

• 46: Number of new final orders (up from 28 in 2016)
• 44: Number of new final orders adjudicating individual (e.g., doctor, dentist, veterinarian) registrations (a pharmacy and a clinic made up the remaining two final orders)
• 1: Number of ISO cases
• 29: Number of cases based solely on loss of state authority (see post here) (up from 15 in 2016)
• 17: Number of cases where the respondent made a timely request for a hearing (i.e., before an ALJ)
• 13: Number of cases with a timely request for a hearing that were decided on summary disposition (i.e., without a hearing)
• 3: Number of cases where the Administrator rejected the presiding ALJ’s recommended decision
• 0: Number of corrective action plans that DEA has accepted (see DEA statement here)

It is important to note that these statistics do not take into account administrative actions where a party surrendered a registration prior to DEA initiating proceedings or cases that DEA and the registrant settled without going to a hearing.

Our readers know that we closely follow DEA’s administrative decisions, and we are committed to keeping you up to date on significant developments in these decisions. Here are some of the highlights of our posts from 2017:

• DEA’s concerning and questionable expanded use of summary disposition to decide cases other than those solely based on a loss of state authority (see posts here and here)
• DEA’s use of official notice (see post here)
• DEA’s finding that the two key elements of a valid prescription contained in 21 C.F.R. § 1306.04(a)—(1) issued for a legitimate medical purpose (2) by an individual practitioner acting in the usual course of professional practice—have no material difference (see post here)
• A new set of requirements (not contained in the regulations) that require practitioners to investigate whether their registrations are being misused for diversion (see post here)

As we embark on a new year, we will continue to keep you posted on new decisions as they are published.

While many were on vacation and preparing to celebrate the New Year, CDRH was announcing yet another pilot program. You may recall FDA recently announced its Digital Health Software Pre-Cert Pilot Program and its Premarket Approval Application Critical to Quality Pilot Program.  The latest pilot program is the Case for Quality Voluntary Medical Device Manufacturing and Product Quality Pilot Program.  The program was announced in the Federal Register.

This pilot program, like others that have come before it, intends to evaluate alternative means of assessing a device company’s quality system. In this program, CDRH has collaborated with the Medical Device Innovation Consortium (MDIC) to develop a “maturity model and appraisal system,” the Capability Maturity Model Integration (CMMI) system.  Details regarding the CMMI system are absent from the Federal Register notice.  Prospective participants would be well-advised to better understand this system prior to enrollment.  Program participants will be required to perform a gap assessment using the CMMI system.  In exchange, FDA intends to forego conducting surveillance inspections of program participants.

CDRH will select up to nine companies to participate in this program, and it began taking applications for enrollment on January 2. The program is scheduled to run through the end of 2018.

Section 513 of the Federal Food, Drug, and Cosmetic Act requires FDA to consider the least burdensome means of evaluating device safety and effectiveness for Class III devices and substantial equivalence for devices requiring 510(k) clearance. Despite this legal requirement, the device industry’s position has been that FDA does not comply with the provisions to require only the “least burdensome” means of establishing device effectiveness or substantial equivalence.  It has often seemed that CDRH was paying lip service to the concept of “least burdensome,” using the phrase but not actually applying it.  The 21st Century Cures Act (Cures), signed into law last December, added language requiring CDRH to assess the implementation of the least burdensome provisions “to ensure that the least burdensome requirements are fully and consistently applied.”

As part of this implementation, on December 15, CDRH issued a revised draft guidance regarding the Least Burdensome provisions.  Once finalized, this guidance will replace FDA’s October 2002 guidance, “The Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles.”

The draft guidance applies a new definition of “least burdensome,” defining it as “the minimum amount of information necessary to adequately address a regulatory question or issue through the most efficient manner at the right time.” In contrast, the 2002 guidance defined least burdensome as “a successful means of addressing a premarket issue that involves the most appropriate investment of time, effort, and resources on the part of industry and FDA.”  The earlier definition focused on premarket issues, whereas the new guidance is broader.  The scope of the draft guidance includes all premarket submissions, including de novos and Q-submissions, neither of which were expressly included in the 2002 guidance.  Both guidances also cover other regulatory obligations, including, for example postmarket surveillance and post-approval studies.

Although Cures was directed at CDRH, the Center has turned around and applied the concepts to industry. The draft guidance emphasizes that least burdensome applies not only to FDA but also to industry. The guidance states that industry should “submit well-organized, clear, and concise information” that is least burdensome to review.  In practice, it is difficult for industry to predict the minimum amount of information necessary in a premarket submission because the Agency continues to request new and different information to establish a reasonable assurance of safety and effectiveness or substantial equivalence.

The new guidance, like the 2002 guidance, provides a number of examples of how FDA has and will apply its least burdensome provisions. The draft guidance utilizes more recent examples of the least burdensome provisions as compared to the 2002 guidance.  For example, the guidance references use of real world evidence, a current hot topic within the Agency.  With these more recent examples, however, some of the more basic examples from the 2002 guidance have been lost.  For example, the 2002 guidance clearly indicated that 510(k) submissions do not need to include manufacturing information.  This same information is not in the 2017 draft.  This document will supersede what FDA said before.  We recommend that FDA include the examples from the 2002 guidance to the extent that they reflect current policy.  In general, we find the new examples to be helpful; however, omitting examples that have been useful in the past will mean a loss of useful illustrations and could potentially create confusion as to whether leaving out the examples means CDRH has changed its policy.

To prevail on an allegation under the False Claims Act (FCA), a plaintiff must allege that the misrepresentation by defendant was “material to the Government’s payment decision.” Universal Health Services, Inc. v. United States ex rel. Escobar, 136 S. Ct. 1989 (2016).  The U.S. Supreme Court explained that “if the Government pays a particular claim in full despite its actual knowledge that certain requirements were violated, that is very strong evidence that those requirements are not material.” Id. at 2003.

As reported last year, there has been a trend to narrow the types of FCA theories that could survive the more stringent test for materiality established by Escobar, with several circuit courts requiring a rigorous scrutiny of the government’s behavior once it became aware of the alleged misrepresentations.  In July 2017, however, the Ninth Circuit bucked the trend, and concluded that whether allegations are material raised matters of proof that could not be resolved on the pleadings (i.e., at the motion to dismiss stage). See United States ex rel. Campie v. Gilead Sciences, Inc., 862 F.3d 890 (9th Cir. 2017).  The Ninth Circuit’s view was that the plaintiffs alleged “more than the mere possibility that the government would be entitled to refuse payment if it were aware of the violations,” and that was sufficient for materiality purposes “at this stage of the case.”

The U.S. Supreme Court now may be poised to provide further clarity on the materiality required for FCA liability. Gilead requested, but was denied, a rehearing en banc.  Gilead now requests in a petition for a writ of certiorari that the U.S. Supreme Court rule on the following question:

Whether an FCA allegation fails when the Government continued to approve and pay for products after learning of alleged regulatory infractions and the pleadings offer no basis for overcoming the strong inference of immateriality that arises from the Government’s response.

Gilead provides several reasons the Court should grant the writ. First, the Ninth Circuit’s approach conflicts with the decisions of six circuits that have addressed this very question and interpreted Escobar differently.  Second, courts have had, and will have, to consider this question with frequency, and the outcome of this case could impact the availability of drugs and medical products to the marketplace.  Last, this case is well positioned to provide “guidance on a significant and recurring issue by clarifying how the Government’s response upon learning of alleged infractions affects the viability of an FCA complaint.”

Response to the petition is due on February 2, 2018.

Hyman, Phelps & McNamara, P.C. is pleased to present this report summarizing leading cases and settlements from 2017 affecting the FDA-regulated industry. Our goal was to provide a concise summary of issues that most impact our clients, many of whom are drug and medical device manufacturers, compounding facilities, and officers of those companies.

For each case or settlement, we summarize the facts and the key takeaways. And we include at the end of the report the hot-button issues that we are monitoring in 2018.

We hope this report proves useful and interesting to you.

FDA gave us all a New Year’s present on January 2nd when it announced the Agency’s new Data Dashboard. The Dashboard graphically breaks down data on FDA Inspections, Compliance Actions (warning letters, injunctions, and seizures – more commonly known by industry as “enforcement actions”), Recalls, and Imports/Import Refusals, by fiscal year (starting with 2009), product category (drugs, devices, food, cosmetics, etc.), and in other helpful ways depending on the data set.  For example, in addition to filtering by fiscal year and product category, inspection data can also be filtered by the inspection classification (NAI, VAI, or OAI), region (foreign or domestic), country, state, or even company name.

Compliance actions can be filtered by the type of action, firm name, region, state, and country. Each Dashboard page features a map that pinpoints the geographic location of subject facilities, and by using the map’s “lasso” function you can select and see data from a custom geographic region.

Of course, the Data Dashboard does not provide any information that is not already publicly available through FDA’s website. And it does not offer specifics about the subject of FDA compliance actions, inspectional observations, or import refusals.  For these specifics, users may find more detailed information in FDA’s preexisting Inspection Classification Database (updated monthly as of November 2017), Electronic Reading Room – Warning Letters, or ORA FOIA Electronic Reading Room.

Importantly, the new Data Dashboard is limited in that “[t]he datasets are updated semi-annually and only include final actions,” and FDA has not indicated when the next semi-annual update will occur. Given that some inspections and compliance actions are not considered “final” for months or even years, the Data Dashboard may not be the best place to look if you are hoping to find companies or products that have been the subject of recent FDA action.  However, if you want to quickly identify and analyze longer-term trends, find general information on FDA activities relating to a certain product category, country, geographic region, or a certain company, the Dashboard makes existing FDA data significantly more accessible and useful – a welcome start to the New Year.