In October, FDA issued a draft guidance titled “Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act,” which will replace a similar April 2011 draft guidance once finalized.  This new draft guidance reflects a significant expansion of FDA’s authority to require postmarketing studies.  FDA is now permitted to establish postmarket requirements (PMRs) to study efficacy in addition to safety.

This expansion of FDA’s PMR authority is the result of section 3041 of the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT Act).  While the SUPPORT Act is generally focused on opioid drugs and treatments for opioid addiction, section 3041 on PMRs is not limited to any particular drug class.

Section 3041 of the SUPPORT Act revised the definition of “adverse drug experience” at section 505-1(b)(1)(E) of the Federal Food, Drug, and Cosmetic Act (FDC Act) to include “reduced effectiveness under the conditions of use prescribed in the labeling of [a] drug.”  The purpose of a PMR is to assess a known serious risk, assess signals of a serious risk, or identify an unexpected serious risk when data indicate the potential for a serious risk.  Id. § 505(o)(3)(C).  A “serious risk” is a risk of a “serious adverse drug experience.”  Id. § 505-1(b)(5).  Because adverse drug experience now includes reduced effectiveness, FDA can issue a PMR for an efficacy study.

After a drug is approved, FDA can require an additional study on the basis of “new safety information.”  Id. § 505(o)(3)(C).  “New safety information” includes information derived from adverse events.  Thus, if FDA finds that there is reduced effectiveness under the conditions of use prescribed in the labeling once a drug is already on the market, it can require a new efficacy study even if that study was not listed as a PMR at the time of approval.

Notably, the SUPPORT Act also expanded FDA’s authority to require labeling changes under the safety labeling change notification process (id. § 505(o)(4)).  Now, FDA can require labeling changes due to new effectiveness information in addition to new safety information (e.g., if FDA determines that the results of an efficacy PMR warrant a change to the drug’s approved labeling).

The SUPPORT Act required FDA to issue guidance “regarding the circumstances under which [FDA] may require postmarket studies or clinical trials to assess the potential reduction in effectiveness of a drug and how such reduction in effectiveness could result in a change to the benefits of the drug and the risks to the patient” within one year of the date of enactment (Oct. 24, 2018).  This draft guidance was issued about one week before the one-year deadline.

The draft guidance clarifies how the SUPPORT Act’s amendment to FDA’s definition of “adverse drug experience” affects FDA’s PMR authority: “In some cases, when a serious risk relates to failure of expected pharmacological action, including reduced effectiveness, the trial might be designed with an efficacy endpoint, for example, to further assess whether a failure of expected pharmacological action, including reduced effectiveness, may result in a serious adverse drug experience.”

The draft guidance provides several examples of clinical trials intended to assess reduced effectiveness, including studies for:

• Determining whether treatment duration of an antiviral drug should be extended;
• Evaluating a newly identified drug-drug interaction that could reduce systemic exposure;
• Evaluating a newly identified antibody response to a biologic; and
• Evaluating a new signal that a subgroup of patients with a life-threatening cancer may not respond to an approved drug.

The draft guidance makes clear that FDA can order labeling changes due to the results of an effectiveness PMR.  The draft guidance states, regarding both safety and efficacy endpoints in PMRs: “FDA will review the data and/or information obtained under a PMR and assess its effect on the benefit-risk profile of the drug in the context of a serious risk being evaluated.  This may result, for example in labeling changes under section 505(o)(4) of the [FDC Act].”

These labeling changes could consist of additional warning statements, but they could also consist of significant changes to the indications for use.  For example, if an efficacy study found that a subgroup of patients (e.g., a gender, ethnicity, or age subgroup) demonstrates reduced effectiveness, FDA could require changes to a drug’s indications for use statement.

Comments on the draft guidance are due January 17, 2020.  However, this expansion of FDA’s PMR authority cannot be meaningfully changed through revisions to the guidance.  Because issuance of the draft guidance was mandated by Congress through the SUPPORT Act, any adjustment to FDA’s new authority to issue effectiveness PMRs will have to be addressed through a legislative fix.  It remains to be seen how this new authority will play out in practice, but industry groups may eventually be motivated to seek a legislative change.

The Government Accountability Office released a new Report last week focusing on the oft-analyzed tactics used by some innovator or brand-name pharmaceutical manufacturers to keep generic versions of products off the market.  Like some facets of then-Commissioner Gottlieb’s Drug Competition Action Plan, the GAO Report focuses specifically on the use of REMS programs to prevent generic companies from obtaining samples.  While FDA and FTC have been working together to help make drug samples easier to obtain (as we at HPM can confirm from personal experience), the GAO Report found that drug companies and stakeholders are not sold on the effect of the agencies’ actions.  This is because the main tools used – letters from FDA, public shaming, FTC review, and waivers from shared REMS systems – lack teeth.  In such situations, there is very little that FDA can do, as it can’t compel reference product sponsors to make products available.  Only the FTC has the ability to take enforcement action for the anticompetitive behavior at issue, but thus far it hasn’t done so.  Therefore, reference product companies may have little incentive to curb these practices.

The need for this GAO Report arose from complains from generic companies that some reference product sponsors use the REMS process to hinder competition by delaying or preventing generic drugs from being developed or coming to market.  Two practices that FDA and FTC are particularly concerned about are the limiting of access to samples of reference standard products needed to show bioequivalence and delaying negotiations for shared REMS programs.  Reference product sponsors may limit access to samples of reference standard drugs both that are subject to REMS, by refusing distribution outside of that REMS, or that are not subject to REMS, by limiting the sale of their reference standard drugs only to certain pharmacies (like specialty pharmacies).  In practice, these activities can restrict all purchases of these products by generic companies who may need them as reference product samples.  Delayed REMS negotiations may occur where the reference product sponsor and the ANDA sponsors cannot come to an agreement on the system, which may delay the approval of an ANDA until such an agreement can be made.

While FDA and FTC have not done much in the way of enforcement, the Report focuses on four actions that FDA and FTC have taken to address these circumstances:

• Draft guidance on Safety Determination Letter: In 2014, FDA issued a draft guidance explaining FDA’s ability to issue a “safety determination letter” to the reference drug company on behalf of the generic manufacturer, assuring the reference drug sponsor that this distribution would not constitute a REMS violation;
• Public Website on Inquiries to FDA About Samples: In February 2019, FDA released a website posting information on inquiries made to FDA by generic companies unable to obtain reference standard samples in an effort to publicly shame innovator companies into providing samples to putative generic manufacturers;
• FTC review: FTC reviewed the inquiries FDA received about samples and filed two amicus briefs related to drugs with REMS, but has not yet brought suit for violation of the Federal Trade Commission Act or the Sherman Act;
• Shared REMS Waivers: FDA has issued waivers of the single shared REMS requirements, allowing generic drug companies to develop a separate REMS system including the same Elements to Assure Safe Use as the RLD.  In 2018, FDA published guidance describing the relevant considerations in its assessment of shared REMS waiver requests, including a comparison of the burdens and benefits of a single shared system and elements of the REMS protected by intellectual property considerations.

The GAO talked to four generic drug manufacturers and five reference standard product manufacturers to get their perspectives on FDA’s and FTC’s efforts to address these practices, in addition to reviewing comments submitted to the federal register with respect to these efforts.  True to form, the generic and reference product manufacturers had differing opinions on these efforts.  The generic companies, for example, found the safety determination letters not useful because they are not enforceable, while the reference product companies who could opine on the issue liked them and noted that they now require them before releasing samples.  The public shaming webpage was an all-around disappointment, as the generic companies got little out of it while some of the reference product companies were unaware of any sample inquiries prior to being included on the webpage.  The waivers also received mixed reviews due to FDA’s timeline for responding to waiver requests, as well as the burden imposed on health care professionals and patients in navigating several REMS systems.  Interestingly, the generic companies thought that the FTC’s amicus briefs were at least helpful, but none of the reference drug companies had any opinions at all on the FTC’s briefs.

The running theme throughout all of these efforts though is that FDA’s efforts are largely fruitless because the Agency cannot compel reference product sponsors to provide samples or to negotiate.  As many lawyers can attest, sometimes a strongly-worded letter just isn’t enough.  And neither is public shaming or a waiver process that ends up taking multiple years.  The FTC is the only one here with any enforcement power, but we’re still waiting to see whether it chooses to exercise it.  It’s taken years of complaining over Citizen Petitions for the FTC to take any action (see our extensive blogging on this case here and here to start), so maybe generic companies just need to bide their time until FTC makes examples out of a few bad actors.  But like with many complaints of anticompetitive conduct, it may to take enforcement action – and use of those regulator teeth – to really get industry attention.

On October 23, 2019, the U.S. Cattlemen Association (USCA) petitioned USDA regarding Made in USA and Product of USA and similar claims on beef.

USCA explains that it is concerned that voluntary “Made in USA” labeling for beef products, without a clear definition of what constitutes “Made in USA” or “Product of USA” or other such similar designations, will lead to consumer confusion if meat from animals that are not born, raised and harvested in the United States is marked with this type of designation.  Therefore, USCA contends that voluntary labels indicating “Made in USA,” or similar claims should be limited to beef from cattle born, raised, and harvested in the United States.

USCA asks that USDA revise its policy and require that any beef product labeled as “Made in the USA,” “Product of the USA,” “USA beef,” or otherwise indicated to be U.S. beef, come from cattle that have been born, raised, and harvested in the United States.

USCA supported the mandatory country of origin labeling (COOL) requirements for livestock.  The COOL law and implementing regulation mandated that meat be labeled with a statement as to where the animals were born, raised, and harvested.  The WTO ruled against the mandatory COOL requirements and the regulations and the law mandating COOL for beef and pork were repealed.  The current Petition does not request that USDA reinstate mandatory COOL.  Instead, it requests that USDA set a standard for voluntary “Made in the USA” and similar claims.

As readers of this blog know, last year, the Organization for Competitive Markets & American Grassfed Association (OCM) petitioned USDA over the same claim.  The USCA Petition does not refer to the 2018 OCM petition, nor does it address why the standard should be USCA’s proposed standard (which specifically requires that the animals are born and raised as well as “harvested” in this country) rather than the standard proposed by OCM, which does not require that animals are born in the United States.

FSIS opened a docket on regulations.gov where comments can be submitted.

On November 5, 2019, the U.S. District Court for the Northern District of California ruled in favor of Theranos founder Elizabeth Holmes and former Theranos president Sunny Balwani, in a battle over access to government documents.  While this represents a small victory for these defendants, it may not ultimately impact the outcome of this high-profile criminal prosecution.

In response to charges of wire fraud and conspiracy to commit wire fraud against key officers of the now-extinct Theranos, Holmes and Balwani moved to compel federal prosecutors to produce documents held by FDA and CMS. Under Ninth Circuit case law, DOJ prosecutors have access to discoverable material, even if held by other government agencies. The prosecution maintained that it could not be compelled to produce documents from governmental agencies outside DOJ because it lacked access to such documents. The court disagreed, however, noting that Rule 16 “grants criminal defendants a broad right to discovery.”  The court noted that while FDA and CMS are not a part of DOJ, they clearly have been involved in the litigation, pointing to the significant access, communication and assistance by-and-between the three Agencies.  The government was thus ordered to produce the documents as part of their Rule 16 obligation and to “assist the Agencies however possible to ensure the timely production of documents.”

Defendants also identified several deficiencies relating to the Agencies’ preservation efforts of the documents the government had produced.  For example, defendants claimed, FDA, rather than produce documents in whole or in original format, “produced [over 1,000 emails] as fragmentary documents – i.e., that the produced emails omit portions of the original email, such as the ‘to,’  or ‘from,’ or the body fields….”  Defendants also complained FDA failed to run appropriate search terms and, in its order, the court dictated the use of specific terms in FDA’s files: “LDT,” “Laboratory Developed Test,” “Theranos,” “fingerstick,” “finger stick,” and “nanotainer.”

Lastly, the court ordered the parties (including FDA and CMS) to meet and confer on outstanding discovery issues, such as production of employee text messages and de-duplication of documents.  The court set a tight production deadline of December 31, 2019, just in time for New Year’s celebrations.

On November 5, 2019, the U.S. District Court for the Northern District of California added another entry in the long running saga United States ex rel. Campie v. Gilead Sciences, Inc. when it granted the DOJ’s motion to dismiss.  We have extensively covered this case (see here, here, here, here, here, here, here, and here), but an overview is helpful to understand the latest development.

This case results from a qui tam complaint filed in 2010 by two former employees alleging that Gilead made false statements to the FDA about the company’s anti-HIV drugs.  According to the relators, if the FDA had been aware of the false statements it would not have permitted Gilead to market the drugs.  Because the drugs were reimbursed by federal healthcare programs, the relators contended that Gilead’s actions resulted in the submission of false claims in violation of the False Claims Act (FCA).  The DOJ declined to intervene in the case, but the relators chose to proceed with the litigation.  The District Court dismissed the relators’ complaint twice for failure to state a claim under the FCA.  However, in July 2017, the Ninth Circuit Court of Appeals reversed the District Court and found that the relators had alleged sufficient facts to state a claim for relief.  Gilead’s petition for rehearing before the Ninth Circuit was denied, so the company filed a petition for certiorari with the Supreme Court in December 2017.  In April 2018, the Supreme Court invited the U.S. Solicitor General to file a brief expressing the views of the United States on Gilead’s petition.  The DOJ’s Statement of Interest, filed in November 2018, generally agreed with the Ninth Circuit decision but also disclosed that the government would affirmatively seek dismissal of the case if it was remanded.  The Supreme Court denied Gilead’s petition for certiorari in January 2019, and the case returned to the District Court.  The DOJ filed its motion to dismiss in March 2019.

The District Court evaluated the DOJ’s motion to dismiss using the two-step analysis established in United States ex rel. Sequoia Orange Co. v. Baird-Neece Packing Corp., 151 F.3d 1139 (9th Cir. 1998).  Under the Sequoia Orange test, the government’s dismissal of an FCA case may be justified based on “(1) identification of a valid government purpose; and (2) a rational relation between dismissal and accomplishment of the purpose.”  If the government satisfies the two-step test, the burden switches to the relators “to demonstrate that dismissal is fraudulent, arbitrary and capricious, or illegal.”

In its motion to dismiss, the DOJ identified two government purposes to support dismissal of the relators’ suit: (1) to prevent undermining the decisions made by FDA and CMS about how to address the conduct at issue, and (2) to avoid the additional expenditure of government resources on a case that it fully investigated and decided not to pursue.  The relators acknowledged that these purposes have previously been identified by the DOJ as relevant considerations (see our post about the Granston memo), but argued that there was an insufficient factual basis to support the asserted government purposes.

The District Court did not agree with the relators’ assessment, in part due to the “substantial evidence” the DOJ presented about its investigation which included interviews with the relators and other witnesses, consultations with experts from FDA, meetings with Gilead, collection of over 600,000 pages of documents, and review of the history of multiple manufacturing lots identified by the relators as having problems.  The Court also looked at FDA’s oversight of Gilead and noted that history included a Warning Letter, Field Alert Reports, and multiple inspections.  Based on this history, the Court concluded that there was a “concrete factual basis” for the government to argue that allowing the case to proceed would undermine the decisions made by FDA and CMS.

The relators also argued that the DOJ did not provide a factual basis for the second identified government purpose, the cost of continued litigation.  Although the Court noted that the DOJ could have provided a more specific and robust cost analysis, the Court ultimately determined that the DOJ had considered the cost and benefit such that its decision to seek dismissal was supported by a rational basis.  The Court also acknowledged that the facts of this case would likely entail extensive discovery of government witnesses and documents due to the unresolved issue of whether Gilead’s alleged false statements were material.  The Court reasoned that discovery into what the government knew and when could not be avoided if the case continued.

After determining that the DOJ had met the two-step Sequoia Orange test, the Court then concluded that the DOJ’s decision to dismiss this case was not arbitrary and capricious.  As such, the Court granted the DOJ’s motion to dismiss, but noted that the relators could still proceed with their remaining claims.

After almost ten years of investigation and litigation, this may be the end of this saga.  Although this case once seemed destined to provide clarity on the materiality standard established in Universal Health Services. Inc. v. United States ex rel. Escobar, 136 S. Ct. 1989 (2016), it appears that we may need to continue to wait for that clarity.  However, this case does reveal how the DOJ is implementing the Granston memo and the factors and evidence that may be used to support the dismissal of FCA claims when the government declines to intervene in a qui tam case.

FDA is issuing final guidance on how device firms may request review of a decision to withhold issuance of a Certificate to Foreign Government (CFG).  What is a CFG?  In many cases, foreign governments will seek official assurance that products exported to their countries are in compliance with U.S. law or meet specific U.S. regulations, such as Quality System Regulations (QSR).  In these cases, firms may request that FDA provide a CFG.  If a domestic firm’s manufacturing establishment has an outstanding Form 483, due to a bad QSR inspection, or is conducting a Class I or II product recall, the non‑compliance may lead FDA to refuse to issue a CFG until it is resolved.

In 2017, Congress amended the export provisions of the Federal Food, Drug, and Cosmetic Act (FDCA) to establish specific procedural rights and appeal options for device companies faced with a CFG denial.  The following year, FDA issued a draft guidance on how the statutory change will be implemented.  We explained the background and summarized FDA’s draft guidance here.

Our main complaint about the draft guidance was a lack of clarity and detail on implementation of the statute.  We are pleased to report that the final guidance is improved in this regard.  Here are the key points:

Grounds for Denial

Pursuant to the amendment to the FDCA, a CFG may denied in the event of an injunction, a seizure action, a Class I or II voluntary recall, or an establishment out of compliance with the QSR.

If a CFG is denied due to non‑compliance with the QSR, FDA will provide a “substantive summary” of the specific grounds for non‑compliance.  It appears likely that this information will be distilled from the inspectional observations in a Form 483.

Plan of Correction                    

A firm may submit a “plan of correction” responsive to the substantive summary.  FDA states that they interpret a plan of correction to be a response to inspectional observations.  The procedure is as follows:

• The firm submits via e‑mail the steps it is taking to address the inspectional observations and prevent a recurrence, including timeframes for completing the actions. The email subject line should state “Plan of Correction.”
• FDA reserves the right to seek clarification of the plan before making a decision. FDA intends to provide a response within 90 days, with due allowance for the complexity of the issues and the responsiveness of the firm.
• If the plan is determined to be sufficient, FDA will issue a CFG (provided no other grounds of denial are present).

Appeal of Denial

A firm whose CFG has been denied has a right to supervisory review and an opportunity for an in‑person meeting or teleconference.  The appeal must be submitted by email within 60 days of denial.  CDRH will follow its usual procedures (per this guidance).  CBER will use its Formal Dispute Resolution Request (FDRR) process (per this guidance).  In both cases, FDA indicates an intent to follow the standard timelines in Section 517A(b) of the FDCA but does not guarantee it, which may be a questionable interpretation of the statute, which directed FDA to follow the standards of the Section 517A(b).

New Information

A firm whose CFG has been denied has the right to request review of the decision based upon new information, including evidence that corrective actions are being or have been implemented to address FDA’s substantive summary of the grounds for denial.  Once again, this review can be obtained by submitting an email.  Once again, FDA says it will target 90 days for a decision, to the extent possible.

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A right of supervisory appeal of a CFG denial is unlikely to be successful unless FDA has issued a Form 483 that is plainly wrong (a high bar in most cases).  The plan of correction (or the request for review based on new information) appear to offer greater potential.  Since it is likely that FDA will put the most important QSR non-compliance in its substantive summary, a firm could use the vehicle of a plan of correction to help unlock CFGs sooner than would ordinarily be the case.  Additionally, there may be a collateral benefit of obtaining a relatively quick read on FDA’s assessment of a corrective action plan addressing the most serious Form 483 issues.  Certainly, it remains to be seen how FDA actually implements the new procedures, but the final guidance holds out the prospect of improved communication with FDA as firms seek to resolve outstanding Form 483s.

Hyman, Phelps & McNamara, P.C. (“HP&M”) has once again been ranked as a “Tier 1” law firm in the area of “FDA Law” (both nationally and in Washington, D.C.) by the folks over at U.S. News & World Report, who teamed up with Best Lawyers for the 2020 “Best Law Firms” rankings.

“The 2020 rankings are based on the highest number of participating firms and client votes received on record.  Almost 16,000 lawyers provided more than 1,229,000 law firm assessments, and more than 12,000 clients participated providing 107,000 evaluations. . . . This year we reviewed 14,931 law firms throughout the United States – across 75 national practice areas – and a total of 2,106 firms received a national law firm ranking,” according to U.S. News.  The “Best Law Firms” rankings are based on a combination of client feedback, information provided on the Law Firm Survey, the Law Firm Leaders Survey, and Best Lawyers peer review.

On November 7, 2019, gene therapy company Regenxbio Inc., filed suit in U.S. District Court in Washington, D.C. against FDA asking the court to set aside a partial clinical hold on one clinical trial and a full clinical trial for another.  The complaint also seeks to have a section of the Food, Drug, and Cosmetic Act (“FDC Act”) – 21 U.S.C. §355(i)(3)(B)(ii); FDC Act §505(i)(3)(B)(ii) – that allows FDA to issue a clinical hold for a reason established by regulation that is other than a determination that the drug involved represents an unreasonable risk to subject safety.

As described in the complaint, FDA issued a clinical hold on the sponsor’s investigative drug for treatment of retinal disease on October 18, 2019 “without notice or explanation,” and has failed to provide the sponsor with a detailed explanation of the basis of the clinical hold other than to say that the INDs were placed on hold due to issues associated with the delivery system.  The company withdrew one IND on October 25, 2019, and the other IND remains on partial clinical hold.  FDA notified the sponsor on November 1^st that it would provide a written basis for the hold by “the due date of 11/15/19.”

The complaint also alleges that FDA failed to comply with its regulations because the original email providing notice of the clinical hold did not “briefly explain the basis for the action,” as required by 21 C.F.R. § 312.42(d).  The same regulation also provides that within 30 days after imposition of the hold, the Division Director will provide the sponsor a written explanation of the basis of the hold.  November 15th is the date by which FDA stated it would provide the sponsor with the written basis of the hold (it falls within that 30 days based on the dates provided in the complaint).

While it seems unlikely that the merits of the clinical hold will be resolved through the judiciary process in a helpful timeframe, the complaint has likely increased the chances that FDA will respond with a thorough explanation of its reason for the hold when it does provide the written basis.

USDA published its much-anticipated interim final rule establishing a domestic hemp production program, as directed by the Agriculture Improvement Act of 2018 (a/k/a the Farm Bill).  The rule sets out the requirements for hemp production plans developed by States and Indian Tribes that choose to have primary authority over production of hemp within their jurisdiction.  The rule also sets out the USDA hemp production program requirements, which will apply in States and Tribal Nations that don’t have their own plans but choose to allow production of hemp within their jurisdiction.

Generally, all hemp producers will be subject to similar requirements, regardless of whether they are licensed by a State, Tribe, or USDA.  These include obtaining a license, submitting information on land areas under cultivation, securing appropriate sampling and testing for TCH content, disposing of plants containing excess levels of THC, participating in compliance audits, and maintaining appropriate records.  USDA has posted a webinar that provides a high-level overview of what producers can expect.  USDA is also maintaining web pages with resources for state departments of agriculture and tribal governments, hemp producers, and hemp testing labs.

Hemp producers and other stakeholders are encouraged to read the regulation and at least the first 12 pages of the preamble, in which USDA has embedded requests for comments on specific issues.  These include appropriateness of a 15-day sampling window prior to harvest, whether USDA should establish a fee-for-service laboratory approval process, whether labs should be required to have ISO 17025 accreditation, and what efforts should be considered as reasonable in determining whether a producer has committed a negligent violation.  Comments are due by December 30.

Readers with the time and inclination may also find it worthwhile to dive into the Regulatory Impact Analysis in the preamble, which starts with this statement: “The future of the hemp industry in the United States (U.S.) is anything but certain.”  The preamble acknowledges that U.S.-based hemp production recently has seen a “massive resurgence.”  Indeed, hemp acreage reportedly increased 8-fold from 2016 to 2018, and is projected to double in 2019.  However, the preamble states that “it remains unclear whether consumer demand will meet the supply.”  Producer interest is said to be “largely driven by the potential for high returns from sales of hemp flowers to be processed into CBD oil,” but products that contain CBD oil and are intended for human or animal use must still comply with whatever federal and state laws apply to those products – including the Federal Food, Drug, and Cosmetic Act and its implementing regulations.

In discussing projected growth in gross revenues and the potential benefits of its hemp program regulation, USDA pointedly states that, “if FDA does not provide clarity about their plans for future regulation of CBD, there will continue to be uncertainty and downward pressure on the CBD portion of the hemp market….  As a result, full realization of the benefits estimated here could be delayed pending regulatory certainty.”

Hyman, Phelps & McNamara, P.C. is pleased to publish the third installment of the FDA Law Alert, a quarterly newsletter highlighting key postings from our nationally acclaimed FDA Law Blog.  Please subscribe to the FDA Law Blog to receive contemporaneous posts on government regulatory and enforcement activities affecting the broad cross-section of FDA-regulated industry.   As the largest dedicated FDA law firm, we are happy to help you or your clients navigate the nuances of the laws and regulations affecting them.

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Patient Engagement

• Patient-Focused Drug Development: James E. Valentine highlights FDA’s guidance on Patient-Focused Drug Development, the second in a series of four guidance documents, which provides approaches to identifying what is most important to patients with respect to their experience as it relates to burden of disease and burden of treatment. Valentine’s post outlines FDA’s new recommendations for quantitative and qualitative research, considerations for specific populations, and the use of social media to elicit patient information.

• Patient Engagement in Clinical Trials: Véronique Li, Larry J. Bauer and Sarah Wicks write about FDA’s Draft Guidance on Patient Engagement in the Design and Conduct of Medical Device Clinical Investigations. The guidance delineates between patients, study/research participants and patient advisors, noting that early input from patient advisors could lead to quicker study/research participant recruitment, enrollment and study completion, streamlined data collection and more relevant data outcomes that are important to patients.

Medical Devices

• Government Investigations: The District of Minnesota required a defendant in a False Claims Act case to turn over to a qui tam relator the presentations the company had made to the government prior to the government’s decision to decline the matter. This post by Rachael E. Hunt, Serra J. Schlanger and Anne K. Walsh discusses the arguments made by Boston Scientific Corporation to protect the materials from disclosure (which ultimately were rejected) and the effect this holding may have on other proceedings to obtain defendants’ presentations.
• Medical Software Policies and Guidance: FDA issued a series of guidance documents relating to medical software this quarter. Véronique Li describes changes to existing medical software policies resulting from the 21^st Century Cures Act, Adrienne R. Lenz details FDA’s second draft guidance for clinical decision support software, and Allyson B. Mullen writes about CDRH’s draft guidance on the Safer Technologies Program.

Human Cell, Tissue, and Cellular and Tissue-Based Products (HCT/Ps)

• Jeffrey K. Shapiro writes about the unique regulatory regime for HCT/Ps, outlines the regulatory definitions of “clinical effect” and “homologous use” and discusses whether advertising the clinical effects/performance characteristics of an HCT/P meets the homologous use regulatory requirement.

Drugs

• Patents and Drug Innovation: Kurt R. Karst discusses how the legal system may be steering researchers away from drugs that take a long time to develop. In this post, Karst summarizes a recent research paper that focuses empirically on the relationship between the patent incentive and drug innovation.
• Compounding: Karla L. Palmer discusses several updates to the bulks list prompted by an August decision from the District Court for the District of Columbia that upheld FDA’s strict interpretation of “clinical need” for use of a bulk substance and removal of vasopressin from the Section 503B bulks list discussed here. Shortly after, FDA released a preliminary determination to remove nine other substances from the bulks list while adding five additional substances that Palmer discusses here and here.

Healthcare

• Fraud and Abuse: CMS and OIG proposed substantial amendments to the regulations implementing the Medicare physician self-referral law (i.e., Stark Law) and the safe harbor regulations under the Federal Anti-Kickback Statute in October. Serra J. Schlanger, McKenzie E. Cato and Alan M. Kirschenbaum highlight the proposed changes in this post.

Food & Dietary Supplements

• Importation: Riёtte van Laack discusses FDA’s first Warning Letter for a violation of the FSMA’s requirements for a Foreign Supplier Verification Program (FSVP). Her post describes the FSVP requirements, including the new responsibility of importers to ensure that products are held to the same safety standards as domestically produced food.
• DMHA Regulation: Douglas B. Farquhar and Ricardo Carvajal discuss the 11^th Circuit Court of Appeals concurrence with FDA that DMAA (1,3-dimethylamylamine) is not a “botanical” or a “constituent” of botanicals and that Hi-Tech Pharmaceuticals, Inc. should not have sold DMAA as a dietary supplement. See their post for details about FDA’s and Hi-Tech’s arguments and stay tuned for further developments in other Hi-Tech litigation previously blogged about here.

DEA & Cannabis

• Medical Cannabis: John A. Gilbert and Larry K. Houck continue the discussion of DEA’s planned doubling of the 2019 aggregate production quota for marijuana (prior posts here and here), which would require DEA to act on pending marijuana manufacturer registrations. Their post describes DEA’s announcement to propose additional regulations to address the process and the many questions that remain unanswered.

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Hyman, Phelps & McNamara has its finger on the pulse of FDA. Our technical expertise and industry knowledge are exceptionally wide and deep. Our professional team possesses extensive experience with the universe of issues faced by companies regulated by FDA.  Please contact us for any questions on the issues described here or others affecting the FDA-regulated industry.

Final rule regarding vending machine calorie labeling

Almost 5 years ago, as part of nutrition labeling requirements under the ACA, FDA issued a final rule which requires operators who own or operate 20 or more vending machines to disclose calorie information for food sold from vending machines.  Under that rule, vending machine operators may choose to rely on front-of-pack (FOP) labeling to disclose calories on food items that consumers can see in glass-front vending machines, provided the declaration for calories is at least 50% of the size of the largest printed matter on the label.  FDA had received several objections against the type size requirements for the FOP, arguing that the requirement was impractical, needlessly burdensome, and would disrupt existing voluntary industry FOP nutrition labeling programs.

In response, FDA proposed to revise the type size requirement to be linked to the size of net quantity of contents statement rather than to the largest printed matter on the front panel.  On October 28, 2019, FDA issued the final rule.  The final rule is largely the same as the proposed rule.  FDA made a minor revision clarifying that the size must be at least 150% of the required minimum size of the net contents statement, rather than 150% of the net contents statement as it actually appears on the label. FDA also clarified that only the numerical value indicating the total calories, rather than the word “calories,” is subject to the final rule’s type size requirements.

The compliance date for the new font size requirement is July 1, 2021. FDA also announced that it will continue its enforcement discretion with respect to the vending machine labeling requirements for gums, mints, and roll candy products sold in glass-front machines in packages that are too small to bear FOP labeling. FDA had previously announced its intention to exercise enforcement discretion until at least January 1, 2020, to allow for further consideration of the issue. In the final rule, FDA announced that it will continue to exercise enforcement discretion for these products on an on-going basis.

More enforcement discretion re nutrition labeling for retail foods

In case you missed it, at around the same time as FDA issued the final rule re FOP calorie labeling for vending machine, FDA “announced” enforcement discretion for nutrition labeling of foods sold at retail.

As readers of this blog know, FDA published amended (new) nutrition labeling regulations in 2016.  Changes were quite extensive, and FDA set the compliance date at July 26, 2018, for manufacturers with more than $10 million in annual sales (smaller companies were to get an additional year).  However, upon requests from industry and, in light of timing of FDA’s review of dietary fiber petitions, questions about added sugar labeling, etc., the compliance date was extended to Jan. 1, 2020.  Although this could have been enough time to revise labels, the timing of pertinent FDA guidance, FDA’s action in response to the Farm Bill prohibiting FDA from requiring the declaration of added sugars on single ingredient product, and some other issues caused industry to request for additional time to comply.  Last week, FDA responded to that request by updating its webpage “Industry Resources on the Changes to the Nutrition Facts Label,” questions and answers. This webpage now states that the agency does not intend to take enforcement actions related to the new nutrition labeling requirements for the first six months following the January 1, 2020 compliance date.  Specifically, FDA added the following Q&A:

I understand that the FDA has received multiple requests from manufacturers to provide additional time to comply with the new requirements. Do I still have to meet the January 1, 2020, compliance date?

The FDA has heard from several manufacturers and groups that more time may be needed to meet all of the requirements.  Therefore, during the first 6 months following the January 1, 2020, compliance date, FDA plans to work cooperatively with manufacturers to meet the new Nutrition Facts label requirements and will not focus on enforcement actions regarding these requirements during that time.

As we have mentioned before, the Industry Resources webpage provides useful information and anyone working on nutrition labeling should check out the page regularly.

In two Federal Register notices and the denial of a citizens petition, FDA laid out a revised enforcement program for homeopathic drugs.

Under the FDC Act, just as allopathic drug product, homeopathic drug products are subject to new drug requirements related to approval, adulteration, and misbranding.  However, historically drug products labeled as homeopathic have been manufactured and distributed without FDA approval and with perceived Agency tolerance under the enforcement policies in FDA’s Compliance Policy Guide (CPG) 400.400 from 1988.  This permissive regulatory posture allowed the growth and expansion of a market for safe, properly manufactured homeopathic products as the public interest in nutrition and alternative therapies has grown.

However, as readers of our blog may recall, in response to comments resulting from an FDA public hearing in 2015 and several incidents related to improperly manufactured homeopathic drug products, FDA more recently became concerned about safety.  In 2017, the Agency announced the availability of a draft guidance describing FDA’s intent to switch to a risk-based enforcement approach to homeopathic products marketed without FDA approval.  In the 2017 draft guidance, FDA indicated that it would withdraw the CPG once it finalized the new guidance, because, according to the Agency, the CPG is inconsistent with a risk-based approach to regulatory and enforcement action.

The draft guidance, particularly FDA’s proposal to withdraw the CPG once the guidance, generated many adverse comments. In 2018, Americans for Homeopathy Choice petitioned FDA to keep the CPG or convert it to a regulation so as to allow the continued marketing of and consumer’s access to homeopathic drug products.

FDA was not convinced.  In actions last week, the Agency not only denied the Petition, it also decided to withdraw the CPG now rather than wait until it finalizes the draft guidance.  According to the Agency’s announcement, FDA has concluded that CPG 400.400 is inconsistent with the Agency’s risk-based approach to enforcement generally and that the CPG no longer accurately reflect the Agency’s current thinking.  FDA stresses, both in the announcement of the withdrawal and in its denial of the Petition, that the withdrawal of the CPG does not represent a change in the legal obligations that apply to homeopathic drugs under the statutes FDA administers.

FDA also announced issuance of a revision to the 2017 draft guidance.  The revised draft guidance includes a definition of “homeopathic drug product” for purposes of the guidance, additional explanation of some of the safety issues that contributed to the development of the draft  guidance, and clarification of FDA’s intent to use risk-based factors to prioritize enforcement and regulatory actions involving the marketing unapproved homeopathic products.

Until the draft guidance is finalized, FDA intends to apply its general approach to prioritizing regulatory and enforcement action, which involves risk-based prioritization considering all the facts of a given circumstance.

To ensure that the Agency considers comments to the draft guidance before it begins work on the final version of the guidance, comments should be submitted by January 23, 2020.

What do you get when you “cross an approach to discovery à la Inspector Clouseau with a corporate lawyer caricature found in cartoon caption contests?” According to Judge Steven Rau of the District of Minnesota in a 32-page order that required an “exhaustive” 15-page factual outline, you would get the 2011 qui tam case U.S. ex rel. Higgins v. Boston Scientific Corp., 11-cv-02453, Dkt. No. 313 (D. Minn. Oct. 16, 2019).  In this “disaster” of a case, Judge Rau sanctioned Defendant Boston Scientific Corporation (BSC) for failing to disclose a “central” witness until the final day of a year-long discovery. Notably, the court justified its finding that BSC acted intentionally with respect to its discovery strategy because an alternative finding would mean that BSC acted nefariously during the nearly five-year government investigation that preceded this case.

Higgins caught our attention earlier this month due to the potential ramifications of Judge Rao’s dramatic decision ordering BSC to produce presentations it had made to the government as part of settlement discussions.  We explained how this ruling could potentially discourage defendants from engaging in candid discussions with the government in the future.

Here, the court issued a new order regarding BSC’s failure to identify four key custodians until the final day of a year-long discovery process. One of these witnesses, Erika Huffman was “central” to the litigation, given her communications with FDA on pertinent matters. The court found that these incomplete discovery disclosures violated BSC’s disclosure obligations under Rule 26 because they were without any justification, they “prejudiced” the Relator, and affected the “entire course of discovery in this matter.” Moreover, “it [was] readily apparent to the Court that this was an intentional discovery tactic by Boston Scientific . . . Essentially, Boston Scientific calculated that since the discovery endpoint was not likely to shift, it would be worthwhile to delay and obstruct discovery to hamstring Relator’s efforts to gather information to support his claims.” The court said that it “will not reward such gamesmanship.”

The court rejected BSC’s arguments that the Relator should have realized Huffman’s importance to the litigation as “disingenuous and mendacious.” By that token, the court reasoned, BSC itself should have realized Huffman’s importance—particularly after going through a 4.5-year government investigation on the matter. He found BSC’s arguments that it did not know that Huffman had discoverable information “absurd” and “stretch[ing] all credulity,” given that BSC “operates in a heavily regulated medical device industry and, as such, has compliance departments in contact with federal agencies like the FDA.” The court concluded that BSC “intended to use Huffman as a witness and hid that information until the final moments of discovery.”

Of particular note is how the court related BSC’s behavior at discovery to its actions during the government qui tam investigation. The court reasoned that “either Boston Scientific knew of Huffman’s importance and deliberately left her off its list of initial disclosures,” or the company “withheld documents from the federal government during its investigation.” The court concluded that it was “much more palatable to believe Boston Scientific committed a discovery violation than impeded a government investigation.” Order at 22-23.

In the end, the judge used the judicial discretion permitted under Fed. R. Civ. P. 37(c)(1) and tailored sanctions for the circumstances of the case in an effort to “cleanse” the “taint of Boston Scientific’s Rule 26 violation.” The court ordered BSC to produce within 14 days all documents from the four newly disclosed custodians that hit on the parties’ search terms; barred BSC from using any documents or testimony that had not been produced to Relator in the normal course of discovery; and required BSC to pay Relator’s costs and attorney’s fees for this motion and for any additional discovery required beyond the discovery deadline. The court did not go as far as to apply an “adverse inference sanction,” as requested by Relator, but left open that possibility “should Boston Scientific fail to meet its obligations under this Order.” Although judge Rau called out the Relator for not being diligent enough and backloading discovery to near the end of the process, he refused to punish “the bully and the victim” equally, where the “Relator was essentially fighting with a blindfold on because of Boston Scientific’s discovery actions.”

This case illustrates the risks defendants face when litigating claims declined by the government.  Not only are there tremendous costs for the protracted investigation and discovery process, but even “technical” discovery violations can result in painful rulings that could potentially affect the outcome of the case. The judge’s admonition to outside counsel is also worth noting. “Even if lead counsel was merely implementing directives from Boston Scientific’s in-house counsel, lead counsel ultimately bears the burden of Boston Scientific’s actions. . . . [I]t was outside counsel’s obligation to actually counsel Boston Scientific as to the propriety of such a tactic.” Order at 27, n.13 (emphasis in original).

It is generally accepted that FDA’s authority under the Federal Food, Drug, and Cosmetic Act (FDCA) does not allow for FDA to regulate the practice of medicine.  FDCA § 1006 (21 U.S.C. § 396) explicitly states that FDA may not interfere with the practice of medicine related to legally marketed medical devices.  However, when it comes to the practice of medicine related to prescription drugs, this line is not always bright.  A complaint filed in September in the District Court for the District of Idaho by Rebecca Gomperts, a European physician, and Aid Access, a website designed to “serve women with unwanted first trimester pregnancies globally”, draws new attention to FDA’s role in regulating access to prescription medications and how FDA’s authority may intersect with the practice of medicine.  Gomperts v. Azar et al., 1:19-cv-003450DCN (D. Idaho Sept. 9, 2019).  At the outset, we note that this case is centered on two potentially divisive issues – telemedicine and medical abortion.

As discussed in our article, in March 2019, Aid Access received a Warning Letter from FDA alleging that Aid Access violated the FDCA by introducing misbranded and unapproved new drugs into interstate commerce.  This lawsuit appears to be a direct consequence of that Warning Letter.

Before discussing the allegations in the complaint, it is helpful to understand the regulatory background of the drugs used for medical abortion.  Mifeprex (mifepristone) is used with misoprostol to end an early pregnancy.  FDA approved Mifeprex in September 2000 with a REMS program that includes an Element to Assure Safe Use (ETASU).  The ETASU allows only specially certified prescribers that have completed a Prescriber’s Agreement to prescribe Mifeprex.  In order to prescribe Mifeprex to a patient, a certified prescriber must have:

1. the ability to date a pregnancy and diagnose an ectopic pregnancy,
2. made plans for the patient to receive surgical abortion care in cases of incomplete abortion or severe bleeding, and
3. ensured that the patient has access to medical facilities equipped to provide blood transfusions and resuscitation, if necessary.

The certified prescriber must also agree to provide the patient with the Medication Guide and a Patient Agreement, discuss the Patient Agreement with the patient, have the patient sign the Patient Agreement, and counter-sign the Patient Agreement.  Mifeprex may only be dispensed in certain health care settings, specifically clinics, medical offices, and hospitals, by and under the supervision of a certified prescriber.  Mifeprex may not be distributed or dispensed through retail pharmacies.

According to the complaint, the REMS and ETASU imposed by FDA pose an undue burden on the rights of U.S. women to terminate unwanted pregnancies during the early stages.  Because of the high cost of in-clinic abortion services and the limited availability of misoprostol and mifepristone in the U.S., the complaint argues that many women in the U.S. are forced to use the internet to obtain the medications necessary to end their unwanted pregnancies.  The complaint alleges that women who live in rural or medically underserved areas, have low income, are experiencing domestic abuse and/or are young, are the most impacted by the restrictions imposed by FDA.  The complaint characterizes FDA’s restrictions on these drugs as “actively using the power of the US government to deny Plaintiffs’ patients their constitutionally protected right to terminate their unwanted pregnancies.”

Dr. Gomperts founded Aid Access in 2018; she uses the website to serve women with unwanted first trimester pregnancies by prescribing misoprostol and mifepristone after a telemedicine consultation.  The complaint explains that, between March 30, 2018 and August 27, 2019, over 37,000 women in the U.S., spanning all fifty states and the District of Columbia, contacted Aid Access.  Dr. Gomperts prescribed misoprostol and mifepristone to 7,131 of these women.  According to the complaint, Dr. Gomperts only prescribes the drugs to women in the U.S. if, in her professional judgment as a licensed physician, she believes that the woman can safely have a medical abortion.

Since the REMS specifically state that these drugs may not be distributed or dispensed through retail pharmacies, Dr. Gomperts provides her patients with instructions for how to get the misoprostol and mifepristone delivered to them in the U.S.  Patients are directed to send their prescriptions to a merchant exporter of prescription medications in India.  The exporter sends the prescription medications from India directly to the U.S. patients with customs declarations describing the contents of the packages as “Personal Supply of Rx Medicines.”  Notwithstanding this apparently accurate description, the complaint alleges that FDA, through U.S. Customs and Border Patrol and the U.S. Postal Service, has seized between three and ten individual doses of misoprostol and mifepristone prescribed and exported to individuals in the U.S.

The complaint alleges that FDA is violating Dr. Gomperts’ patients’ substantive due process rights to liberty and privacy.  The complaint includes a number of allegations that the FDA is violating Dr. Gomperts’ and her patients’ right to equal protection under the Fifth Amendment by treating Dr. Gomperts and her patients differently from other similarly situated parties without a sufficient state interest.  The complaint also includes several claims under the Administrative Procedure Act, such as FDA is acting in excess of its statutory authority under the FDCA, and that FDA’s treatment of these drugs is arbitrary, capricious and an abuse of discretion.

FDA has not yet filed a response to this complaint, but we expect that the Agency will fight to preserve its authority to regulate access to these prescription medications under the FDCA.  As mentioned above, although the practice of medicine is generally outside of FDA’s statutory purview, this case presents facts that may tip the balance in FDA’s favor.  For example, Dr. Gomperts is not licensed to practice medicine in the U.S.  FDA typically avoids issues related to the practice of medicine because the regulation of the practice of medicine has been delegated to the states.  Each state sets its own licensure requirements and the individual state Boards of Medicine enforce compliance with those state laws.  Here, however, where multiple states are implicated, it may be that FDA is an appropriate agency to regulate the practice of medicine for these particular products.

FDA’s statutory authority does allow the Agency to regulate medications that are in the stream of commerce.  As already asserted in its Warning Letter to Aid Access, FDA will likely argue that Dr. Gomperts has violated the FDCA by causing the introduction of an unapproved and misbranded drugs, since the misoprostol and mifepristone prescribed by Dr. Gomperts and shipped directly to the patients from India is not in compliance with the REMS provisions for these drugs.  We note that FDA’s website includes numerous warnings that patients should not buy Mifeprex or mifepristone over the internet because doing so “will bypass important safeguards designed to protect your health.”

We will continue to monitor this case and other developments related to FDA and the use of telemedicine.

On October 8, 2019, the California Chamber of Commerce (CalChamber) filed a lawsuit in federal district court against the State of California requesting that the Court enjoin the State, its agents and private enforcers from requiring Prop. 65 warnings on foods that contain acrylamide.  Plaintiff claims that the requirement for a Prop. 65 warning is illegal because it compels Plaintiff’s members and other entities that produce, distribute, or sell acrylamide-containing food products to make false, misleading, and highly controversial statements about their products.  In addition, the warning requirement allegedly will mislead consumers into avoiding certain foods based on incorrect information.  Further, over-warning purportedly dilutes the effectiveness of Proposition 65 warnings on other products that actually pose a risk of harm to consumers, diminishes consumers’ confidence in public health messages and the authorities who promulgate them, and may result in avoidance of foods that are part of a well-balanced diet.

Prop. 65 is officially known as the Safe Drinking Water and Toxic Enforcement Act of 1986.  With some exceptions, Prop. 65 prohibits businesses with ten or more employees from knowingly and intentionally exposing California residents to a chemical known to the State to cause cancer without providing required warnings.  Prop. 65 requires that the California Office of Environmental Health Hazard Assessment (OEHHA) maintain a list of chemicals known to the state to cause cancer or reproductive toxicity.  A chemical is “known to the state to cause cancer” if “a body considered to be authoritative by [the state’s qualified] experts has formally identified it as causing cancer.”  No warning is required if the exposure is below the No Significant Risk Level (NSRL), i.e., the level at which exposure poses no significant risk, assuming lifetime exposure at the level in question for the substance.

Prop. 65 has what is often referred to as a bounty hunter provision.  Under the statute, any person (even one who has suffered no injury) may bring a private enforcement action for an alleged failure to provide an adequate warning.  Such private enforcers are eligible to recover 25 percent of the penalty (the statute imposes penalties up to $2,500 per day for each violation) and their reasonable attorneys’ fees and costs, creating very strong incentives for private enforcement.  Such bounty hunters have a low burden.  In alleging an exposure to a listed chemical, they are not required to prove that an exposure exceeds the NSRL.  Instead, the burden is on the defendant business to prove that exposure is below the NSRL (a potentially costly endeavor).

Acrylamide is the result of a chemical reaction (known as the Maillard reaction) which takes place in certain types of starchy foods when they are cooked at high temperatures or otherwise processed using heat.  The Maillard reaction contributes to taste, aroma and color.  It occurs in a multitude of foods such as French fries, breakfast cereals, baked goods and roasted coffee.  FDA has recognized that acrylamide forms during the cooking process and is present in both store-bought foods and home-cooked foods.

Acrylamide has been on the Prop. 65 list as a potential carcinogen since 1990 based on identification by “authoritative bodies,” namely the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (“EPA”).  Both the EPA and IARC classifications of acrylamide as a “probable” human carcinogen were based on studies in laboratory animals in which virtually pure acrylamide was administered orally or via injection to rats and mice.  However, according to Plaintiff CalChamber, there is no evidence that acrylamide is a carcinogen in humans, and IARC, EPA, and as the State have acknowledged the lack of evidence that dietary acrylamide is a human carcinogen.  Further, studies have shown that certain foods that contain acrylamide, such as coffee, may reduce the risk of cancer in humans.

Nevertheless, dietary acrylamide remains on the Prop. 65 list and remains a popular target for bounty hunters.  According to CalChamber, since its addition to the list, there have been more than 500 notices for alleged violations of the Prop. 65 warning requirement related to acrylamide in food products.  Companies trying to avoid the cost of defending actions and penalties, as well as costly and complicated testing, may decide to include the warning.  Thus, consumers may be misled and be exposed to over-warning.

CalChamber requests that the Court declare that the Prop. 65 warning requirement for cancer relating to acrylamide in human food products violates the First Amendment of the United States Constitution, and enjoin the State as well as bounty hunters from enforcing or threatening to enforce the Prop. 65 warning requirement for cancer relating to acrylamide in human food products.