Attorney East Hampton

By Karla L. Palmer —

As we stated in our earlier blog post, on November 21, 2019, FDA released another draft guidance addressing compounding of animal drug products from bulk substances.  Recall that FDA first released its draft animal drug compounding guidance in 2015 (blogged about here).  With the release of that draft, FDA also withdrew its 2003 animal drug compounding guidance (Compliance Policy Guide Sec. 608.400).  FDA’s 2015 iteration of the compounding guidance was greeted with about 160 comments from industry.  Based on FDA’s consideration of those comments, it withdrew the draft guidance in 2017, which move likely reflected FDA’s significant struggle with determining its authority over animal drug compounding and the fact that the Drug Quality and Security Act (Title I, the Compounding Quality Act) and FDCA Section 503A by their terms do not apply to animal drug compounding.  Like the 2015 draft guidance, FDA’s latest attempt would exponentially expand FDA’s regulatory authority over veterinary medicine and the animal drug compounding space, which traditionally has been a state-regulated practice.  FDA likely will receive many comments on this latest draft, reflecting, among other issues, an alleged federal usurpation of state authority, and FDA’s overstepping through the use of guidance its limited statutory authority in the animal drug compounding space. Notably, the latest draft seems even more restrictive in terms of what may be compounded for use in animals than FDA’s withdrawn version.

Those interested in commenting on the draft should do so by February 18, 2020.  Comments should be submitted to this docket. (FDA-2018-D-4533).  In the Federal Register notice announcing publication of the draft, FDA states that it is specifically requesting comments on guidance section III.A.5, which provides that if that compounded drug contains the same active moiety as a marketed FDA-approved, conditionally approved or indexed drug, but as a different salt, ester, or other non-covalent derivative, there should be a difference between the compounded drug and the FDA approved, conditionally approved or indexed animal drug or FDA-approved human drug that will provide a clinical difference in the patient and the medical rationale is documented in the proscription.  If the veterinarian compounds the drug, the difference should be noted in the patient’s medical record.  Does this sound familiar?  It reminds this blogger of Congress’ prohibition on “essentially copies” of FDA-approved human drug products pursuant to Federal Food, Drug, and Cosmetic Act Sections 503A and 503B.  Notwithstanding, FDA states it is concerned that compounded versions (salts, esters, or non-covalent derivatives) of these products may affect the “absorption, distribution, metabolism excretion and stability of the compounded animal drug,” all of which factors contribute to a drug’s “safety and effectiveness.”  FDA also notes that compounding an animal drug from a different  salt, ester, ester, or other noncovalent derivative of the same active moiety as a marketed FDA-approved, conditionally approved or indexed animal drug or FDA-approved human drug may impact “incentives for seeking legal marketing status” of a new animal drug, and could serve as a disincentive for new animal drug sponsor to research or otherwise develop new animal drugs.

By Karla L. Palmer —

FDA recently released its latest revised draft guidance addressing compounding of animal drug products from bulk substances.  This iteration is not only a re-do of the draft guidance that FDA released in 2015 (blogged about here), but it also includes some new concepts such as a proposed animal drug “bulks” list with its own industry nomination process.  FDA’s 2015 attempt at crafting a guidance document for compounding of animal drugs from bulk substances was met with industry criticism, as set forth in the approximately 160 comments from industry that FDA received before it quietly withdrew that guidance draft in 2017.  As set forth below, FDA’s latest attempt would significantly expand FDA’s regulatory authority over veterinary medicine and animal drug compounding by both pharmacies and vets (which traditionally has been a state-regulated practice).

FDA’s announcement releasing the guidance states that it addresses particular situations concerning compounding animal drugs from bulk substances including: (1) filling patient specific prescriptions for nonfood-producing animals; (2) compounding for “office stock” from bulk drug substances for nonfood-producing animals; and (3) compounding antidotes for food producing animals.

The draft guidance spends many pages describing the “legal pathways” for marketing animal drugs and the Agency’s traditional exercise of enforcement discretion in certain circumstances when no other medically appropriate treatment options exist for the animal.  Akin to the statutory exemptions that Congress granted FDA for human drug compounding, FDA addresses those instances where it would — through the guidance document alone — exercise enforcement discretion for violations of the Federal Food, Drug, and Cosmetic Act’s (FDCA) requirements for animal drug approval, adequate directions for use and cGMP requirements if compounders meet the circumstances described in the guidance.  See Guidance at 4.  FDA expresses its most significant animal drug compounding “concerns” as the following: (1) when compounds present particular human or animal safety concerns; (2) are intended for use in food producing animals; (3) are copies of marketed FDA-approved, conditionally approved or indexed drug products; or, (4) are compounded without a patient specific prescription (i.e., for office stock).  FDA further states that the guidance would not apply in those instances involving investigations of new animal drugs, or those formulations compounded from marketed, FDA-approved (human or animal) drug products, which FDA’s considers extra label use (so long as FDA’s statutory and regulatory requirements for the same are met).

With many similarities to the 2015 draft that FDA rescinded in 2017, this draft guidance also addresses patient specific compounding in pharmacies and compounding for office stock (but omits specific mention this time of “outsourcing facilities”).  The most significant difference between the two drafts, however, is FDA’s request for nominations of bulk substances for its new animal drug bulk substances list, which — we note again — is not authorized by any federal statute, unlike the bulk substance nominations process for FDCA Sections 503A and 503B.

FDA’s guidance draft next details the Agency’s proposed use of enforcement discretion concerning: (1) patient specific prescriptions in nonfood producing animals (please pay particular attention to FDA’s onerous “copies” limitations in bullets 4-6, labeling, and adverse event reporting requirements); (2) compounding without patient specific prescriptions (i.e. office stock) for nonfood-producing animals (note in particular the bulks list reference/limitation at bullet 2, labeling and adverse event reporting requirements); and (3) compounding drugs for use as antidotes for treating toxicoses in food-producing animals, when (among compliance with other conditions listed in the guidance), using substances on FDA’s animal drug bulk substances list.

The “Bulks” Appendix

The Appendix to the draft guidance discusses FDA’s establishment of a public docket (FDA-2018-N-4626) for nominations and comments on bulk substances for (1) compounding office stock for use in nonfood-producing animals and (2) compounding antidotes for food-producing animals. Each nomination should be submitted as its own separate nomination.  FDA’s Appendix includes at pages 15-16 detailed information it expects to be included in the nominations.

FDA sets forth five general conditions for its bulks list, which are worth repeating verbatim here:

1. There is no marketed FDA-approved, conditionally approved, or indexed animal drug that can be used as labeled to treat the condition;
2. There is no marketed FDA-approved animal or human drug that could be used in an extra label manner under section 512(a)(4) or (a)(5) of the FD&C Act and 21 CFR part 530 to treat the condition;
3. The drug cannot be compounded from a marketed FDA-approved animal or human drug consistent with 21 CFR part 530;
4. Immediate treatment with the compounded drug is necessary to avoid animal suffering or death; and
5. FDA has not identified a significant safety concern specific to use of the bulk drug substance in animals.

(emphasis added).

If the bulk substance is to be used as an antidote in a food-producing animal, then, in addition to the above:

6. There is sufficient scientific information for the veterinarian to determine appropriate withdrawal, withholding, or discard time(s) for meat, milk, eggs, or any food which might be derived from the treated animal(s).

Comments to the draft guidance are due February 18, 2020.  Any comments should be submitted to the following docket: Docket No. FDA-2018-D-4533.  Note this docket is different than the bulk substance nominations docket, at FDA-2018-N-4626.

By Riëtte van Laack —

FDA has repeatedly declared that cannabidiol (“CBD”) cannot be lawfully used in food or dietary supplements because FDA approved CBD as an active ingredient in an epilepsy drug before the first marketing of CBD as a dietary supplement or food.  This has not stopped the growth of the CBD industry, however.  The 2018 Farm Bill removed “hemp” from control under the federal Controlled Substances Act, which gave a boost to the hemp industry, and a patchwork of state rules has resulted in a proliferation of a wide array of CBD products.  Several states have passed legislation allowing the use of CBD in foods and supplements, but many other states have declared such uses illegal.  Although FDA maintains its position that the use of CBD in food and dietary supplements is illegal, FDA enforcement has been relatively minimal.

In testimony to before the Senate Committee on Agriculture, FDA asserted that it is exploring regulatory pathways available to hemp products containing CBD, but the Agency predicted that completing a potential rulemaking may take 3 – 5 or more years.  In a letter to FDA, a bipartisan group of members of Congress expressed its concern about this time line, suggesting that FDA announce a policy of enforcement discretion and consider the path of an interim final rule to establish a clear regulatory framework for CBD as a dietary supplement and food additive.

Meanwhile, industry has explored ways to get more clarity on CBD in dietary supplements and foods.  Early in October, four of the major trade associations, AHPA, CRN, CHPA and UNPA, seemingly frustrated by the state of affairs, sent a letter urging Congress to pass legislation that would make CBD derived from hemp a legal dietary ingredient for use in dietary supplements.

On November 14, 2019, CHPA (one of the signatories of the letter to Congress sent a month earlier) submitted a citizen petition requesting swift action from FDA regarding CBD.  Specifically, CHPA asks four things:

1. Establishment of a regulatory pathway to legally market dietary supplements containing CBD derived from hemp by promulgating regulations under the FDC Act, stating that hemp-derived CBD is lawful. Rather than going through the time-consuming process of notice and comment rulemaking, CHPA requests that FDA, under section 553(b) of the Administrative Procedure Act, proceed by issuing an interim final rule.  Alternatively, if FDA were to decide to go through notice and comment rule making, CHPA asks that, in the interim, FDA issue guidance on enforcement discretion for companies that act consistent with the proposed rule.
2. For CBD drugs, continue to enforce the requirements and protections under the new drug application process.
3. Increase enforcement actions against “unscrupulous manufacturers” of CBD-containing products that market their product with illegal drug claims or otherwise fail to comply with the FDC Act.
4. Monitor safety issues, if any, concerning CBD-containing products.

FDA has expressed concern about lack of information on the safety of CBD products and is hesitant to issue a rule stating that CBD may legally be used in supplements without predetermining the safety of CBD for such use.  Rather than putting this burden on FDA, CHPA proposes that FDA’s regulation specify that manufacturers of CBD-containing products must submit new dietary ingredient (NDI) notifications for CBD; CHPA asserts that “NDI notifications would provide FDA with much-needed data on CBD since they must include evidence establishing a reasonable expectation of safety when used under the conditions recommended or suggested in the product’s labeling.”

On November 25, 2019, FDA announced that it had issued another 15 Warning Letters to companies marketing CBD containing supplements or foods.  As before, the Warning Letters targeted companies that market CBD containing foods or dietary supplements with disease claims.  FDA also revised its consumer update outlining specific potential risks associated with CBD consumption.

We will continue to monitor CBD developments.

By Deborah L. Livornese & Dara Katcher Levy —

Just as many object to holiday music in November, the Office of Prescription Drug Promotion (“OPDP”) objected in an untitled letter issued earlier this month to claims made for an investigational drug.  The statements (since removed) appeared on a company website about an investigational drug for the treatment of brain cancer.

In the untitled letter (OPDP’s sixth this year, and eighth enforcement letter overall in 2019), OPDP provided the following examples of statements it characterized as promoting the drug as safe and effective:

• [the drug] “has cured a rare form of brain cancer”
• “Delivering human antibodies for the treatment of cancer”
• “After 5 years, patients treated with [the drug] have an overall survival rate of 25-30%, compared to 3% standard therapy, demonstrating antibodies are safe and effective.”

In addition to objecting to specific claims about the investigational drug, OPDP noted that the website did not “include information to clearly indicate that [the drug] is an investigational new drug that has not been approved for commercial distribution in the United States.”   OPDP also stated that these claims were “especially troubling” because brain cancer is associated with a poor prognosis.  While we do not know how or why this particular website came under scrutiny, this language, along with recent pre-approval promotion enforcement letters, raise the question of whether the individual statements would have drawn an untitled letter if the website had included other language making clear that the drug was investigational and not yet approved, or if it had been for an investigational drug being studied for the treatment of a less serious disease with other approved effective treatments.

OPDP’s focus on pre-approval promotion has not appeared to shift over the past several years.  As we have previously noted (here), FDA may feel it is on safer ground given that its First Amendment case losses have related to information disseminated about marketed products – not wholly investigational products.

This is the second pre-approval promotion letter OPDP has issued this year. The earlier letter concerned an imaging agent for recurrent prostate cancer.  In 2018, OPDP issued one letter about pre-approval promotion (out of a total of seven letters for 2018) for an investigational treatment for AML in which it noted, similar to its most recent letter, that the claims were especially concerning given the seriousness of the disease and the relatively few treatment options.  It may be that OPDP’s pre-approval promotion surveillance focuses on drugs for cancer and other very serious diseases with few available treatment options as this may be an area of greater risk of public harm.  In any event, despite an overall drop in total annual letters since 2013, pre-approval promotion appears to remain an area in which OPDP enforcement is active.

By Sarah Wicks & James E. Valentine & Frank J. Sasinowski —

On November 13, 2019, the National Academies of Sciences, Engineering, and Medicine (NASEM) Forum on Regenerative Medicine hosted a workshop on Exploring Novel Clinical Trial Designs for Gene-Based Therapies. The Forum was tasked with exploring the design complexities and ethical issues associated with gene- and gene-editing-based therapies such as optimal dosage, delivering the product effectively and successfully recruiting patients to what may be “single chance” trials. Co-chaired by FDA’s Celia Witten, Deputy Director of the Center for Biologics Evaluation and Research (CBER), with a broad array of stakeholder participants, the workshop united the voices and perspectives of academic and industry researchers, regulatory officials, clinicians, bioethicists, and patients and patient advocacy groups. This blog post summarizes some of the key challenges identified during the workshop related to designing and conducting clinical trials for gene therapies, and some of the emerging practices shared to help overcome these challenges as we work together to bring more promising therapies to patients.

Challenge 1: Collecting High-Quality Natural History Data

Recently, there has been a great deal of emphasis on the importance of natural history studies, particularly for rare genetic diseases where little is understood about the progression of disease and response to available treatment (see previous coverage of FDA’s Rare Disease Natural History Studies Guidance here). Natural history studies are not only a tool to describe the disease (e.g., to inform development of endpoints) but can also be valuable as external controls (i.e., historical control and patient-as-their-own control). However, the rare or ultra-rare nature of many genetic diseases often makes it difficult to obtain robust natural history data.

But some natural history data is better than none, as one sponsor for a gene therapy for retinal diseases described. Even with a retrospective chart review of approximately 70 individuals, the sponsor was able to describe progression of disease. Another gene therapy sponsor for spinal muscular atrophy described that robustness can come from a mix of natural history data, such as prospective data, retrospective data, and lead-in cohorts. Dr. Witten summarized that natural history datasets can be made more robust with frequent visits, standardized measures, and an effort to collect high-quality patient-level data.  She also noted the importance of identifying the genetic diagnosis in patients, which could help with understanding genotype-phenotype relationships, in order to select clinical trial populations.

Challenge 2: Approaching Patient Concerns through Community, Informed Consent, and Partnership

We know that there is a high tolerance for risk in rare, progressive diseases with no approved therapies. However, patient advocates from Parent Project Muscular Dystrophy and the Friederichs’s Ataxia Research Alliance, among others, explained that there are unique patient concerns when considering whether to participate in a gene therapy trial:

• Because patients receive only a single dose, how do we know the first dose is therapeutic?
• Is it worth it to participate given that participation will exclude you from clinical trials for other investigational therapies?
• Will affected siblings be able to gain access?

Given these unique concerns, how do we set expectations and discuss this with patients, particularly with pediatric populations?

While this is no easy question, Courtney Fitzhugh from the National Heart, Lung, and Blood Institute (NHLBI) at NIH, who is investigating a gene therapy for Sickle Cell Disease (SCD), described 3 factors that she found to influence patients when considering joining a clinical trial: family, faith and other patients. By conducting a survey, Dr. Fitzhugh learned that whether a patient has family that are providing moral support, a strong spiritual belief and community, and has talked with other patients who have participated in clinical trials greatly influences a patient’s decision to enroll in a study. John Tisdale, who is also working at NHLBI with Dr. Fitzhugh on SCD, discussed how sponsors of gene therapies know that the first dose is therapeutic. He described the typical trajectory of first studying investigational therapies in cell culture, then progressing to small and large animal models before ultimately moving into first-in-human trials. Dr. Tisdale emphasized the importance of selecting large animal models that are biologically relevant so that therapeutic doses observed in the large animal model are more predictive of therapeutic dose in the first trial patients. Dr. Witten summarized that patients and families should be partners in the R&D process, and that there is an opportunity to improve the informed consent process for gene therapy trials to help answer these unique patient questions and concerns.

Challenge 3: Inclusion of Pediatric Populations in Gene Therapy Trials

For many genetic diseases, the earlier intervention is received, the better the eventual outcome, which increases the interest of including pediatric populations from the very outset of intervention development. Newborn screening is an important tool to help identify infants with these conditions, and when done at a population-level, it promotes fair access to cutting-edge technologies in clinical trials.

But to include children in interventional trials, when there is more than minimal risk, there must be a prospect of direct clinical benefit and the risk-benefit must be at least as favorable over other available therapies, which typically are nonexistent. Additionally, sponsors need to be specific across the type of pediatric population they wish to study (i.e., newborn, infant, child, adolescent) because there may be unique differences between these subgroups, and compared to adults, that leads to different trial designs and outcome measures.

Challenge 4: Developing Efficacy Endpoints for Gene Therapy Trials

For rare genetic disorders for which there are no other treatments available, a novel endpoint usually must be established. Larissa Lapteva, Associate Director of the Division of Clinical Evaluation, Pharmacology, and Toxicology (DCEPT) within CBER’s Office of Tissues and Advanced Therapies (OTAT), described three points to consider when developing efficacy endpoints for gene therapy trials:

1. Consider the long-term or potentially irreversible effects of gene-therapy treatment; Dr. Lapteva noted that there is little room for uncertainty about endpoint performance and sponsors are therefore required to increase vigilance in validity and accuracy of endpoint measurement.

2. Mechanistically agnostic endpoints that are reflective of common pathogenetic pathways may not be sufficiently sensitive in gene-therapy trials;

Sponsors need to consider that the increased availability of genetic screening, early diagnosis, and advanced lab testing has shifted the demand toward surrogate and clinical endpoints that are reflective of early disease manifestations. Additionally, the identification of genetic defects associated with non-well-characterized phenotypes has increased the need for novel clinical endpoints.

3. Opportunity to identify and validate surrogate endpoints along the pathway of gene transcription, transgene protein synthesis and level, functional activity and clearance.

Following Dr. Lapteva’s remarks, an investigator studying a gene-therapy for SCD described how pain as a primary outcome is overly subjective, making it difficult to identify the unique cause of the pain and to differentiate chronic versus acute pain. She also noted that biologic endpoints in SCD, while each with limitations, are based primarily on predictive value and are only associated with disease severity, not disease modifiers. Meanwhile, the sponsor of a now-approved gene therapy for an inherited retinal dystrophy provided a case study detailing how the lack of a clinically meaningful endpoint for rod vision led the sponsor to develop a novel functional vision endpoint that was the primary basis for approval (see our previous coverage of this gene therapy’s development and endpoint here).

Challenge 5: Considerations for Long-Term Follow-Up (LTFU)

Tejashri Purohit-Sheth, Director of DCEPT, described the importance of LTFU and considerations for sponsors to manage such follow-up. LTFU is needed because gene-therapy products are designed to achieve prolonged or permanent therapeutic effects and such long-term exposure may result in undesirable or unpredictable adverse outcomes that may occur past the period of monitoring. Sponsors should take into account multiple factors when considering their risk-assessment, including product characteristics, the target cell/tissue/organ, and preclinical and clinical information. Characteristics that increase risk include integration activity of the gene-therapy product, genome editing activity, prolonged expression of the transgene, potential for latency, and establishment of persistent infections. For more information on LTFU, we direct you to FDA’s Draft Guidance on LFTU After Administration of Human Gene Therapy Products here.

Dr. Witten summarized that patient registries, mobile health applications, and other remote tools may help with the collection of patient-reported outcomes in the subsequent 10 years of post-marketing follow-up when subjects should be contacted a minimum of once a year.

In addition to those provided in-text, our readers can find some of our additional coverage of gene therapy regulation:

• Gene Therapy and Orphan Drug “Sameness” here
• FDA’s Comprehensive Policy Framework for Regenerative Medicines here
• FDA “State of Cell and Gene Therapy Statement” here
• Historic Approval of First Systemically-Administered Gene Therapy here

 

By McKenzie E. Cato & Josephine M. Torrente —

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.

By Sara W. Koblitz —

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.

By Riëtte van Laack —

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.

By Véronique Li, Senior Medical Device Regulation Expert & Sarah Wicks —

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-extant 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.

By Serra J. Schlanger —

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.