By Allyson B. Mullen –

On April 1, FDA issued an updated draft guidance regarding the policies and procedures for Emergency Use Authorizations (EUAs). The EUA procedures cover all types of medical products including drugs and biologics (e.g., vaccines and therapeutics) and devices (e.g., personal protective equipment and in vitro diagnostic tests).  The updated draft guidance is intended to replace the 2007 and 2009 draft guidances on this same topic.  The substance of the updated guidance is relatively unchanged from the 2007 draft, with the exception of a few key points, discussed below.

IVDs.  The updated draft guidance provides more specific guidance with regard to IVDs.  For example, the update guidance now gives examples of both effectiveness and safety data that should be included in an IVD EUA application.  This information is particularly useful for IVD manufacturers given the need for adequate tests to diagnose disease that present emergencies, such as Zika and Ebola.  In fact, the majority of current EUAs relate to diagnostic products (see a list of currently in effect EUAs here).

In addition, the updated guidance provides information regarding categorization of diagnostic tests (i.e., point-of-care versus laboratory use). An authorized diagnostic test will be deemed waived if FDA determines that “the categorization would be beneficial to protecting the public health; and the known and potential benefits of such categorization under the circumstances of the authorization outweigh the known and potential risks of the categorization.”  This categorization is independent of the CLIA categorization for an approved or cleared test and will last as long as the EUA is authorized. 

Government Entities.  The 2007 draft guidance indicated that applications for EUAs could come from both government and private entities.  The updated guidance, however, suggests that government entities rather than private entities are likely to be sponsors of EUAs.  The updated guidance indicates it is FDA’s experience that government entities submit the most requests for EUAs.  We found this addition curious because according to FDA’s website the currently authorized EUAs are split pretty evenly between government and private entities.

The updated guidance also indicates that private entities seeking EUAs should “first seek support from relevant governmental stakeholders that may be engaged in official response efforts (e.g., HHS ASPR, CDC, DoD, or state/local public health authorities) to ensure that the use encompassed by the request is appropriately coordinated and will not interfere with official response plans.” While this addition to the guidance appears logical, adding a step of contacting a government agency, will likely slow down and may even deter private entities attempting to have its product authorized under an EUA.  It is unclear if FDA would refuse an EUA if a private applicant does not (or is unable to) obtain input from the relevant governmental authorities.

Fact Sheets. Although the updated guidance continues to provide helpful instruction regarding the type of information required in an EUA application, it omits the Appendices from the 2007 draft guidance, templates for the EUA Fact Sheets.  Fact Sheets are documents provided to the healthcare professionals and recipients of the unapproved product describing, among other things, the product and its emergency use.  It is unclear from the draft guidance whether FDA intentionally omitted these appendices because it no longer thinks the forms are applicable.  Absent clear indication from FDA that these forms should no longer be used, entities planning to submit an EUA should be aware of these older templates.  Copies of the templates can be found in the original draft guidance, here.

By Allyson B. Mullen –

For the past several years, a public-private stakeholder Planning Board has been evaluating the possibility of a new National Medical Device Evaluation System (NMDES). See our earlier posts on this initiative here and here. As discussed in our earlier posts, the NMDES is intended to aggregate significant amounts of both pre-and postmarket information into a single system, including information from claims and administrative systems, patient-generated data, EHRs, and device-specific and clinical care registries.  This information is intended to be useful to a wide variety of stakeholders, including CDRH.

In late 2015, FDA requested that the Duke-Margolis Center for Health Policy (Duke) convene the Planning Board to lead the next phase in development of the NMDES. This phase of development focused specifically on the NMDES governing body, the Coordinating Center and its Governing Board. On April 5, Duke issued the latest National Medical Device Evaluation System Planning Board Report. 

The report provides a framework for the Coordinating Center and its Governing Board. The Coordinating Center is intended to “provide governance, coordination, and standardization to drive down time and cost of generating evidence on medical devices, while increasing the accessibility and usability of real-world data.” The Planning Board recommends that the Coordinating Center be organized as a non-profit entity with both public and private representatives sitting on the Governing Board. The report outlines the principles, goals, capabilities, and objectives of the Coordinating Center.

The report gives the sense that creation and implementation of a NMDES may happen sooner rather than later, which was generally lacking in other reports on this same topic. For example, the report highlights that it is a goal of CDRH to establish the Coordinating Center in the near-term as part of its 2016-2017 Strategic Priorities. As a practical matter, the report indicates that it would not be possible to create a de novo entity to act as the Coordinating Center in a short timeframe. Therefore, the report recommends that the Coordinating Center be incubated at “an established hosting organization.” The report acknowledges that there could be inherently competing interests in structuring the Coordinating Center this way and suggests that there be a plan to ultimately spin off the Coordinating Center from the hosting organization into its own independent entity.

Like the earlier reports on NMDES, however, there are many still unanswered questions in this report. The Planning Board continues to state that the NMDES will not be adequately funded by FDA seed money alone and will need to be a financially stable and independent entity. The report suggests that the hosting entity obtain matching funds to support the Coordinating Center. The report states that manufacturers, health insurance organizations, and research organizations could provide funding for NMDES development. It is unclear why such private entities would voluntarily provide funding for NMDES development without some incentive. Longer-term, the report indicates that funding could come from a variety of sources including patient groups (it is unclear why patient groups would use their scarce resources to provide funding), and funding for research studies from clinicians, hospital systems, manufacturers, health insurance organizations, and research organizations. It is possible that funding could come from philanthropic donations, but there is no mention of this potential funding source in the report.

Perhaps the most curiously unanswered question, however, relates to next steps, including who will appoint the hosting center for the Coordinating Center. The organization and compensation (if any) of the hosting entity and Coordinating Center could significantly affect the role and impact of NMDES. The report concludes with an optimistic timeline: 

• Within 6 months after selection of the host entity for the Coordinating Center, appoint an interim executive director to provide day-to-day leadership.

• Within 1 year – public appointment of the Governing Board for the Coordinating Entity; propose and initiate two demonstration projects (projects that demonstrate the value of NMDES); create initial governing policies for the Coordinating Center and NMDES; and charter and convene expert committees to advise the Coordinating Center.

• Within 2 years – create a publicly accessible clearing house of medical device evaluation activities; create publicly accessible expert guidelines for evaluating patient signals and patient-focused processes for information dissemination; and initiate two additional demonstration projects.

• Within 3 years – complete two demonstration projects.

• Within 5 years – have a financially stable, independent Coordinating Entity.

There are no details about the immediate next step to get the NMDES program started: appointing the host entity for the Coordinating Center and who is responsible for this appointment. In addition, the plan does not appear to address creation of the actual data systems necessary for NMDES, unless these systems are what the plan describes as the “publicly accessible information clearing house of medical device evaluation activities.” The report indicates that this is the first in a series of papers that will be issued by the Planning Board; perhaps additional details will follow. We will certainly keep you posted.

By Jennifer D. Newberger –

The Federal Trade Commission (FTC) recently released a guidance titled “Mobile Health App Developers: FTC Best Practices,” intended to provide tips to developers about data security. FTC also released an accompanying on-line tool to assist developers in determining the federal laws that apply to their mobile apps. The guidance and interactive tool were developed in collaboration with FDA, the Department of Health and Human Services Office for Civil Rights, and the Office of the National Coordinator for Health Information Technology.

The tool consists of a series of high-level “yes” or “no” questions to be answered by the app developer. The answer to any individual question directs the user to a subsequent question, and ultimately informs the user as to the applicability of HIPAA, the FTC Act, and/or the Federal Food, Drug, and Cosmetic Act (FDC Act).

The tool is fairly straightforward and provides basic information to a novice developer. What it fails to do is explain in more detail how an app should comply with the law, should it potentially apply to a particular app, and what the relationship is between the laws. For example, Questions 5, 6, and 7 help the user determine whether the app is a mobile medical app and, if so, whether it is the type of app over which FDA intends to exercise its regulatory authority. Regardless of the applicability of the FDC Act to the app, the tool then asks whether the app developer is a non-profit organization. If the answer is “no,” the tool states that the FTC Act likely applies, and that the FTC Act “prohibits deceptive or unfair acts or practices,” meaning that the developer “cannot make deceptive or misleading claims to consumers about things that are important to them,” and “cannot engage in acts or practices that cause, or are likely to cause, substantial injury to consumers that they cannot avoid, and that do more harm than good.”

Stating that the FTC Act “may apply” even to regulated medical devices is an interesting perspective, given the broad regulatory authority of the FDA over regulated medical devices with respect to claims made about the product. Although FDA technically has authority only over the “labeling” of a medical device, and FTC over the advertising (with certain exceptions), courts and FDA have broadly interpreted the meaning of labeling such that it includes nearly all promotional activity of a manufacturer. Therefore, even if the FTC Act were to apply to a regulated mobile app, it is far more likely that FDA, rather than FTC, would take action against a company for false or misleading claims. Neither the tool nor the guidance provides insight regarding precisely how, if at all, the FTC Act, rather than the FDC Act, would govern misleading promotional claims about a mobile app. Developers of mobile medical apps over which FDA will exercise its regulatory authority should assume that their promotional claims will be subject to oversight by FDA, rather than FTC.

By Andrew J. Hull –

FDA often seeks permanent injunctions against FDA-regulated companies that allegedly run seriously afoul of FDA’s cGMP requirements. FDA usually asks courts, in granting a permanent injunction (the agency’s most powerful civil enforcement tool against U.S. facilities), to order the complete shutdown of a facility’s operations. Indeed, in the proposed consent decrees that the agency usually offers to industry as an alternative to a court battle, FDA routinely requires a shutdown provision that only terminates when FDA reinspects a facility and issues what is commonly referred to (at least by FDA litigation wonks) as a “green light letter.”

A recent case in the Eastern District of Michigan, United States v. S. Serra Cheese Co. (No. 2:14-cv-13077), however, signals a hesitancy by courts to allow such a drastic provision in an injunction, as well as likely unwillingness by the government to press for a company’s shutdown when it receives pushback from either the company or the court.

After multiple inspections revealing cGMP violations and a Warning Letter issued in 2013, the government filed a complaint for a permanent injunction in August 2014 against S. Serra Cheese Company (“Serra”), a manufacturer of ready-to-eat cheeses, and its co-owners. The government alleged that the defendants: (1) introduced or delivered for introduction adulterated food, as defined by the FDCA, into interstate commerce; and (2) caused the adulteration of articles of food while such articles were held for sale after shipment of their component parts into interstate commerce. Complaint at 6. Specifically, the government alleged that the cheese products had been

prepared, packed or held under insanitary conditions whereby they may have become contaminated with filth or rendered injurious to health. The insanitary conditions include the presence of generic, nonpathogenic E. coli and L. innocua and Defendants’ failure to implement effective monitoring and sanitation controls in accordance with [cGMP] requirements for food.  

Id. at 4.

In the complaint, as well as in the government’s proposed permanent injunction, the government sought an order prohibiting Serra and its co-owners from “receiving, preparing, processing, packing, holding, and distributing all food at or from their facility . . . unless and until” they bring such operations into compliance with the FDCA and FDA’s regulations “to FDA’s satisfaction.” Id. at 8-9.

Ruling on a motion for summary judgment filed by the government, the Court held that the company had violated the FDCA by introducing adulterated food into interstate commerce and causing food to become adulterated while it was held for sale after shipment, and it granted the government’s motion for summary judgment. Order at 10. The Court held that the government was entitled to injunctive relief, but noted that it was “not disposed to immediately close the facility; the fact that it has continued to operate during the pendency of the case is of significance.” Id. at 14. The court then ordered the parties to reach a resolution on the language of the injunction.

It appears that the government acquiesced in the judge’s concern that Serra be permitted to continue operations, despite the government winning its motion for summary judgment. The only issue that the government and defendants were unable to resolve without the Court’s involvement was the extent of time for which the injunction would remain in effect. The government wanted it to remain for five years; the defendants wanted a sunset provision of one year.

In the injunction issued on April 4, 2016, the Court imposed various cGMP controls and reporting requirements upon the defendants, presumably as the parties had negotiated, but it sided with the government by imposing a five-year sunset provision. The Court, however, did not order a shutdown of Serra’s operations.

The most interesting fact in this case is that the Court did not want to allow a shutdown of Serra’s operations, and that the government apparently backed off from seeking this provision in the injunction.

Often, larger drug and device companies will feel the need to ensure peace between them and FDA, and they will not challenge a shutdown provision in a proposed FDA injunction for fear of further angering FDA. Food companies, on the other hand, are often smaller, and scrutiny from FDA is rarer than with drug and device companies. These food companies may feel less of a need to stay in FDA’s good graces, and might freely challenge proposed injunction provisions that they believe are too onerous. And, from other cases we have observed, these food companies appear to be having some success with pushing back against shutdown provisions and continuing operations throughout the entirety of the term of an injunction. See, e.g., Permanent Injunction, United States v. Am. Mercantile Corp., No. 2:11-cv-02371 (W.D. Tenn. Nov. 8, 2012) (a case in which this firm represented the defendants).

Of course, all cases are fact specific, and it is impossible to know how a particular court or the government will act in other civil injunction cases. It does appear, though, that, in civil injunction cases, if FDA-regulated companies push back against the government’s proposal for a shutdown of company operations, courts may reject the government’s demand for an injunction that completely shuts down a company’s operations and puts most or all of its employees out of work. And the government may be willing to acquiesce to this objection if properly pushed.

By James C. Shehan –

FDA issued it second-ever approval of a biosimilar on Tuesday, April 5, giving the nod to Celltrion’s and Pfizer’s Inflectra, a biosimilar version of J&J’s Remicade (infliximab). The approval follows some of the precedents established in FDA’s approval of the first biosimilar (i.e.,Zarxio) – specifically, reliance on clinical data to support approval and extrapolation of data to support approval of multiple indications for which the biosimilar sponsor did not submit clinical data. The approval is also noteworthy for FDA’s decision to follow some precepts that the Agency decreed in recent draft biosimilar guidances, including: (1) requiring that Inflectra’s prescribing information identifying it as a biosimilar of Remicade; (2) Inflectra being given a product name with a meaningless four syllable suffix (“infliximab-dyyb”); and (3) the prescribing information including four different means of product identification (“Inflectra,” “Remicade,” “infliximab-dyyb” and “infliximab”) as appropriate to the circumstances.

Inflectra was reviewed by FDA’s Arthritis Advisory Committee on February 9, 2016 (FDA briefing document here). The Committee recommended approval by a vote of 21-3, with the three no votes apparently tied to concerns over extrapolation.

The Inflectra NDA included the following data: 

• Extensive analytical data showing that (i) Inflectra and US-licensed Remicade are highly similar; (ii) Inflectra can be manufactured in a well-controlled and consistent manner; and (iii) that data comparing European Union (EU)-approved Remicade EU)-approved to Inflectra could be used to show biosimilarity to US-licensed Remicade.
• A single dose PK study comparing Inflectra, US-Remicade and EU- Remicade.
• A clinical study comparing Inflectra and EU-Remicade – 54 weeks, randomized, double-blind, parallel group study conducted outside the US in approximately 600 patients with moderate to severely active rheumatoid arthritis. The primary endpoint was the proportion of patients who remained in the study and achieved an American College of Rheumatology 20% (ACR20) response at Week 30.
• A 54-week randomized, double-blind, parallel-group study conducted outside the US in 250 patients with moderate to severe ankylosing spondylitis.
• An assessment of safety and immunogenicity in patients undergoing switches in an open label extension of the rheumatoid arthritis study.
• Scientific justifications for extrapolation to the six indications for which Inflectra is approved but didn’t submit clinical data.

Although clinical trials were only conducted in patients with rheumatoid arthritis and ankylosing spondylitis, FDA permitted extrapolation to six other indications for which Remicade is approved. But Inflectra was not approved for one indication held by Remicade, pediatric ulcerative colitis, because Remicade has pediatric exclusivity for that use until September 2018.

Based on recent FDA guidance (see our post here), Inflectra’s labeling contains the following statement:

INFLECTRA (infliximab-dyyb) is biosimilar* to REMICADE (infliximab) for the indications listed.  

* Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product.

It is not clear at this time whether Zarxio’s prescribing information is being changed to include a similar statement.

Per last year’s naming guidance (see our post here), the proper name assigned by FDA to Inflectra is“infliximab-dyyb.” There’s no indication whether FDA or the sponsors picked this suffix. One wonders whether this is a sign that FDA has rejected the option proposed in the guidance of these four letter suffixes being assigned to companies, as is the case with the filgrastim-sndz name assigned to Zarxio.

Because of litigation, the launch date of Inflectra is uncertain. J&J and Celltrion are in litigation over a patent that expires in 2018, but a J&J court filing indicates that Celltrion and Pfizer have agreed to not enter the market until at least June 29, 2016.

Inflectra is currently approved in numerous countries, including Korea, Canada, Japan and the EU.

Based on a slim sample of two approvals, it seems that getting a biosimilar approved will require the generation of clinical data from at least one large non-inferiority trial using patients with a condition that the reference product is approved to treat. It also appears that extrapolation will be readily permitted, that the meaningless four letter suffix may be a permanent fixture for biologics and that FDA is serious about labeling containing a statement that a biosimilar is a biosimilar. As for interchangeability, while perhaps not as mythical as El Dorado, Atlantis or the Kingdom of Prester John, it remains for the time as elusive as that next Chicago Cubs world championship.  

By Riëtte van Laack –

As required by the Sunscreen Innovation Act (SIA), FDA published its proposal for the review of Time and Extent Applications (TEAs) for non-sunscreen ingredients (the SIA lays out the framework for sunscreen ingredients). It now is evident that a TEA will take time, considerable time.

FDA’s proposed regulation addresses several aspects. First, it proposes new regulation 21 C.F.R. 330.15 which lays out the timing of a TEA. Second, this new regulation describes measurable metrics that FDA will use to track the timelines set forth.

The TEA process consists of several steps, the eligibility determination, the filing determination, review of the safety and effectiveness data, preparation of a proposed rule, comment period, and preparation of a final rule. The timing laid out in the proposed rule essentially means that this process likely will take more than 6 years. That is, if the sponsor provides the data without any delay, the data are complete, FDA determines that the ingredient is GRASE, and the comment period for the proposed rule is limited to 90 days.

The TEA process beings with the submission of the TEA containing data that support the marketing history. If the data meet the eligibility data, FDA publishes the notice of eligibility. As proposed, FDA will make the eligibility determination within 180 days (6 months) of submission of the TEA. Next, the Agency must make a filing determination. FDA proposes that it will make this determination within 90 days (3 months) after the sponsor has confirmed that it considers the data complete. If the sponsor submits the safety data at the same time as the TEA, FDA will make the filing determination within 90 days after the eligibility determination.

FDA will issue a notice of proposed rulemaking regarding the safety and effectiveness of the ingredient within 1,095 days (36 months). If the Agency determines the ingredient is not GRASE, it will inform the sponsor earlier of this determination via a feedback letter (within 730 days (about 24 months)). A final rule would be issued within 912 days (30 months) after closing of the comment period. Thus, the process from start to finish may take 6 + 3 + 36 + 3 +30 = 78 months. This assumes that there are no extensions, the sponsor submits complete data with the submission of the TEA, and FDA determines that the ingredient is GRASE.

The proposed framework does not apply to the TEAs that were pending before the enactment of the SIA. Sponsors of those TEAs had the option of requesting their own framework. Three of the six pending TEAs requested a framework previously. For the three remaining pending TEAs, FDA proposes to use the date that FDA publishes the final rule, 21 C.F.R. § 330.15 as the date of filing (i.e., the sponsors of these TEAs may expect a response from FDA at the latest 36 months after the publication and if the ingredient is determined GRASE, a final rule codifying that determination will issue within 69 months).

FDA also proposes to amend the current regulation for TEAs, i.e., 21 C.F.R. § 330.14. Notably, FDA proposes to include provisions that spell out how FDA will determine whether it will file the TEA, i.e., whether the safety and effectiveness data are sufficiently complete to allow a substantive review. In addition, FDA proposes definitions of certain terms, and a provision regarding the withdrawal of a TEA and safety and effectiveness data.

Thus far, the TEA process has been used infrequently. Since 2002, FDA has received six TEAs. Nevertheless, FDA estimates that it will receive two additional non-sunscreen TEAs per year.

By Larry K. Houck –

The Substance Abuse and Mental Health Services Administration (“SAMHSA”) has published a proposed rule that would increase the number of patients with opioid abuse disorder that a qualified physician can treat with buprenorphine. Medication Assisted Treatment for Opioid Use Disorders, 81 Fed. Reg. 17,639 (Mar. 30, 2016). Three weeks ago the Centers for Disease Control and Prevention (“CDC”) released opioid therapy and prescribing guidelines for chronic pain (see our previous post here). Both documents represent federal efforts to address what SAMHSA characterizes as “an unprecedented increase in prescription opioid abuse, heroin use and opioid-related overdose deaths.” 81 Fed. Reg. at 17,650. The CDC guidelines set out cautionary opioid therapy practices while the SAMHSA rule would expand patient access to medication assisted treatment (“MAT”). SAMHSA cites evidence that the current maximum 100-patient limit is a barrier for patient access to needed treatment. Id. at 17,651. The proposed rule would expand access to MAT by doubling the maximum number of patients that a qualified practitioner could treat for opioid use disorder with buprenorphine to 200. Practitioners authorized to treat the higher patient number would be required “to accept greater responsibility for ensuring behavioral health services and care coordination are received and for ensuring quality assurance and improvement practices, diversion control, and continuity of care in emergencies” in addition to compliance with SAMHSA’s data reporting and monitoring requirements. Id. at 17,640.

Currently, under the federal Controlled Substances Act (“CSA”), qualified practitioners can prescribe, administer or dispense buprenorphine products for the treatment of opioid use disorder in an office, community hospital, health department or correctional facility. 21 U.S.C. § 823(g)(2). To qualify, the practitioner must be a physician, hold a valid medical license and DEA registration, have the capacity to refer patients for counseling and other ancillary services, and have completed required training. 21 U.S.C. § 823(g)(2)(G). The practitioner submits notification of intent to dispense or prescribe buprenorphine to a maximum of 30 patients at a time for use in maintenance or detoxification treatment. 21 U.S.C. § 823(g)(2)(B)(iii). This precludes the practitioner from having to obtain a separate DEA registration as an opioid treatment program (“OTP”-formerly referred to as a “narcotic treatment program.”) The practitioner may file a second notification of intent after a year to increase the number of patients they can treat to 100 patients at a time. Id. SAMHSA’s proposed rule would increase the maximum number of patients to 200 that a practitioner could treat at one time if they meet certain criteria. To be eligible to treat up to 200 patients, practitioners must have held a waiver to treat 100 patients for at least one year without interruption and possess a subspecialty board certification in addiction psychiatry or addiction medicine or practice in a qualified practice setting. Medication Assisted Treatment, at 17,660. Practitioners cannot have had their enrollment and billing privileges in Medicare revoked or have been found to have violated the CSA. Id. Practitioners meeting these requirements must submit a request to increase their patient limit to SAMHSA certifying that they will “adhere to nationally recognized evidence-based guidelines for the treatment of patients with opioid use disorders” as well as “adhere to a diversion plan to manage the covered medications and reduce the possibility of diversion of covered medications from legitimate treatment use.” Id. at 17,661.

SAMHSA will approve or deny a practitioner’s request within 45 days of receipt. Id. Practitioners approved to treat the increased number of patients must submit reports, documentation and data to SAMHSA to demonstrate compliance, which may include requests for information about the average monthly caseload of MAT patients per year, percentage of active patients “that received psychosocial or case management services” in the prior year, percentage who had a prescription drug monitoring query in the prior month and number of patients at the end of the reporting year who completed treatment or no longer receive buprenorphine. Id. at 17,661-62. Practitioners would submit reports within a year after the date SAMHSA approves their request. Id. SAMHSA may verify reports with other data sources including prescription drug monitoring programs (“PDMPs”). Id. at 17,662. The agency may suspend a practitioner’s approval in order to protect the public health and safety, and revoke it if the practitioner made misrepresentations or the practitioner no longer satisfies requirements or has violated the CSA. Id.

While inviting interested parties to submit comments on all aspects of the proposed rule, SAMHSA poses specific question areas for comment. For example:

• Would a prescribing limit other than 200 patients proposed by the rule be more appropriate?
• Is the level of training required to request a patient limit increase appropriate?
• Are there other ways to affirm practitioner competence without specialty board certification?
• Are there additional ways for a practitioner to become eligible to apply for the increased patient limit?
• What costs will be associated with compliance with the rule’s requirements and how many practitioners will be able to fulfill them?
• How many patients must a physician treat to make training, administrative and other requirements not cost prohibitive depending on clinical environment?
• Is requiring renewal of the waiver every three years sufficient or should practitioners renew more frequently?
• Should SAMHSA synchronize the three-year waiver renewal with the practitioner’s DEA registration?
• How many practitioners not currently eligible to treat 200 patients would as a result of the rule, take steps to qualify?
• How many practitioners eligible to treat 200 patients will seek to do so?
• Should SAMHSA combine the reporting with other existing reporting requirements?
• Does the proposed rule strike the appropriate balance between ensuring that the required credentials are obtainable for interested practitioners?
• Are MAT programs practical to implement?
• Are reporting requirements perceived as a barrier to participation?

Id. at 17,658-59.

SAMHSA “hope[s]” that the proposed rule “will stimulate broader availability of high-quality MAT both in specialized addiction treatment settings and throughout more mainstream health care delivery systems.” Id. at 17,640. In our opinion, to fulfill that hope, the proposed rule’s graduated MAT authority for the first 30 patients, then 100 patients and finally 200 patients over two years is reasonable. Practitioners who cannot comply with treating 30 patients should not be authorized to treat up to 200 patients. Conscientious practitioners may conclude that they cannot responsibly treat more than 30 or 100 patients. Doubling the number of patients for practitioners already providing MAT may require expending only minimal additional resources. However, qualified practitioners may perceive detailed reporting requirements as too onerous to offer MAT or increase their patient numbers. Increased scrutiny and enforcement by SAMHSA and DEA may deter some practitioners. For the proposed rule to increase availability of treatment, SAMHSA should tailor regulatory requirements and costs to protect patient health and safeguard against controlled substance diversion, making them as least burdensome as possible. For example, if SAMHSA determines that waivers should be renewed every three years, it should synchronize their renewal with the practitioner’s DEA registration cycle. In addition, with accessibility to state PDMPs, SAMHSA may be able to monitor MAT activity for specific practitioners without requiring the submission of detailed annual reports.

SAMHSA must receive comments to the proposed rule no later than May 31, 2016.

For generic drug companies, the biggest and most expensive challenge to a US product launch is the patent that covers the Active Pharmaceutical Ingredient (“API”). Notoriously, only one such patent has ever been invalidated for obviousness.

On Thursday, April 14, 2016, from 9:00 AM – 10:00 AM EST, Kurt R. Karst (Hyman, Phelps & McNamara, P.C.) and Jeffrey A. Hovden (Robins Kaplan LLP) will present a primer on strategies for generic drug manufacturers to get around API patents, using the 505(b)(2) application. This route can enable a generic company to use a prodrug or deuterated drug to avoid the API patent—and brand marketing exclusivities—while still benefiting from brand safety and efficacy data.

The presenters will use particular examples to illustrate the pros and cons of this basic strategy, discussing current law and FDA regulations, helping you to plan for and maximize such opportunities. You can register for the webinar here.

By Jay W. Cormier –

Just a little more than four months after FDA approved AquAdvantage Salmon (AAS) – the first genetically engineered (GE) animal intended for food use – several organizations filed suit against FDA and the U.S. Fish and Wildlife Service (FWS) challenging that approval.  Plaintiffs include the Center for Food Safety (not to be confused with FDA’s Center for Food Safety and Applied Nutrition, or CFSAN), Earthjustice, and Food and Water Watch, among others.  As we predicted when FDA approved AquaBounty’s AquAdvantage Salmon last November, Plaintiffs filed suit and allege that FDA and FWS violated various statutes, including the FDCA, the Administrative Procedures Act (APA), the National Environmental Policy Act (NEPA), and the Endangered Species Act (ESA). 

Without going through each of the thirteen alleged causes of action and the twelve actions requested of the U.S. District Court for the Northern District of California, we briefly discuss the merits of the case below. For a detailed description of AAS, see our earlier post regarding Food and Water Watch’s petitions to FDA, which FDA denied when the agency approved the new animal drug application (NADA) for AAS.

FDCA Claims

Plaintiffs claim that the FDCA does not grant FDA the authority to approve NADAs for GE animals. Recall that FDA has asserted its authority over GE animals through the “structure-function” clause of the drug definition.  That clause defines a drug as any article “intended to affect the structure or any function of the body of man or other animals.”  FDCA § 201(g)(1)(C).  FDA has argued for over a decade that the recombinant DNA (rDNA) construct used to genetically engineer AAS is an article that is intended to affect the structure and function of the body of the salmon, and, therefore, the rDNA construct meets the statutory definition of a drug.  Because the construct is present in the genome of the salmon, and is heritable from one generation to the next, FDA has argued that it has jurisdiction over the salmon itself in perpetuity. 

Plaintiffs’ claim that FDA lacks statutory authority to approve NADAs for GE animals faces two hurdles. First, a government agency generally is given deference when the agency is interpreting a statute it administers (referred to as Chevron deference).  FDA will likely argue that its regulation of GE animals as new animal drugs is consistent with the plain meaning of the statute, and, to the extent that there is any ambiguity in the statute on this point, that FDA’s interpretation of the statute is reasonable.  Second, the District Court for the District of Columbia has implicitly addressed FDA’s jurisdiction over GE animals.  In International Center For Tech. Assess. v. Thompson, 421 F.Supp.2d 1 (D.D.C. 2006), the court considered whether FDA’s exercise of enforcement discretion over GE ornamental zebrafish was permissible.  Because FDA would not be able to exercise enforcement discretion if it had no jurisdiction over GE animals, the court’s finding that FDA’s actions were lawful implies that FDA has the statutory authority to regulate these animals.  Although the court wasn’t asked to specifically address FDA’s jurisdiction by either party, it would be surprising if FDA were to ignore such a helpful precedent in its filings in the AAS case. 

NEPA Claims

The bulk of Plaintiffs’ case revolves around allegations of violations of NEPA. While the NEPA issues are numerous, in essence, Plaintiffs allege that FDA’s environmental assessment and finding of no significant impact failed to consider the environmental impact of future GE salmon grow-out facilities, failed to consider alternative actions, and relied excessively on risk mitigations strategies.

In alleging that the scope of NEPA review was deficient, Plaintiffs seem to ignore the fact that a drug approval is limited to the specific manufacturing sites that are encompassed in that approval. FDA and AquaBounty have stated that any new GE salmon hatcheries or grow-out facilities will be considered changes to an application that will require approval from FDA prior to implementation.  Thus, adding any new facility will trigger a new agency action that will require its own NEPA analysis, and these subsequent approvals may need to consider cumulative effects on the environment.  Until then, it is not clear how FDA could conduct an environmental analysis of fictitious facilities in unknowable locations, as Plaintiff’s position would appear to require. 

With respect to alternative actions FDA could have taken, Plaintiffs allege that FDA could have considered the “development of new projects and policies designed to support and expand sustainable commercial fishing or aquaculture practices; actions to protect and restore native Atlantic salmon populations; and non-GE alternatives to developing ‘faster growing’ salmon . . . .” Complaint at paragraph 191.  Not surprisingly, Plaintiffs point to no statutory authority under which FDA could achieve any of those purposes, however laudable those purposes may be. 

Finally, Plaintiffs allege that the risk mitigation strategies required of AquaBounty are unenforceable, and, therefore, FDA cannot rely on those strategies to come to a finding of no significant impact. Given FDA’s broad statutory authority to inspect foreign and domestic facilities, and FDA’s long history of taking enforcement action based on such inspections, it will be interesting to see how this line of reasoning plays out in the courts.

ESA Claims

Plaintiffs also allege that there were violations of the ESA because FDA failed to adequately consult with other government agencies (such as FWS) regarding whether the approval “may affect” wild Atlantic salmon, an endangered species. However, FDA’s final environmental assessment of AAS includes a letter from FWS that states “[FDA’s] ‘no effect’ determination seems well supported for this approval.”  That same document includes a letter from the National Oceanic and Atmospheric Administration’s National Marine Fisheries Service that identifies eight meetings between that agency and FDA regarding the potential effects (or lack thereof) of an approval on wild Atlantic salmon populations. 

Plaintiffs also allege that, under the ESA, once FDA determined there were “no effects” of approving AAS on endangered species, FDA was not permitted to consult with, and seek concurrence from, other agencies. It is not clear what a victory for Plaintiffs on this point would gain.

Potentially Broad Implications

In a Wall Street Journal article regarding the AAS lawsuit, one of the attorneys for the plaintiffs is reported as saying that “the groups’ lawsuit is aimed at GMO animals raised for food production, though it could ‘indirectly affect’ the FDA’s jurisdiction over other modified animals.”  This is a curious characterization of the scope of the lawsuit, given that the first claim in the complaint alleges that FDA lacks the jurisdiction to approve GE animals in toto.  In any event, the import of this “indirect effect” acknowledged by Plaintiffs should not be lost on our readers.  One of the interesting consequences of a victory for Plaintiffs would be that FDA would no longer have the statutory authority to regulate GE animals, absent circumstances that trigger application of another statutory provision.  Because no other federal agency would appear to have authority to regulate the kinds of GE animals currently regulated by FDA, those animals might not face any regulatory hurdle before marketing.  This result would seem to go against Plaintiffs’ interests and play to the hands of those who have argued against any regulation of GE animals.  What would come next is unclear.  Congress could enact clarifying legislation to explicitly give FDA jurisdiction over these GE animals, but the prospects for that type of legislation appear highly uncertain. 

Defendants must file a responsive pleading within 60 days of being served the complaint. We will continue to closely watch developments in this case.

By Jeffrey N. Gibbs & Allyson B. Mullen –

Imagine that you were working at a device company and you received a letter today from FDA saying that FDA was “correcting” the FDA clearance you received nineteen (19 – that is not a typo) years ago.  You would probably think about all the things that have changed in 19 years, your original 510(k) submission not being among them: a second gulf war, 9/11, the Great Recession, our first African-American president, the Red Sox finally winning a world series (and then two more), the Yankees winning five world series, and the Cubs – well not everything changes. Then you might suspect that this was just an April Fool’s prank.   It probably isn’t.

Recently, we found a letter from FDA that did precisely that.  According to FDA’s 510(k) database, the Whatman Body Fluid Collection Paper was originally cleared via K932661, on April 17, 1996. On February 6, 2015, FDA sent the company a letter stating “this letter corrects our substantially equivalent letter of April 17, 1996” (a copy of the letter can be found here).  The letter offered no explanation for why the correction was issued, let alone why FDA felt it needed to correct a clearance letter issued during the first term of the Clinton Administration.  It is possible, however, that the nature of the correction may simply not be clear to us because of the limited information available regarding this 510(k) due to its age.

A similar device, the Ahlstrom 226 specimen collection paper, was originally cleared on October 19, 2007, and received a nearly identical 510(k) “correction” letter. Both the Whatman and Ahlstrom correction letters were issued on the very same day, February 5, 2015 (a copy of the letter can be found here).  Because the Ahlstrom clearance is more recent, there is a 510(k) Summary available.  The only discernable difference between the information in the 510(k) Summary and the “corrected” clearance letter is the product code.  The Ahlstrom paper was originally cleared under product code JKA (tubes, vials, systems, serum separators, blood collection devices, 21 C.F.R. § 862.1675).  The “corrected” clearance letter cites product code PJC, which is the product code for Newborn Screening Specimen Collection Paper (21 C.F.R. § 862.1675). (The legal significance of product codes is not altogether clear; that is a different topic for a different day).

While it is not unusual for FDA to change or obsolete product codes for administrative reasons, this change appears substantive in that it could affect the products’ intended use and their suitability as predicates. The Ahlstrom paper, and presumably the Whatman paper because Ahlstrom cited it as its predicate, were cleared for use “as a medium to collect and transport blood specimen spots to be laboratory.”  There was no specific assay or analyte specified in the intended use.  However, the Ahlstrom 510(k) decision summary prepared by FDA (available here) indicates that the device was tested to Clinical Laboratory Standards Institute (CLSI) standard NCCLS/CLSI LA4-A3: Blood Collection on Filter Paper for Newborn Screening Programs; Approved Standard—Third Edition.  The “corrected” product code is specific to newborn screening.  The definition of product code PJC (the “corrected” code), in FDA’s product classification database, states “newborn screening specimen collection paper is a blood collection device intended to be used as medium to collect and transport whole blood specimens from newborns to the laboratory for in vitro diagnostic analysis.”  This definition uses the nearly identical language as the Ahlstrom clearance, but is limited to newborn screening only. 

Was FDA attempting to limit the scope of the Ahlstrom clearance ex post facto? Possibly.  The public record does not say.  Anyone trying to obtain clearance for an IVD collection device (e.g., blood, saliva) today certainly knows that FDA will no longer allow a broad indication for use like the original Ahlstrom use without very extensive clinical testing. 

Seeing these letters made us wonder if this was a unique event.  It turned out that post-clearance corrections of 510(k)s are not all that unusual.  We found nearly 400 letters doing just that. (While a low frequency event, it can still be a disconcerting one for those receiving such a letter).  Based on a sampling of these letters, none of the letters appear to give an explanation for the “correction.”  Many of the letters appear to “correct” the product code originally assigned to the device.

Although this issue of changing a product code years after the 510(k) clearance may seem relatively minor, it does raise more profound questions.  What do belated "corrections" mean for the stability and predictability of the regulatory process?  Do the letters truly represent corrections, or changes in policy?  Assuming that the letters are due to changed policy, does FDA have the statutory authority to alter the scope of the clearance?  Can these changes in product code restrict the ability of other companies — and the 510(k) holder — to use the cleared device as a predicate for the indications for use for which it was cleared?  

We do not know. But, in light of the amount of effort that goes into the FDA review process for 510(k)s, it is remarkable how many post-clearance corrections there have been.  Given how long it can take to obtain a 510(k) clearance, many applicants are relieved when the process is over.  The Whatman “correction” letter shows that sometimes it ain’t actually over even when it is over. 

Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

By James C. Shehan –

On March 31, 2016 FDA released its promised guidance on labeling for biosimilar products. A few parts caught our eye, including another change of mind by FDA on the issue of whether a biosimilar’s labeling should identify itself as a biosimilar,

The guidance primarily affects prescribing information (a.k.a. the package insert) but a few sections affect patient labeling. FDA lays out a few general principles before proceeding to some specific recommendations.

Under general principles, FDA begins with the premise that, because the Biologics Price Competition and Innovation Act ("BPCIA”) requires that biosmilars have “no clinically meaningful differences from the reference product in terms of safety, purity, and potency, and because the labeling of the reference product reflects FDA’s findings of safety and efficacy, that labeling “may be relied upon to provide health care practitioners with the essential scientific information needed to facilitate prescribing decisions” for the biosimilar. Thus, biosimilar labeling should “include a description of the clinical data that supported safety and efficacy of the reference product as described in the FDA-approved product labeling” for that reference product, with appropriate biosimilar-specific modifications.

The guidance then makes some detailed recommendations on treatment of clinical study data in biosimilar labeling. These positions seem to coincide with positions advocated by biosimilar applicants. FDA states that clinical studies of biosimilars should not be included in their labeling, unless it is necessary to do so to “inform safe and effective use.” In support, FDA points out that clinical studies of biosimilars are usually designed to detect clinically meaningful differences between the biosimilar and the reference product and not to independently demonstrate safety and effectiveness. As a result, a biosimilar’s clinical studies may use different endpoints and different patient populations than were used in reference product studies. This leads FDA to conclude that information about such clinical studies is “not likely to be relevant to a health care practitioner’s considerations regarding safe and effective use of the biosimilar.” Including it “may cause confusion, resulting in an inaccurate understanding of the risk-benefit profile of the product.”

FDA also states that biosimialrs follow the content and format requirements of the physician labeling rule and the pregnancy and lactation labeling rule, regardless of whether the labeling of the reference product does or does not follow those rules.

Turning to specific issues, FDA states that those sections of the biosimilar product labeling based on the reference product labeling should be similar but need not be identical. For example, differences in administration, storage or safety information may require different labeling.

The guidance devotes several pages to describing when biosimilar sponsors should use their biosimilar’s name, the reference product’s proprietary name and the “core name” of the product, the latter term referring to that portion of the proper name that does not include the four letter suffix proposed in FDA’s draft guidance on biologics naming (see our post here). FDA recommends that:

• The biosimilar’s name (proprietary or proper) be used in labeling where information is (1) specific to the biosimilar product or refers solely to the biosimilar product, such as in Indications and Usage and Dosage and Administration sections; and (2) for directive statements and recommendations for preventing, monitoring, managing, or mitigating risks, typically included in sections such as black box warnings, Contraindications, Warnings and Precautions, and Drug Interactions.

• The reference product name be used when clinical studies or data of the reference product are described, e.g. in the Adverse Reactions and Clinical Studies sections.

• The core name should be used in labeling sections where risks apply to both the biosimilar product and the reference product, such as black box warnings, Contraindications, Warnings and Precautions, and Adverse Reactions. In such sections, the labeling should refer to the core name followed by the word “”

• More than one name be used where necessary to accurately convey information.

While this part of the guidance appears to be logical, it may result in labeling that is confusing to users, considering that the labeling will apparently switch back and forth between three different names to make distinctions whose subtlety may escape a busy or uninformed end user.

The guidance briefly addresses labeling for biosimilars that are approved for fewer indications than the reference product, noting that text regarding those indications should not be in the biosimilar labeling, except when necessary to ensure safe use. In those situations, FDA admonishes biosimilar applicants to write labeling “in a manner that does not imply that the biosimilar product is approved for a reference product indication(s) or use(s) that has not been approved for the biosimilar product.” Notably, the guidance does not address AbbVie’s request that the labeling of a biosimilar call out that it is not approved for all the indications of the reference sponsor (see our post here).

The section of the guidance that may generate the most discussion is the one calling for the labeling of biosimilar products to identify these products as biosimilars. FDA originally called for this to be done in a 2012 draft guidance, deleted that point in the 2015 final version of that guidance, but now has reinstated it here.

FDA “recommends inclusion of a statement, on the line immediately beneath the initial U.S. approval date in Highlights, that the product is biosimilar to the reference product.” This statement should read “[BIOSIMILAR PRODUCT’S PROPRIETARY NAME (biosimilar product’s proper name)] is biosimilar* to [REFERENCE PRODUCT’S PROPRIETARY NAME (reference product’s proper name)] for the indications listed.”

FDA provides precise wording and placement for the asterisked statement, essentially a paraphrasing of the BPCIA’s definition of a biosimilar: “Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. the a s

By Jeffrey K. Shapiro & Charlene Cho –

In the emerging world of regenerative medicine, there is a stark dichotomy in the level of regulation applied to products derived from human cells and tissues, or what FDA calls “human cells, tissue or cellular and tissue‑based products” (HCT/Ps).

If an HCT/P meets certain requirements, it is eligible for regulation solely under section 361 of the Public Health Service (PHS) Act. A “361 HCT/P” does not undergo any premarket review by FDA prior to marketing.   Once marketed, under 21 C.F.R. Part 1271, such products must comply with donor screening and eligibility requirements, as well as labeling, adverse event/manufacturing deviation reporting to FDA and product handling (Good Tissue Practice) requirements.

To qualify as a 361 HCT/P, a product must meet the following requirements in 21 CFR 1271.10(a):

• Be minimally manipulated;
• Be intended for homologous use (as reflected in labeling and advertising); 
• Not be manufactured by combining cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent;
• Not have a systemic effect and not be dependent upon the metabolic activity of living cells for its primary function, with certain limited exceptions.

If any of these requirements are not met, the HCT/P is still subject to regulation under 21 C.F.R. Part 1271, but in addition is likely subject to biologic, drug or medical device regulation. In practice, many of the HCT/Ps in regenerative medicine that do not qualify as 361 HCT/Ps are regulated as biologics subject to section 351 of the PHS Act or “351 HCT/Ps.”  A 351 HCT/P requires approval of a biologics license application (BLA), typically supported by significant clinical data gathered under an Investigational New Drug (IND) exemption.  The IND/BLA process is perhaps the most burdensome and lengthiest premarket review process that FDA imposes.

This regulatory framework has inhibited innovation by creating regulatory uncertainty in many cases as to whether a product is regulated as a 361 HCT/P or as a 351 HCT/P. The applicability of the 361 HCT/P requirements are often debatable, with said debate leading to one of two extremely different outcomes: no premarket review at all versus full IND/BLA review.  Additionally, many products that arguably do deviate from the 361 HCT/P requirements simply do not pose a level of risk that would justify the high regulatory hurdles imposed in the IND/BLA process.

Congress is now considering a legislative solution, the “Reliable and Effective Growth for Regenerative Health Options that Improve Wellness” or the “REGROW Act.” With rare bipartisan support in both the House and Senate, the REGROW Act was introduced on March 16, 2016 by Senators Mark Kirk (R-IL), Joe Manchin (D-WV) and Susan Collins (R-ME) in the Senate (S. 2689) and by Representatives Mike Coffman (R-CO), Mark Takai (D-HI) and H. Morgan Griffith (R-VA) in the House (H.R. 4762). The House Bill is identical to the Senate Bill, so for convenience, the discussion below refers only to S. 2689.

The REGROW Act would allow FDA to grant a five year conditional approval of a cellular or tissue therapeutic product that demonstrates preliminary clinical evidence of safety and a reasonable expectation of effectiveness. The firm is required to use this time to initiate an IND study and, ultimately, to submit a BLA for FDA to review.

There is no definition of what a “cellular or tissue therapeutic product” is, but it seems likely from the criteria that apply (described below) that this category corresponds to what FDA defines as HCT/Ps in 21 C.F.R. § 1271.10(a). (The bill refers to both “cellular” and “tissue” products, but some provisions and headings refer to “cellular” products while others refer to “cellular and tissue” products.  And sometimes the word “therapeutic” is included and sometimes it is not.  The inconsistencies appear to be unintentional.)

The conditional approval would cover the manufacture, distribution and sale as well as use of a cellular or tissue therapeutic product, provided that a BLA is filed within five years. Additionally, S. 2689 says FDA “may” continue the conditional approval during review of the BLA.  (Given the length of BLA review, the bill should be revised to make it mandatory unless a significant safety concern exists.)

A number of requirements would apply in order for a product to qualify for conditional approval:

The manufacture, distribution and sale as well as use of the cellular or tissue therapeutic product must be consistent with the current regulations, including good manufacturing practices (GMPs).

The cellular or tissue therapeutic product also must satisfy all of the following criteria:

• The cells or tissue are adult human cells or tissues;
• The cells or tissues do not provoke a significant immunogenic response;
• The cells or tissues are either minimally manipulated and for a non-homologous use or more than minimally manipulated and for either a homologous or non-homologous use but in either case, not genetically modified;
• The cells or tissues are for a specific indication;
• The cells or tissues are produced exclusively for a use that performs, or helps achieve or restore, the same, or similar, function in the recipient as in the donor.

(It may be worth noting that the language in the last bullet seems similar to the language defining “homologous use” in FDA’s Draft Guidance on Homologous Use of HCT/Ps, which we blogged about here. Accordingly, the last bullet seems to contradict the third bullet, which allows the cells or tissue to qualify even if intended for a non-homologous use.) 

During the five year conditional approval period, the sponsor must submit a BLA as well as annual reports and adverse event reports, which must contain all information generally required for approved biological products.

The sponsor must have submitted an IND for treating the patients with the cellular therapeutic product during the five year conditional approval period.

And finally, the sponsor must not have obtained a conditional approval for the cellular therapeutic product for the same indication.

If all of the above-described conditions are satisfied, the cellular or tissue therapeutic product would be permitted to remain on the market unless and until FDA denies BLA approval.

The notion of applying conditional approval to these products is not as novel as it might seem. For many years, when an HCT/P has been found by FDA to have stepped outside the 361 requirements, the firm has been required to initiate an IND/BLA process, but has been in some cases also allowed to continue marketing under enforcement discretion if there is not a serious public health risk.  In a sense, this statute would codify that approach but in a manner that provides greater regulatory certainty.

The last part of the bill addresses devices involved in the recovery, isolation, processing and delivery of cellular therapeutic products used in regenerative medicine. It includes language that does not alter the general regulatory scheme for devices, but seems intended to nudge FDA toward regulating with a lighter touch, focusing premarket review and classification of the devices based upon their functional performance in handling and preserving cells, as opposed to the specific clinical uses to which the cells are being put.

All in all, the REGROW Act deserves serious consideration. It holds out hope that the young regenerative medicine industry will be allowed to continue developing beneficial therapies in a way that is commercially viable, but with appropriate public health assurances.  Whatever the shape of the final legislation, this draft is a good first step in the right direction.

By Karla L. Palmer –

On Tuesday, March 15, 2016, HHS Secretary Burwell testified before the House Education and the Workforce Committee, during which Representative Buddy Carter (R. Ga.), who is a pharmacist, asked Secretary Burwell about office use compounding. Representative Carter expressed his concern about FDA’s interpretation of legislative intent dealing with “office use only” compounded medications. He addressed the fact that office use compounding, where the physician has the ability to use the medication on patients in the doctor’s office, has traditionally been permitted in several states, and inquired about the status of FDA guidance on the same. Secretary Burwell stated that FDA does not have guidance preventing office use compounding, and that such compounding should be occurring, adding confusion to whether office use compounding is indeed currently permitted. Representative Carter stated that Congress is looking for guidance on this issue, as it involves patients getting the care they need. The Secretary responded she would like input on office use compounding as FDA formulates its guidance on its permissibility. See the clip of the relevant hearing testimony here.    

Following up on Secretary Burwell’s testimony, Representative Carter sent a letter dated March 22, 2016 to the Secretary, in which he further addressed his questions to her about office use compounding relating to physician offices, and the lack of guidance by FDA. He noted her response to his questions “indicating that there is nothing preventing a 503A pharmacy from compounding for ‘office use’ purposes failed to address FDA guidance that has yet to clarify that 503A pharmacies will be exempt from individual prescription requirements.”

Representative Carter added that section 503A pharmacies are currently “being regulated under Good Manufacturing Practices (cGMP) standards rather than U.S. Pharmacopeia (USP) Convention standards, which have been the standards for 503A pharmacies for years.” He also stated that he is concerned that “FDA’s application of DQSA section 503A requirements to 503A pharmacies in the same manner as large outsourcing facilities is placing undue burden on 503A pharmacies and the patients they serve.” (Recent Form 483s of traditional pharmacies posted on FDA’s website highlight that FDA is routinely holding section 503A pharmacies to cGMP during inspections since at least spring 2013.) Stating that pharmacies that produce small amounts of compounded medications in advance of receiving individual prescriptions, which practice in states that authorize “office use” compounding, should not be the focus of FDA’s oversight; such oversight “by FDA of 503A pharmacies is unreasonable and was not Congress’ intent during passage of DQSA.”  

In order to address concerns, Representative Carter requested a response from the Secretary to the following questions:

1. It is my understanding that FDA is currently working on guidance to clarify that 503A pharmacies, who are regulated by State Boards of Pharmacy, will be exempt from DQSA requirements when participating in "office-use" compounding. When can we expect FDA to release this guidance?
2. For years, 503A pharmacies have operated under the standards contained in the U.S. Pharmacopeia (USP) Convention for sterile and non-sterile compounding. What prompted FDA to begin inspecting these 503A pharmacies under current Good Manufacturing Practices (cGMPs) as opposed to USP standards?
3. The FDA has begun inspecting state licensed 503A pharmacies using cGMP standards rather than USP standards or other applicable pharmacy inspection standards adopted by state law or regulation in the state where the pharmacy is licensed. Section 105 of DQSA states that any finding by the FDA must be turned over to the appropriate State Board of Pharmacy for review and consideration of corrective actions to bring the pharmacy back into compliance with state law. What authority, with clear congressional intent to state otherwise, does FDA have to inspect 503A pharmacies with cGMPs when federal oversight of 503A pharmacies was never the intent of Congress?

Representative Carter requested responses to the above questions within ten business days of the date of the letter (i.e., by April 5, 2016). Answers to the three questions may have a significant impact on the thousands of compounding pharmacies across the United States that are grappling with not only the permissibility of office use compounding but also the propriety of FDA’s dramatically increased scope of the Agency’s inspections of compounding pharmacies. Will the Secretary respond? We will let you know what happens next. Stay tuned.

By James C. Shehan –

On March 21, 2016, Amgen filed a brief opposing Sandoz’s request that the Supreme Court overturn last year’s Federal Circuit ruling that the Biologics Price Competition and Innovation Act’s ("BPCIA's") notice of commercial marketing provision is mandatory and can only be given after FDA licensure of a biosimilar (see our previous posts here, here and here).  But Amgen also filed a certiorari cross-petition, asking that, should the Court decide to review the commercial marketing ruling, it should also review and overturn the Federal Circuit’s ruling that the patent dance information exchange procedures of the BPCIA are optional. The case involves the first and only approved US biosimilar product, Sandoz’s filgrastim product Zarxio, which referenced Amgen’s filgrastim product Neupogen in order to be approved.

Amgen’s reply brief asserts that the Supreme Court should reject the Sandoz certiorari request for three reasons.  First, Amgen argues that the only issue that Sandoz can appeal based on the record was correctly decided below – the Federal Circuit’s unanimous holding that notice of commercial marketing can only be given post-licensure.  Second, Amgen contends that Sandoz’s requests concerning a private right of action and the availability of injunctive relief are moot based on the facts in the case because the issues were not decided by the Federal Circuit.  Third, Amgen posits that Supreme Court review would be premature, noting that BPCIA issues are currently being litigated in seven pending cases, including in a case that the Federal Circuit will hear on April 4, 2016.

On the notice of commercial marketing issue, Amgen’s main argument continues to be that the BPCIA’s language is clear (“The subsection (k) applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k)” (emphasis in original)) and that the Federal Circuit correctly applied principles of statutory construction in holding that the notice is mandatory.  Amgen also asserts that the Federal Circuit holding is not in conflict with either the statute or any Supreme Court ruling, and thus is not an appropriate case for review.  Amgen goes on to say that “Sandoz offers a raft of policy arguments for why [mandatory notice] is supposedly a bad or unfair rule, arguments that are wrong on their merits but that in any event cannot overcome the statute’s text.”  Amgen also contends that “requiring that a [biosimilar] be licensed before notice of commercial marketing ensures the existence of a fully crystallized controversy regarding the need for injunctive relief” and “provides a defined statutory window during which the court and the parties can fairly assess the parties’ rights prior to the launch of the biosimilar product.”

Amgen devotes a couple of pages of its brief to distinguishing between marketing exclusivity and data exclusivity, saying that the BPCIA does not protect brand name products from competition and pointing to the example of Teva’s filgrastim product Granix, which was approved under a BLA and competes with Amgen’s Neupogen.  In addition, addressing the Sandoz contention that notice after approval makes no sense because approval is public, Amgen points out that commercial marketing cannot be presumed to occur 180 days after approval, and therefore mandatory notice after approval serves a purpose in helping a reference product sponsor determine when and whether to file a lawsuit.

Amgen’s second basis for asking the Supreme Court to reject Sandoz’s request is based largely on procedural matters and state law. One major point made by Amgen is that Sandoz did provide Amgen with notice of commercial marketing, so the issue of what might happen if Sandoz had not done so is moot.

Regarding the third basis, arguing that the Supreme Court should wait for further lower court decisions before taking a BPCIA appeal, Amgen states that there are seven BPCIA lawsuits pending in the lower courts. Amgen also argues a lack of urgency, given that only one biosimilar (Zarxio) has been approved by FDA and that the 15% discount off of the Neupogen wholesale price that Sandoz is offering demonstrates that waiting will have a minimal impact on consumer costs.

In its cross-petition on the patent dance provisions, Amgen asks that, should the Supreme court decide to review the notice of commercial marketing issue, that the Court also take under review the Federal Circuit’s ruling that the patent dance is a voluntary proceeding. Amgen argues that the two issues are “inextricably intertwined” and that the Federal Circuit ruling is incorrect under Supreme Court precedent on statutory interpretation. Regarding the latter point, Amgen’s basic contention is that the word “shall” employed in the patent dance provisions of the BPCIA is a mandatory word, just as it is in the notice of commercial marketing provisions.

Sandoz’s response to Amgen’s cross-petition is due on April 22nd. Meanwhile, interest in the case form third parties remains high, including amicus briefs from Hospira, Apotex and the Biosimilars Council.

By Kurt R. Karst –

For several years now we have been following instances in which FDA designated, and later approved, a drug (including a biological product) as an “orphan drug” on the basis that it is not the “same drug” as a previously approved product containing the same active moiety (or, in the case of macromolecules, containing the same principal molecular structural features) for the same orphan condition because the subsequent product is “clinically superior” to the prior product.  In those instances, the subsequent product can be approved notwithstanding an unexpired period of 7-year orphan drug exclusivity for another product that is otherwise the same orphan drug, and/or the subsequent product can earn a period of orphan drug exclusivity. 

Unfortunately, there is no FDA database that compiles the various drug products approved on the basis of a clinical superiority determination. FDA’s Orphan Drug Designations and Approvals Database, although it sometimes provides a hint as to whether or not a product was designated or approved on some clinical superiority basis, is generally opaque on the issue.  That means to find precedents folks generally have to sift through approval documents, submit FOIA requests to FDA, or otherwise look for “magic language” in company press releases announcing FDA’s grant of an orphan drug designation (or orphan drug approval).

We’ve tried to lift the veil of darkness by posting on clinical superiority precedents as we come across them, for example, here, here, here, and here.  With our recent discovery of yet another clinical superiority precedent – yet again involving the so-called Major Contribution to Patient Care (“MC-to-PC”) basis for demonstrating that an orphan drug is clinical superiority to another drug that is otherwise the same drug – we thought it was high time to put together a list of precedents.  But before we get to that list and the precedent we recently found, some background is in order, particularly for those folks new to the orphan drug space. . . .

FDA’s orphan drug regulations (21 C.F.R. Part 316) define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways:

(1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;

(2) greater safety in a substantial portion of the target population; or

(3) demonstration that the drug makes a major contribution to patient care.

To support a claim of “clinical superiority” based on greater effectiveness, generally the same kind of evidence is needed as that required to support a comparative effectiveness claim for two different drugs. That is, the second drug must demonstrate an improvement as assessed by “effect on a clinically meaningful endpoint in adequate and well-controlled clinical trials.”  FDA’s regulations also provide that, “in most cases, direct comparative clinical trials would be necessary” to demonstrate greater effectiveness. 

To support a claim of “clinical superiority” based on superior safety, the second product must provide “[g]reater safety in a substantial portion of the target populations, for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects.” FDA’s regulations also state that “[i]n some cases, direct comparative clinical trials will be necessary.”

With respect to a MC-to-PC “clinical superiority” claim, FDA states in the Agency’s regulations that it make such determinations only in “unusual circumstances.” While MC-to-PC determinations are made on a case-by-case basis, in the preamble to FDA’s final 1992 orphan drug regulations, the Agency commented that “convenient treatment location; duration of treatment; patient comfort; improvements in drug efficiency; advances in the ease and comfort of drug administration; longer periods between doses; and potential for self administration . . . when applicable to severe or life threatening diseases, might sometimes be legitimately considered to bear on whether a drug makes a major contribution to patient care.”

Although MC-to-PC clinical superiority decisions are supposed to be unusual, of the three clinical superiority bases FDA lays out in the Agency’s orphan drug regulations, it appears that it is the most common basis accepted by FDA’s Office of Orphan Products Development (“OOPD”) (at least in recent years). A precedent that recently came to our attention involves Sotalol Hydrochloride Injection, which FDA approved on July 2, 2009 under NDA 022306 for use as a substitute for oral sotalol in patients who are unable to take sotalol orally.  (Oral sotalol is indicated for maintenance of normal sinus rhythm in patients with history of highly symptomatic atrial fibrillation/flutter, and for treatment of documented life-threatening ventricular arrhythmias.)  The approved indication really says it all insofar as FDA’s clinical superiority basis is concerned; however, additional detail on the determination is provided in OOPD’s Orphan Drug Designation Review Memorandum.

Precedents for each of the three clinical superiority bases are grouped below. Each precedent concerns an approved product for which clinical superiority was determined by FDA to be necessary to break another sponsor’s orphan drug exclusivity, and/or for a sponsor to qualify for orphan drug exclusivity.  Other clinical superiority precedents exist, but they have either not yet come to fruition (e.g., because a product was merely designated based on a plausible hypothesis of clinical superiority and the product has not progressed to the FDA approval stage where FDA has to more closely examine the issue of clinical superiority), or a company’s bid for orphan drug exclusivity was unsuccessful (e.g., because the product for which designation was granted based on a plausible hypothesis of clinical superiority was approved for a use broader than the designated use, or because the sponsor failed to demonstrate clinical superiority . . . an issue that has been litigated in recent years – see here).  For example, we understand that EPANED (enalapril) for Oral Solution (NDA 204308), although designated for the treatment of hypertension in pediatric patients, failed to demonstrate clinical superiority; and SOTOLYZE (sotalol hydrochloride) Oral Solution (NDA 205108) was approved for a use broader than the orphan drug-designated use: for the treatment of documented life-threatening ventricular arrhythmias and the maintenance of normal sinus rhythm in pediatric and adults patients with history of highly symptomatic atrial fibrillation/flutter.  To the extent FDA Law Blog readers are aware of additional clinical superiority approval precedents, we’re all ears.

Greater Effectiveness Clinical Superiority Determinations

• In 2002, FDA determined (here and here) that Serono’s REBIF (interferon beta-1a) (BLA 103780) was “clinically superior” to Biogen’s AVONEX (interferon beta-1a) (BLA 103628) for the treatment of relapsing-remitting multiple sclerosis based on data from a head-to-head clinical trial demonstrating improved efficacy of REBIF over AVONEX in the frequency of multiple sclerosis exacerbations.  The effect of FDA’s approval of REBIF is that it broke AVONEX’s orphan drug exclusivity with respect to the marketing of REBIF only. 

Greater Safety Clinical Superiority Determinations

• In 1992, FDA determined that Armour’s MONONINE (coagulation factor IX) (BLA 103597) was clinically superior to Alpha Therapeutic’s ALPHANINE (coagulation factor IX) (BLA 103249).  This determination was based on manufacturing data in the MONONINE BLA that allowed FDA to conclude that the viral inactivation process used in manufacturing MONONINE “may result in a product less likely to transmit hepatitis C infection than . . . AlphaNine,” and further, that the prospect of improved viral safety allowed FDA to conclude that MONONINE was “probably a safer drug,” and thus approval of MONONINE was not blocked by ALPHANINE’s orphan drug exclusivity. 
• In 1996, FDA determined that Biogen’s AVONEX (interferon beta-1a) (BLA 103628) was clinically superior to Berlex’s BETASERON (interferon beta-1b) (BLA 103471) based on a reduced risk in AVONEX of one adverse event (injection site necrosis) associated with BETASERON.  FDA made its clinical superiority determination by comparing the labeled reports for BETASERON versus the injection site reaction attack rate and severity in the AVONEX pivotal study. 
• In 1997, FDA determined that Genetics Institute’s BENEFIX (coagulation factor IX) (BLA 103677) was clinically superior to MONONINE and ALPHANINE based on the fact that “BeneFix™ is inherently less likely to transmit human blood-born viruses and other infectious agents, and is also less likely to transmit animal-derived zoonotic agents.” 
• In 1997, FDA determined that Fujisawa’s AMBISOME (amphotericin B) (NDA 050740) was clinically superior to Enzon’s ABELCET (amphotericin B) (NDA 050724) based on the fact that “AmBisome appears to have a reduced frequency of the typical amphotericin B infusion reactions as compared to Abelcet, particularly with respect to hypotension and tachycardia, dyspnea, hypoxia or ‘severe asthma.’” 
• In 2010, FDA determined that United Therapeutics Corp.’s TYVASO (treprostinil) Solution for Inhalation (NDA 022387) was clinically superior to the company’s REMODULIN (treprostinil) Injection (NDA 021272), thus granting the company a second period of ODE for a second generation drug product.  Specifically, FDA determined that TYVASO, as an inhaled prostacyclin analogue, represents an important safety gain compared to prostacyclin analogues that had to be given subcutaneously or via a central venous line.  The widespread and severe nature of the pain associated with subcutaneous treprostinil and the risks of sepsis and death from the intravenous administration of treprostinil via indwelling venous catheter made the inhaled product clinically superior. 

MC-to-PC Clinical Superiority Determinations

• In 1998, FDA determined that Novartis’ reformulated SANDOSTATIN LAR (octreotide) (NDA 021008) was clinically superior to a previously approved subcutaneous dosage form of SANDOSTATIN (NDA 019667), because “patients can be managed with one injection per month instead of sixty to ninety injections.” 
• In 2007, FDA determined that Indevus’s histrelin acetate implant drug product, SUPPRELIN LA (NDA 022058), was clinically superior to SUPPRELIN (NDA 019836) on the basis that “a single histrelin subcutaneous implant could provide therapeutic blood levels for a period of 1 year versus 365 daily injections of Supprelin.” 
• In 2008, FDA determined that Antisoma’s Fludarabine Phosphate 10 mg Tablets for Oral Use (NDA 022273) was clinically superior to FLUDARA (fludarabine phosphate) for Injection (NDA 020038) because of a change in dosage form from injection to oral (a change identified by FDA as constituting a major contribution in the preamble to the Agency’s orphan drug regulations).
• In 2009, FDA determined that Academic Pharmaceuticals’s Sotalol Hydrochloride Injection (NDA 022306) was clinically superior to BETAPACE (sotalol HCl) Tablets (NDA 021151 and NDA 019865) because of a change in dosage form from oral to injectable and for patients unable to use the oral dosage form of the drug (e.g., because of surgery, intubation, acute illness, etc.).
• In 2011, FDA determined that Arbor's NYMALIZE (nimodipine) Oral Solution, 60 mg/20 mL (NDA 203340), was clinically superior to Bayer’s NIMOTOP (nimodipine) Capsules (NDA 018869) on the basis that the oral formulation “represents a major safety initiative that [FDA has] undertaken to eliminate a rare, but persistent error that may be, and has been, fatal.”  Specifically, it addressed the concern arising from health care providers extracting the capsule contents with a syringe and administering it intravenously. 
• In 2013, FDA determined that Raptor’s PROCYSBI (cysteamine bitartrate) Delayed-release Capsules (NDA 203389) was clinically superior to Mylan’s CYSTAGON (cysteamine bitartrate) Capsules (NDA 020392) based on a new dosing regimen.  According to FDA, “[s]ince it is recognized that cysteamine must be dosed at a strict q6h regimen to achieve its maximum benefit in cystinosis patients and that it is documented that many patients with cystinosis are unable to follow a strict q6h regimen throughout their lifetime, a q12h cysteamine product that can maintain cystine at the [white blood cell] levels to achieve maximum benefit can provide a MC to PC over a q6h cysteamine product.” 
• In 2015, FDA determined that Eagle’s RYANODEX (dantrolene sodium) for Injectable Suspension (NDA 205579) was clinically superior to DANTRIUM IV (dantrolene sodium for injection) (NDA 018264) on the basis that “the ability of the anesthesiologist to reconstitute and administer Ryanodex within one minute allowed the anesthesiologist to concentrate on continued supportive care and treatment of the patient with malignant hyperthermia compared to treatment with the previously approved dantrolene product that required up to one hour to reconstitute and administer, which would not allow the anesthesiologist to fully concentrate on the other aspects of treatment and support of the patient.” 

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