By William T. Koustas – 

We have previously reported (here and here for example) on the litigation between Regenerative Sciences, LLC (“Regenerative”) and FDA.  Regenerative is a Colorado company that owns a medical procedure known as the Regenexx Procedure.  It is a non-surgical procedure by which physicians take bone marrow and blood samples from a patient, culture and process the stem cells, and inject them back into the same patient in order to treat joint, muscle, tendon, or bone pain.  The Regenexx Procedure is exclusively licensed for use by the Colorado clinic where its inventors practice. 

As reviewed in more detail in our prior posts, FDA contends that, among other things, the stem cells processed in the Regenexx Procedure are a drug under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and must therefore only be created pursuant to a New Drug Application and under current Good Manufacturing Practices.  Regenerative responds that the Regenexx Procedure is the practice of medicine, which is outside of FDA’s jurisdiction and the stem cells are not introduced or delivered for introduction into interstate commerce since the entire process is performed in Colorado. 

The U.S. District Court of the District of Columbia ultimately sided with FDA, although it called the decision a “close question.”  The Court found that the stem cells used in the Regenexx Procedure are a drug as defined under the FDCA and that FDA has jurisdiction to regulate this procedure “because a component of the [Regenexx Procedure] shipped through interstate commerce prior to its administration to the patient,” thus satisfying the interstate commerce requirement in the FDCA.

However, with the case now pending before the U.S. Court of Appeals for the District of Columbia Circuit, a new report authored by Richard A. Epstein from the Manhattan Institute’s Center for Legal Policy (“the Report”) calls into question the legal and policy bases for FDA’s regulation of autologous stem cell procedures like the Regenexx Procedure.

The Report, titled “The FDA’s Misguided Regulation of Stem-Cell Procedures: How Administrative Overreach Blocks Medical Innovation,” contends that FDA “has taken the aggressive position that it has oversight authority over any stem-cell procedure that reinjects harvested stem cells into the same person from whom they were removed, so long as those cells were grown and cultured outside the human body.”  Among other things, the Report argues that FDA and the district court incorrectly interpret the interstate commerce provision in the FDCA while also improperly determining that the stem cells in the Regenexx Procedure are drugs rather than part of the practice of medicine. 

With respect to FDA’s position that is has authority to regulate autologous stem cell procedures pursuant to the interstate commerce provision in FDCA § 301(a), the Report contends that the statutory authority provided in the FDCA does not extend as far as the Constitution’s Commerce Clause.  The Report points to the fact that the interstate commerce language in the FDCA pre-dates the Supreme Court’s Wickard v. Filburn, 317 U.S. 111 (1942), decision and is therefore meant to reflect a pre-Wickard reading of interstate commerce.  As such, “the statutory requirement…is not whether a reagent used in the process has moved in interstate commerce but whether the dangerous (‘adulterated or misbranded’) article itself has moved in interstate commerce.”  Therefore, while the Constitution’s Commerce Clause would allow Congress to regulate autologous stem cells due to use of reagents that traveled through interstate commerce, the FDCA’s interstate commerce provision would not. 

In addition, the Report suggests that the “held for sale” language of FDCA § 301(k) only applies to articles that were themselves part of an interstate commerce transaction.  However, the stem cells used in the Regenexx Procedure were never part of an interstate transaction themselves and were therefore not held for sale in an interstate transaction.

The Report also makes the case that the Regenexx Procedure is the practice of medicine rather than the manufacture of a drug as FDA contends.  The Report analogizes the Regenexx Procedure to dental work by noting that, “[t]he process in question would normally be regarded as a provision of services for which the growth of the cells under these highly specified procedures would be regarded as, at most, an ‘incidental’ element to the transaction, just as a dentist who prepares mixtures for fillings is regarded as having supplied services and not as having manufactured and sold a mixture of silver and bonding solutions.”  The report also notes the basic differences between cultivating autologous stem cells and the mass production of drugs, arguing that the “…uniqueness [of the cultivating of stem cells] makes it relatively easy…to engage in the upstream regulation of these products” by state medical boards instead of FDA-approval.  In contrast, the Regenexx Procedure does not lend itself to FDA regulation as the process is slightly different for every patient.

The Report also seeks to rebut FDA’s argument that it is entitled to extensive deference in its interpretation of the definition of “drug.”  It points to the Supreme Court’s decision in FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120 (2000), in which “the Court pushed back on the FDA when it sought to include cigarettes and tobacco as drugs under the [FDCA]…”  The Report goes on to state that, “…even if it takes great skill to figure out how to regulate drugs, and the government’s broad claims for Chevron deference here should not override the ordinary meaning of ‘drugs’ versus ‘medicine.’”  

Given the arguments laid out in the Report, it will be interesting to see how the case is resolved in the Court of Appeals.     

By Jeffrey K. Shapiro –

As everybody has noticed, FDA finalized its guidance on Mobile Medical Applications earlier this week.  We blogged on the draft version here.

The final guidance is similar to the draft guidance – but with improved clarity.  Hence, it has expanded from 29 to 43 pages.  Most of the additional pages are appendices with examples and other supplementary information.  This guidance is sensible and well written.

FDA’s general approach to mobile medical applications (mobile apps) is to define large swaths of territory that will be either unregulated because they are considered outside of FDA’s jurisdiction or because FDA will simply refrain from regulation on the basis of low patient risk.  When FDA refrains from regulating products within its jurisdiction, it is called an exercise of “enforcement discretion.”

This general approach makes sense, because FDA and industry both have limited resources, so it is realistic to apply the expensive and burdensome FDA regulatory system only to mobile apps that pose a significant risk to patients.  In technical regulatory terms, this approach is known as getting the most bang for the buck.

Because much of the mobile apps industry is not very familiar with FDA regulation, this guidance has an unusually detailed description of the entities, mobile apps, and activities that will not be regulated.  These include:

• Platform products without medical device claims.
• Third party app distributors who do not develop apps.
• Providers of general development tools and hardware/software infrastructure.
• Licensed practitioners who develop their own apps for their own use.
• Mobile apps developed solely for non-clinical research, teaching or analysis and not introduced into commercial distribution.
• Mobile apps that are essential e copies of medical textbooks and reference material.
• Mobile apps used for provider or patient medical training and education.
• Mobile apps used to automate operations in a healthcare setting and not for use in the diagnosis or treatment of disease.
• Mobile apps that are generic aids or general purpose products.

There is also a description of entities and activities for which FDA will exercise enforcement discretion based upon low risk to patients.  Of note, the guidance provides welcome relief for the “health coaching” apps by placing them under enforcement discretion.  There has been a lot of innovation in this area, but also an overhang of regulatory uncertainty.  The enforcement discretion categories are:

• Mobile apps that help patients self-manage their disease or conditions without providing specific treatment suggestions.
• Mobile apps that provide simple tools for patients to organize and track health information.
• Mobile apps that provide easy access to information related to patients’ health conditions or treatments.
• Mobile apps that automate simple tasks for health care providers.
• Mobile apps that enable patients or providers to interact with electronic health records ("EHRs").

A few interesting examples: 

• Mobile apps that help patients diagnosed with psychiatric conditions.  
• Mobile apps that use patient characteristics to provide patient specific screening, counseling and preventive recommendations from well known and established authorities.
• Mobile apps that remind patients about pre determined dosing schedules (medication reminders). 

The last example is especially welcome.  For a number of years, FDA has been actively regulating medical reminders under 21 C.F.R. § 890.5050 (product code NXQ).  The active regulation of these products has created a headache for developers of health and wellness coaching apps, who risked device regulation by including this useful and low risk functionality in their products.  FDA’s decision to exercise enforcement discretion here is wise, and consistent with the overall approach of this guidance. 

The mobile apps that FDA will regulate are called “mobile medical apps.”  What mobile apps fall under this category?  FDA discusses the following broad types:

• Mobile apps that connect to medical devices to control them or to display, store, analyze or transmit patient specific medical device data.
• Mobile apps that transform a mobile platform with device functionality by using attachments, display screens, or sensors.
• Mobile apps that perform patient specific analysis and provide patient specific diagnosis or treatment recommendations.

This last type of mobile medical app looks very much like clinical decision support software (“CDSS”).  However, FDA expressly says that this guidance does not address CDSS.  FDA is expected to issue a draft guidance on that topic in the near future. 

At the same time, it would be odd for FDA to regulate a particular CDSS functionality if provided via mobile app but not if it is on some other platform.  That is especially true because FDA goes out of its way to say in this guidance that its oversight approach to mobile apps is focused on functionality and not platform.

Most likely, the CDSS draft guidance will take a similar approach to the mobile medical apps guidance, subjecting CDSS software with higher risk functionality to regulation while specifying CDSS functionality that is unregulated or under enforcement discretion.  This upcoming guidance will probably apply to CDSS functionality on any platform, mobile or not.

In this guidance, FDA provides only a few examples of mobile apps providing diagnosis or treatment recommendations that will be regulated.  The examples are:  apps that use patient specific parameters to calculate dosage or create dosage plans for radiation therapy; Computer Aided Detection (“CAD”) software; image processing software; radiation therapy treatment planning software. 

These apps are all examples of what FDA describes as “mobile apps that perform sophisticated analysis or interpret data (electronically collected or manually entered) from another medical device” (p. 15).  Unfortunately, FDA does not provide examples of mobile CDSS apps that are not regulated.  We will probably need to wait for the overall CDSS guidance to more fully clarify what mobile CDSS functionality will or will not be regulated.

The awkwardness here is probably due to the fact that FDA geared up development of a guidance for mobile apps before discovering, as the software industry developed, that the focus really needs to be on functionality rather than type of platform.  For anyone who needs to predict the likely regulatory status of stand alone software that is not a mobile app, this guidance should still be a valuable tool.  It is a fair inference that much of the substance here applies when the same type of functionality is placed on a non-mobile platform.

Finally, if a mobile app falls within one of the mobile medical app categories, that is only the beginning of the analysis.  The next step will be to determine its classification (Class I, II or III), because that will drive the determination of what regulatory requirements apply.  This guidance does not directly address the determination of regulatory classification.

By Allyson B. Mullen –

Have you ever heard of an “Immediately in Effect (IIE)” guidance document?  Thanks to a new draft SOP issued by CDRH, you may soon see this new species of guidance on a regular basis.

In section 405 of Food and Drug Administration Modernization Act of 1997 ("FDAMA"), FDA was authorized to issue guidance documents without public comment in certain circumstances.  Specifically, section 701(h)(1)(C) was added to the Food, Drug, and Cosmetic Act (the “Act”) and states that guidance documents “set[ting] forth initial interpretations of a statute or regulation, changes in interpretation or policy that are of more than a minor nature, complex scientific issues, or highly controversial issues” must have prior public participation before implementation “unless the Secretary determines that such prior public participation is not feasible or appropriate.”  (Emphasis added.)

In February 2000, FDA issued proposed implementing regulations.  The preamble to the proposed regulations suggests that FDA deems prior public participation “not feasible or appropriate” if: “(1) there are public health reasons for immediate implementation of the guidance document; (2) there is a statutory requirement, executive order, or court order that requires immediate implementation; or (3) the guidance document presents a less burdensome policy that is consistent with public health.”  65 Fed. Reg. 7321, 7324 (Feb. 14, 2000).  The proposed regulations were finalized in September 2000 and are codified at 21 C.F.R. § 10.115(g)(2). 

Nearly 13 years later, on September 5, 2013, CDRH announced a Draft Standard Operating Procedure ("SOP") “Level 1, Immediately in Effect Guidance Documents on Premarket Data Issues” (the “Draft SOP”).  78 Fed. Reg. 54655 (Sept. 5, 2013).  Some may wonder why FDA would propose an SOP setting forth the process for issuing guidance at this late date.  Could it be because they are intending to make greater use of such a process and implementing more written guidance without prior public participation?

The stated intent of the Draft SOP is to clearly and efficiently communicate changes in CDRH’s expectations and new scientific information that relate to or could impact Investigational Device Exemptions and pre-market submissions (e.g., 510(k)s, PMAs, HDEs).  Draft SOP at 1. The Draft SOP accomplishes this objective by creating a new category of guidance document, called, “Immediately in Effect (IIE) Guidance Documents.”  Id. at 1.  (The Draft SOP replaces CDRH’s earlier attempt in 2011 to establish such a process in its “‘Notice to Industry’ Letters” SOP. 78 Fed. Reg. 54655.)

The Draft SOP proposes a three-pronged assessment to determine if an IIE Guidance Document should be developed: (1) there is new scientific information identified, which raises “new, important safety risk or calls into question the adequacy of currently used test methods or clinical trial design to demonstrate or bear on safety, effectiveness, and/or substantial equivalence of a device type;” (2) as a result of such new information, CDRH needs to change its regulatory expectations  with respect to IDEs and premarket submissions; and (3) “prior public participation is not appropriate or feasible.”  Draft SOP at 2. 

Based on these criteria, it appears as though there could be a high bar for issuance of an IIE Guidance Document.  However, the Draft SOP does not define or put any parameters around what would constitute new scientific information (must it be actual or speculative?) and FDA has previously declined to limit the use of IIE Guidance Documents to “rare and extraordinary circumstances” or “where there is a real demonstrated public health emergency, not just a theoretical emergency.”  65 Fed. Reg. 56468, 56472 (Sept. 19, 2000). 

It seems possible that CDRH could be planning to put this SOP into routine use once finalized since the Draft SOP provides a fairly simple process for issuing IIE Guidance Documents.  The Draft SOP allows for CDRH staff and management to prepare a briefing summary for discussion of proposed IIE Guidance Documents with the Center Science Council ("CSC").  Draft SOP at 3.  The Draft SOP includes a sample (short) format for a briefing summary and states that the briefing summary should include 9 items:

• The new scientific information;
• How the risk/benefit profile of the particular device is changed by the new scientific information;
• The Center’s anticipated changes to regulatory policy in light of the new scientific information;
• Why such changes are necessary;
• The audience who should be made aware of such changes;
• The submission types affected by such changes (future and/or pending submissions) (Yes, you read that correctly – IIE Guidance Documents can impact not only future submissions, but also submissions pending with CDRH at the time the guidance is issued; how will companies keep up?);
• The existing guidance documents impacted by such changes;
• Why an immediate effect guidance document is the “only appropriate method for disseminating this information”; and
• Whether and to whom any further communication regarding the topic at issue is needed.  Id. at 3 & 7.

Based on the discussions facilitated by the briefing summary, the CSC is charged with determining whether the new scientific information warrants a change in the premarket regulatory expectations, whether the change should be communicated through an IIE Guidance Document, and whether additional expertise is needed before making a determination on a particular topic.  Id. at 3-4.

Once the CSC determines that an IIE Guidance Document should be issued, the guidance is drafted and should only be 1 to 2 pages in length, and generally not exceed 3 pages.  Id. at 4.  For information that is critical to industry, such as changing regulatory expectations, it seems that it may be difficult for CDRH to include all of the required elements (e.g., the nonbinding language disclaimer) and still find space in three pages (maximum) to clearly articulate its new expectations.  Once drafted, the IIE Guidance Document must be approved by a number of individuals within CDRH before it is published in the Federal Register.  Id. at 5.  Lastly, the Draft SOP provides for public comment during the 60-day period following issuance of the IIE Guidance Document; and in the 90 days following close of the comment period, CDRH will review the comments and revise the IIE Guidance Document, if necessary.  Id. at 5.
 
Only time will tell how CDRH will utilize this SOP, and whether it will become routine.  However, it appears as though CDRH is establishing a simple process to easily implement guidance without public input and without establishing parameters around critical steps in the process (e.g., what constitutes new scientific information).  Since when does a bureaucracy invest significant effort in developing a regulatory tool and then choose not to use it?  The odds are that you will soon become very familiar with IIE Guidance Documents.

By Kurt R. Karst –      

Anyone from the United States who has visited a foreign city – like São Paulo, Brazil or Mumbai, India – knows immediately upon exiting the sealed environment of their aircraft that they are no longer in the United States.  There’s an indescribable smell to the air.  It permeates everything.  After a few weeks though, the smell loses its force and seems to go away.  Of course, it doesn’t really go away (which you realize upon returning home and opening up your suitcase), you just become accustomed to it.  And you begin to wonder what newcomers and visitors are complaining about.  A similar smell appears to be permeating Rockville, Maryland, and, more specifically, the suite of buildings on Standish Place where the Office of Generic Drugs (“OGD”) is located.  Those of us who visit the OGD campus can smell the change in the air, though others who have grown accustomed to the smell may not. 

Over the past several months we’ve noticed and heard about small, but significant changes in the way OGD has traditionally operated.  Consider, for example, a recent article penned by Bob Pollock on the Lachman Consultants Blog.  In his August 19th post, Bob provides a useful snapshot of ANDA approval times for June.  Bob would have liked to provide information on July ANDA approvals, but he couldn’t.  “[W]e understand that OGD has temporarily stopped releasing its monthly statistics,” says Bob.  “Hopefully, that will be resolved soon because these numbers are the only concrete view that the industry has into OGD’s performance.  This certainly is one piece of information that makes transparency seem alive and well and, now, at least for the short term, that piece of information is not available.”

Then, earlier this week, FDA released a new Manual of Policies and Procedures (“MAPP”) – MAPP 5200.3 – titled “Responding to Industry Inquiries with respect to Abbreviated New Drug Applications in the Office of Generic Drugs.”  The stated purpose of the MAPP is to “clarify[y] the general principles for handling inquiries with respect to abbreviated new drug applications (ANDAs) from the authorized representative for an applicant with an ANDA submission (the authorized inquirer) by Regulatory Project Management (RPM) staff in [OGD].”  The MAPP is specifically tied to implementation of the Generic Drug User Fee Amendments of 2012 (“GDUFA”), stating:

The Center for Drug Evaluation and Research (CDER) believes it is important to timely respond to industry inquiries.  Historically, OGD staff responded to a range of informal, ad hoc inquiries from industry regarding the status of ANDAs.  In order to systematically improve the predictability and timeliness of the ANDA review process, however, industry and FDA negotiated the Generic Drug User Fee Amendment (GDUFA). GDUFA was enacted by Congress and became effective as of October 1, 2012.  Pursuant to GDUFA, OGD implemented certain agreed-upon premarket review efficiency enhancements, such as complete response letters, and also committed to achieve certain agreed-upon application and backlog metric goals.  As OGD works to fulfill its GDUFA performance obligations, industry has an interest in clarity regarding the process for handling inquiries going forward.

After stating that the generic drug industry is responsible for designating “a single individual” to communicate with OGD and must “make all inquiries through that authorized inquirer,” the MAPP goes on to lay our various procedures.  For example:

• Reviewers, team leaders, discipline specific project managers, deputies, division directors, other OGD management or OGD immediate office staff should refer all inquiries from the authorized inquirer on the status of an ANDA or related submissions to the RPM for that ANDA.
• RPMs should not provide dates or time lines for when reviews will be completed, when letters will be issued, or when other actions will be taken. Because workload and competing priorities affect action times, time lines are especially difficult to predict and should not be provided.
• RPM should try to understand the reasoning behind the status inquiry. The underlying principle identified by the authorized inquirer may reveal valuable information to aid FDA in providing a timely review to address a public health need (e.g., patent expiration date, drug shortage). If the justification does reveal previously unknown information, the RPM will communicate this to OGD management and the review team.

It wasn’t long after the posting of MAPP 5200.3 that we began to receive phone calls and emails expressing shock, anger, and frustration.  We started to feel like a therapist for the generic drug industry.  “In return for collecting hundreds of millions of $ in GDUFA fees, OGD is now restricting inquiries to only the Regulatory Project Manager, who will not provide any specific information regarding timing or content of reviews.  To add insult, INDUSTRY is supposed to inform OGD as to WHY THEY NEED THIS INFORMATION!,” read one email.  “This is so obviously a self-serving bureaucratic attempt to hide continuing disastrous performance by OGD, I have started calling it The Dog Ate My DAARTS Log MAPP of 2013,” continued the email, referring to the Document Archiving, Reporting and Regulatory Tracking System FDA uses to track applications.  Another comment we received said that the “transparency that has taken place is like the transparency of a brick wall!”  Some other comments we received we cannot post here – we’re only a PG-rated blog.

So what’s going on?  We call it “UFAization”:  the process by which an FDA component, after the enactment of a User Fee Act, becomes focused on so-called process enhancements to meet goals and commitments at the expense (both literally and figuratively) of those who are subject to such user fees.  (Ok, maybe it’s not a term that will appear in the Oxford English Dictionary, but it’s better than “twerk!”).  While other FDA components have likely undergone similar changes though the years as User Fee Acts have been enacted and implemented, OGD – and the generic drug industry – has a character all its own.  Asking the generic drug industry to change its character is kind of like asking a tiger to change his stripes. 

GDUFA and the accompanying Performance Goals and Procedures FDA and the generic drug industry hammered out and agreed to have three key aims:

Safety – Ensure that industry participants, foreign or domestic, who participate in the U.S. generic drug system are held to consistent high quality standards and are inspected biennially, using a risk-based approach, with foreign and domestic parity.

Access – Expedite the availability of low cost, high quality generic drugs by bringing greater predictability to the review times for abbreviated new drug applications, amendments and supplements, increasing predictability and timeliness in the review process.

Transparency – Enhance FDA’s ability to protect Americans in the complex global supply environment by requiring the identification of facilities involved in the manufacture of generic drugs and associated active pharmaceutical ingredients, and improving FDA’s communications and feedback with industry in order to expedite product access.

What some in the generic drug industry appear to be saying with their criticism of recent changes at OGD is that these changes are not merely growing pains as a result of GDUFA implementation, but that FDA is not meeting the key aims of GDUFA, or worse, that the Agency is reneging on some aspects of them.  We’re certain that we’re not the only outlet for folks to vent their concerns.  The Generic Pharmaceutical Association ("GPhA") is probably getting an earful from its members.  Whether or not the generic drug industry will simply become accustomed to the unusual smell these changes seem to be creating, or whether there will be a call to action, remains to be seen.  A couple of upcoming events – the GPhA/FDA Fall Technical Conference and a House Energy and Commerce Committee hearing on FDA's implementation of FDASIA – might be good venues at which to raise concerns.

Additional Reading:

• Bob Pollock, The MaPP to Nowhere (Sept. 26, 2013)

By Jeffrey N. Wasserstein & Alexander J. Varond –

Last week, ahead of the September 23, 2013 compliance deadline for its HITECH final rule (also referred to as the “Omnibus Final Rule”), the Department of Health and Human Services issued guidance  entitled “The HIPAA Privacy Rule and Refill Reminders and Other Communications about a Drug or Biologic Currently Being Prescribed for the Individual.”  In prior posts, we discussed the HITECH final rule here, here, and here.  The guidance, as you guessed it, addresses the refill reminder exception, from the Omnibus Final Rule, and its two prongs:  (1) whether the communication is about a “currently prescribed drug or biologic,” and (2) if the communication involves financial remuneration, whether the remuneration is “reasonably related to the covered entity’s cost of making the communication.”

Addressing the issues in Adheris, Inc. v. Sebelius

HHS’s guidance sheds light on key issues raised in the lawsuit filed by Adheris, Inc. against HHS, which we blogged about here and here.

At issue in Adheris is whether the company, whose main business involves sending refill reminders and medication adherence communications to patients about their prescribed treatment regimens, and is paid for by pharmaceutical companies, can continue to provide its services under the Omnibus Final Rule.  In its complaint, Adheris argued that the Omnibus Final Rule violated the First Amendment and misconstrued the HITECH Act.

The HHS guidance clarifies the refill reminder exception and provides an example of permissible communications that is applicable in Adheris: “a pharmacy hires a business associate to assist in administering a medication adherence program that involves mailing adherence communications to patients about their currently prescribed drugs, even though the business associate is paid by the pharmaceutical manufacturers, provided the payment does not exceed the fair market value of the business associate’s services.”  HHS’s guidance does not define “fair market value,” but does note that permissible remuneration includes “reasonable direct and indirect costs . . . including labor, materials, and supplies, as well as capital and overhead costs.”  We haven’t heard anything yet, but we expect that this will likely take the wind out of the sails of Adheris’s suit.

Additional points addressed in HHS’s guidance

Also, of interest to many of our readers, HHS’s guidance makes clear that communications about specific new formulations of a currently prescribed medicine are not permitted under the Omnibus Final Rule.  However, the guidance does permit more general communications about new formulations.  So, while a covered entity or business associate can’t say to a patient on an immediate release formulation “Try the new extended release formulation” they can say “speak with your pharmacist about more convenient dosage forms.” 

The guidance also addresses:

• Recently-lapsed prescriptions;
• Drug delivery systems;
• REMS and other “government-mandated” communications; and
• Face-to-face discussions with individuals about specific products or services.

By Kurt R. Karst –    

FDA’s latest Report to Congress, required by FDC Act § 505(q)(3), on the Agency’s experience with so-called “505(q) citizen petitions” during Fiscal Year 2012 (“FY2012”) is largely a rehash of the FY2011 Report to Congress (see our previous post here on the FY2011 report, and our posts here, here, and here on reports from previous years).  FDA continues to express certain concerns about the petitioning process, such as serial petitioning, and continues to say that it is monitoring “the number and nature of 505(q) petitions submitted and [analyzing] whether section 505(q) is effectively discouraging petitioners from submitting petitions primarily to delay the approval of applications.”  But FDA, in the latest report, is more emphatic than in previous reports about expressing frustration with how responding to 505(q) petitions interferes with other Agency work, particularly in light of the enactment of the FDA Safety and Innovation Act (“FDASIA”), which shortened FDA’s response deadline.  The latest report also provides updated numbers and new statistics on the petitions received by and acted on by FDA.

By way of background, FDC Act § 505(q) was added to the law by the 2007 FDA Amendments Act (“FDAAA”) and is intended to prevent the citizen petition process from being used to delay approval of pending ANDAs and 505(b)(2) applications.  The law was amended by § 301 of Pub. L. No. 110-316 (2008), and again by FDASIA § 1135, which, among other things, changed the original 180-day response deadline to 150 days, and made the law applicable to citizen petitions concerning biosimilar applications submitted to FDA pursuant to PHS Act § 351(k).  (See our FDASIA summary here.)  In June 2011, FDA issued final guidance on FDC Act § 505(q).  In January 2012, FDA proposed regulations to amend the Agency’s citizen petition regulations.  FDA is reportedly evaluating the impact of FDASIA § 1135 on both the final guidance and proposed regulations.

Under the current version of FDC Act § 505(q), which was in effect for part of FY2012, the statute says that FDA shall not delay approval of a pending ANDA, 505(b)(2) application, or 351(k) biosimilar application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.”  Under FDC Act § 505(q), which FDA has interpreted to apply only to certain petitions submitted to the Agency after September 27, 2007 (when FDAAA was enacted), “[FDA] shall take final agency action on a petition not later than 150 days after the date on which the petition is submitted.”  FDA may not extend the 150-day period “for any reason,” including consent of the petitioner, and may summarily deny a petition submitted with the primary purpose of delaying ANDA, 505(b)(2) application, or 351(k) biosimilar approval.  FDA has never summarily denied a 505(q) petition.  Instead, FDA seems to have resorted to a form of public shaming (see our previous post here) when the Agency suspects delay tactics.

FDC Act § 505(q)(3) requires that each annual report to Congress specify: “(A) the number of applications that were approved during the preceding 12-month period; (B) the number of such applications whose effective dates were delayed by petitions referred to in paragraph (1) during such period; (C) the number of days by which such applications were so delayed; and (D) the number of such petitions that were submitted during such period.”  FDA says in its Fifth Annual Report that:

Between September 27, 2007, and September 30, 2012, FDA determined that a delay in approving an ANDA was necessary to protect the public health in the case of five ANDAs with related 505(q) petitions.  FDA has not delayed approval of any 505(b)(2) applications or biosimilar biological product applications based on 505(q) petitions.

During the FY 2012 reporting period, the agency approved 42 applications submitted under section 505(b)(2), 517 ANDAs, and no biosimilar biological product applications.  No approvals for any 505(b)(2) or biosimilar biological product applications were delayed because of the filing of a 505(q) petition in this reporting period.  No ANDA approvals were delayed in this reporting period because of pending 505(q) petitions.

During the FY 2012 reporting period, 24 petitions considering 505(q) petitions were submitted to the agency.  FDA did not miss the statutory deadline for responding to any 505(q) petitions during this reporting period.

FDA explained in previous reports that five ANDAs have been delayed because of pending 505(q) petitions.  That number will increase when FDA presents its Sixth Annual Report.  In an August 2013 denial of a March 2013 petition (Docket No. FDA-2013-P-0247) concerning the approval of generic Zoledronic Acid Injection, FDA noted that the petition caused a 25-day delay in ANDA approvals. 

In previous reports, FDA explained that the Agency has timely responded to all but two of the 505(q) petitions within the statutory timeframe.  Although FDA did not blow the statutory deadline in FY2012, FDA’s track record of timely responding to 505(q) petitions within the applicable statutory period will be tarnished in FY2013.  Earlier this month, FDA passed the 150-day deadline for responding to a citizen petition (Docket No. FDA-2013-P-0471) submitted by Bayer HealthCare Pharmaceuticals Inc. requesting that the Agency award 5-year new chemical entity exclusivity for the oral contraceptive NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets (see our previous post here).

The Fifth Annual Report provides some consolidated petition numbers from FYs 2008-2012.  According to FDA, the Agency has received a total of 116 petitions subject to FDC Act § 505(q).  The annual number of petitions has remained relatively steady at around 20 petitions, with the exception of FY 2009, when there were 31 petitions:

New to the Fifth Annual Report is a table summarizing the outcomes for the 505(q) petitions – 97 of them – that were resolved as of September 30, 2012:

That means that as of the conclusion of FY2012, FDA denied about 64% of 505(q) petitions, denied in part and granted in part another 27%, and granted only 7% of the 97 petitions.  (Another almost 2% were voluntarily withdrawn by the petitioner.)

FDA has consistently expressed frustration with how responding to 505(q) petitions interferes with other Agency work.  FDA’s frustration is amplified in the Fifth Annual Report, however, now that the Agency has had experience with the 30-day haircut to the original 180-day deadline.  According to FDA:

The enactment of FDASIA has increased the agency resource requirements for responding to 505(q) petitions.  Section 1135 of FDASIA significantly shortened the time frame by 30 days and has given FDA less time to evaluate the issues, articulate its scientific and legal reasoning, and formulate a response on the issues referenced in the petition.  As a result, FDA has needed to direct resources away from other important initiatives to attempt to comply with the new shorter deadline.

Not included in the Fifth Annual Report (and not required to be) is FDA’s progress with meeting the new 270-day timeframe at FDC Act § 505(w) covering discontinuation petitions submitted pursuant to 21 C.F.R. § 314.161.  That provision was also included in FDASIA.  A quick look at our FDA Citizen Petition Tracker, however, indicates that the Agency is doing well in meeting that statutory mandate.  ANDA suitability petitions are another story altogether.  FDA has regularly failed to meet the 90-day statutory decision deadline for those petitions for years.  We’ll save that analysis for another day.  But in all fairness, we note that FDA does appear to be taking steps to address the situation.  FDA recently published new procedures that are intended to bring the Agency back into compliance. 

By Jennifer D. Newberger –

At long last, it is here: FDA has issued the final rule implementing the unique device identifier (UDI) requirements, originally required by the Food and Drug Administration Amendments Act of 2007 (FDAAA) and then again by the Food and Drug Administration Safety and Innovation Act (FDASIA), enacted in July 2012 (see here at pages 39-40).  The stated purpose of the rule is to “lead to more accurate reporting of adverse events by making it easier to identify the device prior to submitting a report. . . [and to] allow FDA, health care providers, and industry to rapidly extract useful information from adverse event reports, pinpoint the particular device at issue and thereby gain a better understanding of the underlying problems, and take appropriate, better-focused, corrective action.”  Product information will be maintained in FDA’s Global Unique Device Identification Database (GUDID), unless subject to an exemption.  On the same day FDA issued the final rule, it also released a draft guidance, Global Unique Device Identification Database (GUDID), to provide information to device labelers about submitting information to the database.

Each medical device subject to the UDI requirements will be required to bear a UDI on the label and device package of each medical device.  Each UDI must be provided in a plain-text version and in a form that uses automatic identification and data capture (AIDC) technology.  If a device is intended to be used more than once and to be reprocessed before each use, it must also be directly marked with the UDI, so that the identifying information is available even when separated from the original label or packaging. 

Some of the principal changes between the amended proposed rule of November 19, 2012 (see our previous post here) and the final rule include:

• FDA may grant a one-year extension of the compliance date applicable to a Class III device or a device licensed under the Public Health Service Act (PHS Act) when in the best interest of the public health.
• The final rule provides an exception for a finished device that is manufactured and labeled prior to the compliance date that applies to the device, but the exception expires three years after the compliance date.
• A Class I device labeled with a Universal Product Code (UPC) may use the UPC as its UDI, but is still subject to GUDID reporting requirements.
• Each device constituent part of a combination product need not bear a UDI so long as the combination product bears a UDI.  Additionally, any combination product that properly bears an NDC on its label need not bear a UDI.
• Unlike the proposed rule, which would have required the label and device package of each device packaged in a convenience kit to bear its own UDI, distinct from that of the convenience kit, the final rule does not require devices contained within a convenience kit to bear a UDI but does require the label and each device package of every convenience kit to bear a UDI.
• The proposed rule would have required an implantable device to bear a permanent marking providing the UDI; the final rule removed this provision, and does not require an implantable device to be directly marked with a UDI.
• Legacy FDA identifiers for devices, such as National Health-Related Item Code (NHRIC) and NDC numbers, will be rescinded by September 24, 2018.  However, continued use of a labeler code issued under an FDA-accredited system for the issuance of UDIs will be permitted, so long as the use is permitted by the issuing agency that administers the system, and the label submits a request for continued use of the code.  FDA must receive requests for continued use of labeler codes no later than September 24, 2014.
• The proposed rule would have exempted Class I single use devices from the UDI requirements; the final rule extends that to all classes of single use devices, except implants.
• Stand-alone software would have been subject to direct marking in the proposed rule; the final rule does not require direct marking, but is subject to certain specified requirements.  For example, stand-alone software that is not distributed in packaged form (e.g., downloaded from a website), will meet the UDI requirements if a plain-text statement of the UDI is displayed whenever the software is started or through a menu command.  When distributed in package form, the label and device package of the software must include a UDI in plain text and AIDC.
• In addition to the device identifier and production identifier required on the majority of devices, HCT/Ps regulated as devices will also have to include the distinct identification code required by 21 C.F.R. § 1271.290(c). 

The compliance dates for the final rule are unchanged from those described in the amended proposed rule of November 19, 2012, and are as follows:

• September 24, 2014
  • The labels and packages of Class III devices and devices licensed under the PHS Act must bear a UDI;
  • Class III stand-alone software must provide its UDI;
  • Data for these devices must be submitted to the GUDID database.
• September 24, 2015
  • The labels and packages of implantable, life-supporting, and life-sustaining devices must bear a UDI;
  • A device that is a life-supporting or life-sustaining device that is required to be labeled with a UDI must bear a UDI as a permanent marking if the device is intended to be used more than once and intended to be reprocessed before each use;
  • Stand-alone software that is a life-supporting or life-sustaining device must provide its UDI;
  • Data for implantable, life-supporting, and life-sustaining devices that are required to be labeled with a UDI must be submitted to the GUDID database.
• September 24, 2016
  • Class III devices required to be labeled with a UDI must bear a UDI as a permanent marking if the device is a device intended to be used more than once and intended to be reprocessed before each use;
  • The labels and packages of Class II devices must bear a UDI;
  • Class II stand-alone software must provide its UDI;
  • Data for Class II devices required to be labeled with a UDI must be submitted to the GUDID database;
• September 24, 2018
  • A Class II device required to be labeled with a UDI must bear a UDI as a permanent marking on the device if the device is intended to be used more than once and intended to be reprocessed before each use;
  • The labels and packages of Class I devices and unclassified devices must bear a UDI;
  • Class I stand-alone software must provide its UDI;
  • Data for Class I and unclassified devices must be submitted to GUDID.
• September 24, 2020
  • Class I devices and unclassified devices that are required to be labeled with a UDI must bear a UDI as a permanent marking if the device is intended to be used more than once and intended to be reprocessed before each use.

This phased-in approach should allow device manufacturers sufficient time to comply with the rule.  There will undoubtedly be complications, questions, and challenges as manufacturers begin to comply with the rule.  After all the waiting and debating, it will be interesting to see what the impact of the UDI system will be on FDA, industry, and the public.

By Ricardo Carvajal –

Rep. Frank Pallone (D-NJ) introduced legislation – H.R. 3147, the Food Labeling Modernization Act of 2013 – that would grant FDA significant new authorities in the area of food labeling.  In what is identified as the bill’s “signature initiative,” FDA would be directed to establish a standard symbol system for front-of-package ("FOP") labeling for conventional foods.  A food would be misbranded unless its principal display panel ("PDP") bears “summary nutrition information that reflects the overall nutritional value of the food or specified ingredients” as required in regulations that would be issued by FDA.  

In addition, the bill aims to eliminate allegedly deceptive claims for conventional foods and to update nutrition labeling requirements with provisions that include the following:

• FDA would be directed to issue guidance clarifying the substantiation requirements applicable to structure/function claims, and manufacturers would be required to provide FDA with documentation that substantiates their claims within 90 days of a request by the agency.
• Additional trans fat-related restrictions would be imposed on the use of nutrient content claims for cholesterol and saturated fat, and new requirements would be imposed on the use of claims that characterize the level of trans fat.
• FDA would update its definition of “healthy” to address added sugars and whole grains (at least half of the grains in a food labeled as “healthy” would have to be whole grains).
• A food labeled as “natural” would be misbranded if it contains any artificial ingredient, including any artificial flavor, artificial color, synthetic version of a naturally occurring substance, or any ingredient “that has undergone chemical changes” (but not including food that has undergone a traditional process to make it edible, preserve it, or make it safe, and not including a food that has undergone a traditional physical process that does not “fundamentally alter” the food).
• Disclosure of the percent of whole grain would be required for “made with whole grain,” “multigrain,” or similar claims, and disclosure of the percent of whole wheat would be required for “wheat” or “whole wheat” claims.
• If a food contains any added color, any added non-caloric sweetener, or any added flavoring, that fact would have to be disclosed on the PDP.
• Declaration of added sugar would be required, as would the percent of recommended daily calories per serving and the “percent of added sugars recommended for daily consumption” per serving.
• Collective declaration of any sugars, non-caloric sweeteners, or sugar alcohols would be required in the ingredient listing.
• Any product that can be “reasonably consumed on a single occasion” would be treated as a single serving.
• Declaration of the amount of caffeine per serving would be required if the total exceeds 10 mg from all sources.

The bill is cosponsored by Rep. Rosa DeLauro (D-CT) and has been referred to the House Committee on Energy and Commerce.

By David B. Clissold –

Last week, House Democrats and a consortium of public health organizations turned up the heat on FDA to issue “deeming” regulations that would bring electronic cigarettes and other types of tobacco products under the Agency’s jurisdiction. The Family Smoking Prevention and Tobacco Control Act (“Tobacco Control Act”), Pub. L. No. 111-31, 123 Stat. 1776 (2009), broadly defined the term “tobacco product” to include “any product made or derived from tobacco that is intended for human consumption, including any component, part, or accessory of a tobacco product.”  However, the Tobacco Control Act only provided FDA the immediate authority to regulate cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco.  All other “tobacco products” could only be regulated if FDA first issued regulations “deeming” such other tobacco products to be subject to the Federal Food, Drug, and Cosmetic Act (“FDC Act”). 

In a letter dated September 16, 2013, Representatives Waxman (D, CA), DeGette (D, CO), Pallone (D, NJ), and Dingell (D, MI) urged Dr. Margaret Hamburg, Commissioner of FDA, to issue deeming regulations that would assert jurisdiction over electronic cigarettes.  On the same day, these representatives sent a letter to the Chairmen of the House Committee on Energy and Commerce, Subcommittee on Oversight and Investigations, and Subcommittee on Health urging a Congressional hearing on e-cigarettes and other tobacco products.  Among other topics, the authors recommended that the hearing examine trends in the use of e-cigarettes, cigars, and pipe tobacco and statutory changes needed to bolster FDA’s ability to regulate these products.

Finally, the Tobacco Control Legal Consortium filed a Citizen Petition urging FDA to assert jurisdiction over additional tobacco products, including waterpipes (“hookahs”) and electronic cigarettes.

As noted in the letter to Dr. Hamburg, FDA has been “working on these ‘deeming’ regulations for years.”  It remains to be seen whether these additional efforts will encourage the Agency to propose deeming regulations, or whether the Agency believes that additional statutory authority or clarity may be needed first.

By Kurt R. Karst –   

The titles – and sometimes even the content – of some of our posts are inspired by the things we experience (or have experienced) in our regular, non-attorney lives.  For years now we’ve weaved together with food and drug law topics such seemingly disparate things as movies (A Few Good Men and Fletch – see our posts here and here), television (Star Trek and Monty Python and the Holy Grail – see here and here), and even Frau Rommelfanger’s seventh grade German class (see here).  We hope these (clever) mash-ups grab readers’ attention and keep you interested in things that can, at times, seem boring or hypertechnical, or that may not be in your bailiwick, but that matter nevertheless. 

Although one of our posts from way back in 2007 shortly after we started this blog was inspired by the Bard of Avon, William Shakespeare, and the famous line he penned in Hamlet – “To be, or not to be” (see here) –  we’ve never dragged the Bard’s Romeo and Juliet into food and drug law.  As you can see, now we have.  And it’s a nice fit with a Citizen Petition (Docket No. FDA-2013-P-1153) the Generic Pharmaceutical Association (“GPhA”) recently submitted to FDA on biosimilar naming.  If Act I of what will likely be a long-running and many-act play on biosimilars concluded with the March 23, 2010 enactment of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), then Act II has been all about topics related to, but that are not specifically covered by, the BPCIA.  Act II, Scene I is about the continuing state-by-state battle over biosimilar substitution laws (see our scorecard here).  Act II, Scene II is about the battle over whether biosimilar versions of their brand-name reference product counterparts should each be assigned a distinct nonproprietary name specific to the manufacturer.  (Act III, which is only in early development, may be based on the April 2012 Citizen Petition – Docket No. FDA-2012-P-0317 – submitted by Abbott Laboratories requesting that FDA not accept for filing, file, approve, or even discuss with any company any application or any investigational new drug application for any biosimilar that cites as its reference product any product for which the BLA was submitted to FDA prior to the date on which the BPCIA was enacted (see our previous post here)). 

In Act II, Scene II of Romeo and Juliet – the famous balcony scene – Juliet argues that the names of things don't matter, and all that matters is what things are:

'Tis but thy name that is my enemy;
Thou art thyself, though not a Montague.
What's Montague? it is nor hand, nor foot,
Nor arm, nor face, nor any other part
Belonging to a man. O, be some other name!
What's in a name? that which we call a rose
By any other name would smell as sweet;
So Romeo would, were he not Romeo call'd,
Retain that dear perfection which he owes
Without that title. Romeo, doff thy name,
And for that name which is no part of thee
Take all myself. 

While it might be true that names don’t matter when it comes to matters of love, names do matter in other contexts, like in food and drug law.  As such, GPhA respectfully disagrees with the Bard and says that names do matter when it comes to biosimilars! 

In its September 17, 2013 Citizen Petition, GPhA requests that FDA implement its International Nonproprietary Name (“INN”) naming policy equally to all biologics, whether that biological product is approved as a biosimilar under Section 351(k) of the Public Health Service Act (“PHS Act”) as added by the BPCIA, or as a brand-name reference product under PHS Act § 351(a).  More specifically, GPhA says that “because all biologics approved under the Section 351(k) pathway are ‘highly similar’; and thus, have no clinically meaningful differences from the reference protein product (RPP) [they should] share the same INN name as the RPP, just as comparable originator products produced by a change in a manufacturing process or facility (post-change product) share the same INN as the original RPP (pre-change product).” (Emphasis in original)

The BPCIA, as enacted, does not specifically address biosimilar product naming.  Although previous biosimilar legislation did address the issue, such as Representative Henry Waxman’s (D-CA) Access to Life-Saving Medicine Act (H.R. 1038) and Senator Judd Gregg’s (R-NH) Affordable Biologics for Consumers Act (S. 1505) (both from 2007), it was ultimately decided that naming provisions should not be included in the final biosimilars bill.  Given this history, GPhA says that “[w]ithout new statutory authority, FDA lacks specific authority to require separate INNs for biosimilars, and existing conventions for biologics should be expected to prevail.” 

Referencing a 2006 policy paper FDA sent to the World Health Organization (“WHO”) in support of WHO naming conventions, GPhA says:

FDA clearly supports the original purpose of the INN (to identify the active ingredient of a product), rejects the use of nonproprietary names to communicate interchangeability, and states that concerns about pharmacovigilance “transcend a naming convention,” explaining that “[i]t would be the FDA's preference that INNs continue to be granted based only on molecular characteristics and pharmacological class of the active ingredient(s). ”  In this paper FDA agrees that there should be no change in global policy and rejects distinctive INN designations for biosimilars. . . .  While [the] BPCIA was enacted subsequent to this policy position being presented to WHO, nothing in the new statute is incompatible with the 2006 FDA position on biosimilar naming.

Moreover, says GPhA, FDA is obligated to apply its standards equally to all applicants and products:

Requiring unique INNs for biosimilars while allowing sharing of INNs for other biologics in comparable situations would run contrary to this tenet.  FDA routinely allows originator biologic products in the same class approved under separate 351(a) or 505(b) applications and using different manufacturing methods implemented by different sponsors to share the same INN.  For example, a number of Anti-hemophilic Factor (Recombinant) products, some of the most complex biologics licensed in the US, share the same INN.  [(Appendix A to the Petition is an extensive list of products that share INNs.)]  Further, FDA has for many years without question authorized originator manufacturers to modify biologics' manufacturing processes and develop biologics that have minor changes and differences that are not clinically meaningful without requiring a change in non-proprietary name.  This authorization is contingent on a sponsor submitting data that the post-change product is “comparable” to the pre-change product.  If the sponsor demonstrates such comparability FDA deems the (pre- and post-change) products interchangeable for all indications irrespective of the mechanism of action being understood.  The standard for both comparability and biosimilarity is “highly similar” quality attributes.

And what about concerns raised by some that distinct biosimilar names are necessary to facilitate accurate attribution of adverse events?  GPhA addresses that issue as well and says:

GPhA concurs that any concerns with pharmacovigilance call for tailored solutions capable of fixing the actual problem without creating additional confusion.  Unsupported pronouncements of inadequate tracking capabilities for biosimilars with the same INN as their RPPs represents, at best, a hypothetical problem given that no biosimilars have yet been approved in the US and Europe has been successful at tracking biosimilars which share INNs with their RPPs. . . .  Currently, a well-established process exists to track product quality problems that does not rely prirnarily on INNs, but instead uses a product's brand name, manufacturer, lot number and NDC to track quality and safety events.  GPhA does not believe requiring unique I NNs for biosimilars could remedy the poorly defined concerns and, instead would cause confusion and potential harm to patients by interfering with the present system.  In contrast, we fully support vigorous enhancement of track and trace and education of physicians and pharmacists to include NDCs, manufacturer names and other relevant identifiers on all safety reports.  This applies equally to all biologics, and must not be used as a wedge to create an anticompetitive barrier to biosimilar development and commercialization.

On the other side of the debate are organizations like the Alliance for Safe Biologic Medicines (“ASBM”).  As we previously reported, ASBM has urged FDA to adopt unique non-proprietary names for all biological products licensed under the PHS Act, and in particular biosimilar versions of reference products (even those that are interchangeable).

Other than FDA’s 2006 policy paper, the Agency has remained pretty silent on the biosimilars naming issue.  Over the summer, there was a rumor circulating that FDA was in the process of drafting a guidance document on biosimilar naming issues; however, nothing has been confirmed.

In a typical three-act play, the main character encounters a complication in Act II – an obstacle that prevents that character from achieving his or her dramatic need – and reaches his or her lowest point.  In Act II of the biosimilars play at hand, we’re not sure yet who – the brand or generic side of the debate – is playing the role of the main character.  But whoever that is is sure to be disappointed with the outcome.   

Update:

• GPha Press Release: Generic Industry Calls on FDA to Uphold Consistent, Proven International Standard for Biosimilar Naming; Citizen Petition Urges Identical, Non-proprietary Names to Promote Patient Access to More Affordable Biosimilars

By Wes Siegner & Paul M. Hyman – 

The term “medical food” was first defined by statute in the Orphan Drug Act Amendments of 1988.   The medical food category is closely related to the already existing category of “foods for special dietary use,” authorized by the Federal Food, Drug, and Cosmetic Act (FDC Act), section 403(j).  In very simplified terms, medical foods and foods for special dietary use are foods that are formulated to meet the needs of individuals with diseases or conditions that may benefit from ingestion and/or clinical management by specialized foods.  Unlike most other foods, the labeling for foods that fall in these categories may legally mention the disease or condition for which they are intended.  As our understanding of nutrition and its role in both normal and disease processes of the human body advances, many diseases and conditions that could only be addressed through drug therapies are now being improved by combination drug/food therapies.  Access to and development of medical foods is, therefore, of enormous potential importance to public health, both because of the potential for improved health as well as the opportunity to reduce healthcare costs. 

Within the last month, FDA has issued a draft medical food Q&A guidance and a final guidance on INDs that will dramatically impact the availability and development of medical foods.  Previous blogposts on these guidance documents can be viewed here and here.  These guidances also further illustrate the FDA trend of issuing important and controversial policy decisions through legally “non-binding” guidance (see our previous post here), which short-cuts the notice and comment rulemaking process, deprives stakeholders of a meaningful opportunity to change FDA policy, and makes legal challenge to these new policies problematic at best.

Regardless, it is essential for patient groups, physicians, academic researchers, and the industries that these guidances will negatively impact to make their voices heard.

FDA’s Draft Medical Food Q&A

Medical foods help to manage a disease or condition by meeting the “distinctive nutritional requirements” that the disease or condition creates.  As FDA points out in its medical food draft guidance, certain rare inborn errors of metabolism (“IEMs”) such as phenylketonuria (“PKU”) require careful manipulation of the diet to avoid certain nutrients (phenylalanine in the case of PKU).  Failure to do so can lead to serious medical consequences, including death.  It is difficult, but not impossible, for individuals with these diseases to accomplish the necessary dietary manipulation without medical foods that are specially formulated to help manage the disease.  In FDA’s view, “[m]edical foods become indispensable for individuals with these IEMs in order to meet the daily requirements of essential nutrients and to limit the metabolic disturbances associated with the particular IEM.”  Q&A 17. 

However, there is a growing recognition that medical foods can also play important disease management roles in a much broader array of diseases where distinctive nutritional requirements have been established, including cancer, AIDS, arthritis, heart disease, osteoporosis, and gastrointestinal diseases, among others.  As new research into disease, nutrition, and health shows better ways to manage disease through nutrition, medical foods, which are inherently safe and do not therefore require years of costly product safety and efficacy testing and FDA premarket approval, are increasingly becoming a cost-effective component of disease management. 

FDA’s new draft Q&A, as well as a number of recent warning letters to medical food marketers, indicate that FDA is determined to narrowly interpret the definition of “medical food” and prohibit the marketing of many novel products that might fit into this category and benefit patient health.  One of FDA’s primary tools in restricting access to the medical food market is a criterion that FDA promulgated in a medical food labeling regulation, 21 C.F.R. §101.9(j)(8), but that does not exist in the statutory definition.  This regulation requires that, to qualify for an exemption for medical foods from otherwise applicable food labeling requirements, the food must supply “medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone.”  This concept is nowhere implied in the statutory definition, and it makes no sense from a medical perspective in the context of addressing the management of a patient’s disease or condition.

FDA’s draft medical food Q&A guidance relies particularly on that restriction in an attempt to eliminate what is likely the largest potential patient base for medical food products, patients with diabetes.  FDA recognizes that there are distinctive nutritional requirements that are critical to the health of all individuals with diabetes mellitus (“DM”), but nonetheless answers “No” to the following question – “Does FDA consider type 1 or type 2 DM to be conditions for which a medical food could be labeled and marketed?”  Draft medical food guidance, Q&A 22 and 23.  What is FDA’s explanation?  “Diet therapy is the mainstay of diabetes management.  A regular diet can be modified to meet the needs of an individual affected by either type of DM.”

This new policy position ignores the essential role that food convenience plays in compliance with the often difficult dietary manipulations that are needed in a variety of diseases and conditions, including diabetes.  Why should FDA want to make it difficult for patients to comply with diets that are essential to the management of serious, life-threatening diseases?  The new policy position is also arbitrary, as FDA recognizes that medical foods are essential to the management of certain genetic diseases, such as PKU, where dietary manipulation is also difficult but still possible, but not others, such as diabetes.  FDA’s draft guidance is internally inconsistent on this point (see Q&A 17) and raises the question, just how difficult does dietary manipulation have to be for FDA to permit a medical food to be marketed?  As medical foods are inherently safe, it would appear that the question of whether dietary compliance, and therefore patient health, will benefit from a medical food should be left to the medical community, not to FDA. 

Indeed, this approach amounts to FDA’s dictating the therapeutic regimen for these patients, substituting the agency’s judgment for that of the clinician.  No one would stand for FDA’s allowing only one drug or course of therapy to be used for a patient, despite the availability of other effective measures.  Yet FDA here essentially would do just that – prohibit the use of available, safe and effective agents of dietary management of the patient’s disease if, in FDA’s view, management might be accomplished by modification of the diet, regardless of how impractical that might be.

FDA’s draft guidance also leaves open the question of whether there might be medical foods appropriate for pregnant women, as well as the question of whether medical foods intended to manage the wide variety of diseases and conditions that are not “inborn errors of metabolism” would qualify for medical food status.  However, FDA’s draft Q&A combined with a recent increase in FDA warning letters suggests that the entire medical food category is under increased scrutiny and risk of FDA enforcement.  The impact, if the guidance is not revised, will be to stifle creative and cost-effective use of nutrition to improve patient health through use of medical foods. 

FDA’s Final IND Guidance

FDA’s final IND guidance potentially will require FDA approval of an investigational new drug application (“IND”) for most, if not all, clinical studies intended to support the benefits of any medical food.  The “non-binding” medical food IND requirement was inserted into the final guidance in a new section D.2., titled “Conventional Food,” even though there was no such provision in the draft guidance FDA issued in 2010, thereby making any comment on this new policy impossible before FDA issued the final guidance. 

The new requirement poses significant challenges to clinical studies into disease management:

• The final IND guidance attempts to distinguish between medical food studies that do not require an IND – safety studies and studies of the taste, aroma, or nutritive value of a medical food – and those that do require an IND – studies into how the medical food might affect the structure or function of the body in ways that do not derive from “nutritive value,” however FDA might interpret that term.  As set forth by FDA, this distinction is difficult if not impossible to comprehend. The guidance is intended to affect the behavior of institutional review boards ("IRBs") that are not usually willing to second-guess FDA policy.  Therefore, IRBs are likely to require INDs unless FDA is willing to agree that an IND is not needed, which FDA is unlikely to do. 
• The need to conduct studies under an IND will put many novel medical foods in a quandary, as FDC Act §301(ll) potentially prohibits the marketing of a food where the food is first studied under an IND, even if the study is ultimately intended to support food rather than drug use.  Medical food companies might attempt to avoid the prohibition by marketing products as foods or dietary supplements prior to conducting medical food studies, or by using only ingredients already widely consumed as food, but this strategy increases the risk that FDA will challenge the medical food on the basis that the nutritional requirement can be met by modification of the normal diet.  Whether this conundrum is deliberate or is a result of FDA’s failure to think through its new policy, first announced in FDA’s final guidance, is unclear.  Regardless, because IRBs will take FDA’s guidance and gospel, the final guidance will restrict medical food development and research into the understanding of nutrition and disease generally.

In order to create the requirement for an IND for medical food studies, FDA’s IND guidance reverts to a legal theory for regulating structure/function claims for foods that we believed (or hoped) the agency had long ago abandoned. 

Consistent with case law interpreting the “other than food” exception as applying to articles consumed primarily for taste, aroma, or nutritive value, FDA regulates conventional foods (including infant formula) that are intended to affect the structure or function of the body as foods, not drugs, as long as the intended structure or function effect derives from the product’s character as a food — its taste, aroma, or nutritive value.   

IND Guidance at 13 (citing Nutrilab v. Schweiker, 713 F.2d 335 (7th Cir. 1983)).  FDA then goes on to narrowly construe the term “nutritive value” by stating, as an example of a food study that would require an IND, that “a study of the effect of soy isoflavones on bone metabolism would [require an IND].”  Id. 

Contrary to FDA’s assertion that its interpretation is “consistent with case law,” FDA’s reliance on Nutrilab for the agency’s narrow interpretation of the “other than food” provision of the FDC Act is in direct conflict with the opinion of the Seventh Circuit as well as subsequent case law that relied on Nutrilab.  That case law establishes that, in the view of the courts, a “food” may properly make any claim in labeling that is truthful and nonmisleading about a “physiological effect” of the food, including a physiological effect of a component of the food, on the structure or function of the human body, provided that the claim does not represent that the product is intended to cure, treat, mitigate, or prevent disease (which would create “drug” status for the product), and does not “characterize the relationship” between a “substance” and “disease,” “damage,” or “dysfunction” of the body (which would meet the definition of a “health claim” and create separate requirements.  713 F.2d at 338 (“To hold as did the district court that articles used as food are articles used solely for taste, aroma or nutritive value is unduly restrictive since some products such as coffee or prune juice are undoubtedly food but may be consumed on occasion for reasons other than taste, aroma, or nutritive value.”); American Health Products Co., Inc. v. Hayes, 574 F. Supp. 1498, 1507 (S.D.N.Y. 1983), aff’d, 744 F.2d 912 (2d Cir. 1984) (“[I]f an article affects bodily structure or function by way of its consumption as a food, the parenthetical [i.e., the ‘(other than food)’provision in 21 U.S.C. §321(g)(1)(C)] precludes its regulation as a drug notwithstanding a manufacturer's representations as to physiological effect . . . .  The presence of the parenthetical in [21 U.S.C. §321(g)(1)(C)] suggests that Congress did not want to inhibit the dissemination of useful information concerning a food’s physiological properties by subjecting foods to drug regulation on the basis of representations in this regard.”) 

FDA’s IND guidance is yet another example of the agency, contrary to law, “subjecting foods to drug regulation” by requiring any study of the physiological effect of a food that does not derive from “nutritive value” to first be approved as a drug study through FDA’s IND approval process.  As FDA’s isoflavone example illustrates, perhaps intentionally, FDA has so muddled the picture as to what effects of food derive from “nutritive value” and which do not, that even experts will find it difficult to advise clients or, more important, IRBs, when an IND is required.  This will predictably lead IRBs to either require INDs for virtually all clinical studies that examine structure/function effects or any beneficial effects of foods, or to require that FDA’s drug center be consulted before conducting such studies, which will likely yield the same result.

Oddly, according to FDA’s IND guidance, it appears that if the same isoflavone study on bone metabolism were conducted as a dietary supplement study rather than a conventional food study, no IND would be required, since “a dietary supplement is not considered a drug and is not subject to the premarket approval requirements for drugs if the intended use for which it is marketed is only to affect the structure or any function of the body (i.e., not intended to be used for a therapeutic purpose).”  IND Guidance at 12. 

What Should Be Done?

The question for patients, physicians, academic researchers and industry is “now what?”  Some short term measures may bring temporary results, including:

• File comments – FDA has withdrawn and/or rewritten controversial draft and final guidance in the past in response to negative comments.  Given the important medical, research, and patient health implications of FDA’s recent guidances, comment from patients, researchers, and medical specialty associations will be important to a change of FDA’s course. 
• Enlist the help of Congress – congressional representatives can effectively influence FDA’s course through letters, hearings, and other measures.
• Some companies in the medical food arena may qualify as small businesses, which may make it possible to engage the Small Business Administration (“SBA”).  SBA has been an effective advocate for small business in other flawed FDA initiatives.
• Carefully design study protocols to avoid IND implications, or if that is not possible, conduct studies that IRBs and FDA will not permit in the U.S. without an IND in Canada or Europe.

A longer-term industry strategy is also needed.  It is clear that FDA is determined to severely restrict both access to and research on medical foods in the U.S., regardless of the potential importance of such products to public health and the effect on the cost of medical treatment.  Currently, there is no trade association devoted to protecting the interests of the medical food industry, but it appears that the time has arrived for one to be created.  A trade association could help the industry interact more consistently with FDA, would help develop long-term allies in Congress, and provide industry with the necessary resources to litigate critical issues if necessary. 

By Riëtte van Laack –

As previously reported here, in July, the American Meat Institute and several international meat industry organizations filed a lawsuit in an effort to stop the Agricultural Marketing Service ("AMS") of the USDA from implementing the Country of Origin Labeling ("COOL") rule, which requires packages of beef, pork and poultry products to say where animals were raised, slaughtered, and processed.  In August, four agricultural and consumer groups, the National Farmers Union, U.S. Cattlemen's Association, Sheep Industry Association and the Consumer Federation of America, filed to intervene in the case in support of the new COOL regulation. 

On September 11, 2013, Judge Ketanji Jackson of the U.S. District Court for the District of Columbia issued an 80-page ruling holding that USDA can continue implementing its regulations for mandatory country-of-origin labeling.

Plaintiffs argued that the amended rule constituted unduly compelled speech in violation of the First Amendment of the Constitution.  However, the Judge disagreed.  She held that the amended Final Rule mandates ‘“purely factual and uncontroversial disclosures about where an animal was born, raised and slaughtered”’ and constitutes compelled commercial speech.  This type of speech is not subject to the strict scrutiny standard.  In fact, “when the compelled speech is commercial and purely factual in nature, the speaker’s First Amendment rights are not unduly burdened “‘as long as [the] disclosure requirements are reasonably related to the [government’s] interest in preventing deception of consumers.’”  The judge determined that there is “clearly a reasonable relationship between the government’s interest in preventing consumer confusion about the origins of muscle cut meat, on the one hand, and the required disclosure of specific production step information, on the other.”  Thus, Plaintiffs’ First Amendment challenge is unlikely to be successful. 

Plaintiffs’ loss does not mean that the battle is over.  On September 12, 2013, they appealed the denial of the preliminary injunction (D.C. Circuit Case No. 13-5281).  Moreover, in August, Canada and Mexico filed a complaint with the World Trade Organization, and a ruling is expected later this year.  Thus, the future of the COOL regulation remains uncertain.

By Etan J. Yeshua –

Three months after announcing a strategic research plan to support its regulatory agenda, FDA's Center for Food Safety and Applied Nutrition ("CFSAN") this week announced its regulatory priorities for 2013 and 2014, giving those in the food, dietary supplement, and cosmetic industries an indication of what to expect from FDA in the near future.  The priorities include publishing and finalizing rules to enforce the Food Safety Modernization Act’s ("FSMA’s") food safety requirements and the Affordable Care Act’s menu labeling provisions, revising food labeling regulations, finalizing the Agency’s controversial New Dietary Ingredient ("NDI") guidance, developing a strategy to regulate energy drinks, and issuing various guidance documents regarding cosmetics.

The six “program goals,” most of which correspond to a dozen or so specific objectives are to:

1. Reduce foodborne illness rates and cosmetic injury rates each year;
2. Establish regulations, policies, guidances, and inspection and compliance strategies based on best science, prevention, and public health risk;
3. Increase compliance with newly created preventive control standards across the farm-to-table continuum;
4. Improve public health indicators through better nutrition and dietary choices;
5. Develop and swiftly deploy the fastest most effective methods for identifying, containing, and eliminating food and cosmetic hazards; and
6. Achieve optimal use of staff and resources.

The full list of over 80 specific objectives is available on FDA’s website divided by program goal, but we’ve identified a few that we think may be of particular interest to our readers and organized them by subject area.  Check the FDA Law Blog for regular updates as FDA moves forward with the rules, guidance documents, and policies that the Agency forecasted this week.

Food

Continuing its effort to implement FSMA, CFSAN plans to issue new regulations regarding food safety, and will develop approaches to several topics about which the Agency has yet to finalize its position.  By the end of 2014, FDA plans to publish proposed rules for preventive controls in food transportation and for recordkeeping requirements for high-risk foods.  By 2015, FDA plans to finalize rules regarding intentional food contamination, third party auditor accreditation, and preventive controls for food processing facilities and produce safety.  Although we do not know whether to expect a proposed rule, draft guidance, or something else, FDA also plans to “address [an] approach to determine” the most significant foodborne contaminants (for FSMA § 104(a)) and an approach to determine high risk foods (for FSMA § 204(d)(2)).

To promote better dietary choices, FDA plans to roll out a number of new food labeling regulations.  In the coming year, CFSAN plans to propose rules to update the nutrition facts label and serving size information and, before 2015, intends to propose rules about dietary guidance statements in food labeling (“to improve consumer understanding of the usefulness of a food or a category of foods in maintaining healthy dietary practices”); CFSAN also plans to issue final guidance about labeling foods made without bioengineered ingredients (e.g., “GMO-free”).  In 2014, FDA intends to finalize rules that are required by the Affordable Care Act (and were delayed earlier this year) to require nutrition information on menus and on vending machines.  To supplement these efforts, CFSAN also plans to complete a review of “nutrition and related activities to identify, with respect to nutrition in America, what problems we have now, in the near future, and in the next 10–15 years, and how CFSAN might best address them.”  Together with this review, and for implementation in 2015, FDA will “complete a plan . . . to promote broad, gradual reduction of added sodium in the food supply.”

Other goals of note include determining whether to issue guidance or otherwise weigh in on arsenic levels in foods other than apple juice and rice, and publishing draft guidance on conflicts of interest for experts participating in GRAS panels—an issue spurred in part by the PEW Charitable Trust’s Food Additives Project.

Dietary Supplements

In the supplement area, FDA may be making big waves in the coming years.  The Agency intends to finalize its draft guidance on new dietary ingredients (NDIs) in 2014.  The draft guidance has been a source of much recent debate between FDA and the supplement industry. 

FDA also plans to “modernize [the] postmarket surveillance system for regulating dietary supplements.”  Earlier this year, the National Institute of Health launched a database of supplement labels—a resource that the Agency may very well use in this effort.

Weighing in on a topic that may attract as much attention from Congress and the media as it will from industry, FDA intends to develop a regulatory approach in 2013 for energy drinks.  This effort will include publication of a “final guidance to help dietary supplement and beverage manufacturers and distributors determine whether a liquid food product (such as energy drinks) may be labeled and marketed as a dietary supplement.” 

Cosmetics

Finally, this year, FDA plans to finalize its 2012 guidance regarding the safety of nanomaterials in cosmetic products and, in 2014, intends to develop draft guidance on lead in lipstick.

By Delia A. Stubbs –

As previously reported, the Physicians for Responsible Opioid Prescribing (“PROP”) filed a Citizen Petition in March requesting that FDA limit the labeling of “controlled release” opioids to severe-only pain in non-cancer patients.  The petition also requested that FDA impose certain quantity and day limits on those medications.

After over 1900 comments on the petition were posted, including a rare endorsement by DEA, FDA issued its response last week (“PROP Petition Response”).  (FDA also responded to another similar petition, here).  Therein, FDA granted and rejected in part PROP’s requests.  FDA agreed to propose changes to the approved labeling of all Extended-Release/Long-Acting (“ER/LA”) opioid analgesics, but rejected PROP’s request for quantity and day limits.  It also rejected PROP’s request that the labeling changes be limited to “non-cancer” pain.

In sum, FDA’s proposal, which it issued pursuant to its authority under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (“FDCA”), requests that all ER/LA opioid application holders, including NDA, BLA, and ANDA holders, modify those products’ labels as follows:

• Change the indication to “the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.”  This change deletes the reference to moderate pain and adds the requirement to rule out other treatment options.  FDA explained that the change is intended to encourage prescribing decisions based on an individualized assessment.  PROP Petition Response at 8.
• Add to the Limitations of Use section:  “Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve [the product] for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.”  Id.
• Change the boxed warning to include the risk of neonatal opioid withdrawal syndrome (NOWS) and to urge providers to asses and monitor the patient’s risk of abuse/misuse of the drug.

FDA’s full changes are captured in its letter to affected application holders (“FDA Letter”).

FDA explained its reasoning for imposing these changes on ER/LA opioid analgesics only.  FDA’s decision is based on data demonstrating that the risk associated with these medications is greater than it is for their immediate-release counterparts.  See PROP Petition Response at 7.

FDA rejected, however, PROP’s requests to impose quantity and day limits on these medications.  FDA stressed that it could not grant those requests based on the data submitted by PROP, noting, among other reasons, that “creating a maximum dose of 100 mg MED, or another dose ceiling, could imply a superior opioid safety profile under that set threshold, when there are no data to support such a conclusion.”  PROP Petition Response at 12. 

Likewise, pursuant to its authority under Section 505(o), FDA is requiring ER/LA opioid analgesic application holders to conduct post-marketing studies to evaluate, among other things, the impact of long-term use of these medications on misuse, abuse, hyperalgesia, addiction, overdose, and death.  Interestingly, the scope of the data requested by FDA extends beyond the mere physiological effects of these drugs to behavioral and social phenomena associated with their misuse and abuse.  For example, FDA is requesting that holders conduct “a study to define and validate ‘doctor/pharmacy shopping’ as outcomes suggestive of misuse, abuse and/or addiction” that will then be used to inform the design and analysis of a study providing “quantitative estimates” of their “serious risks.”  See FDA Letter at 3-4.  Currently, concerns regarding doctor/pharmacy shopping are addressed on a federal level through enforcement actions by DEA.  FDA stated it expects application holders to “work together” to complete the post-approval studies.  It set milestones for completion which range from 2014 to 2018. 

So, what impact will these changes have on industry?  From a law enforcement perspective, likely little-to-none.  DEA’s enforcement actions against physicians, pharmacists, and other registrants, are predicated on proof that controlled substances were prescribed for “illegitimate medical purposes,” and that determination is based on an interpretation of state law, which permits physicians to prescribe drugs for “off-label” purposes.  However, physician and pharmacy boards may more carefully scrutinize the prescribing and dispensing of medications for off-label purposes, and may consider the treatment recommendations provided in these products’ labeling, if revised as FDA intends, as instructive of the standard of care. 

The results of the post-marketing studies could also inform FDA’s decision-making regarding scheduling recommendations for these and other drugs with potential risks of abuse.  One potential outcome would be the obtainment of an acceptable measure of a substance’s abuse potential, which is a required finding for determining whether, and in which category, to schedule a drug (or other substance) for control by DEA.  In a recent advisory committee meeting regarding the up-scheduling of hydrocodone combination products, clear concerns arose regarding the lack of such an agreed upon standard.  See our previous post, here. 

Douglas Throckmorton, M.D., Deputy Director of Regulatory Programs in FDA’s Center for Drug Evaluation and Research, stated “[t]he new labeling requirements and other actions are intended to help prescribers and patients make better decisions about who benefits from the use of these medications.”  Some might welcome these changes as a substitute for enforcement actions targeted at removing that discretion.  See Larry Houck, AMA Tells Pharmacists: “Don’t Call Us We’ll Call You.”

In response to FDA’s action, all ER/LA opioid analgesic application holders must submit a prior-approval supplement with revised labeling consistent with FDA’s proposal, or a declination and a statement of reasons for the declination, by October 10, 2013.  FDA stated that it may, after discussions with stakeholders, issue an order directing these (or other) labeling changes. 

By Kurt R. Karst –     

In the 1992 movie A Few Good Men, military lawyer Lt. Daniel Kaffee (played by Tom Cruise) handles the court martial of two U.S. Marines charged with the murder of a fellow Marine.  The Marines contend they were acting under orders – a “code red” that came down from Col. Nathan R. Jessup (played by Jack Nicholson), Commanding Officer Marine Ground Forces Guantanamo Bay, Cuba – when they disciplined their fellow Marine who died.  During the court martial, Lt. Kaffee faces off against prosecuting attorney Capt. Jack Ross (played by Kevin Bacon).  Though there are several memorable scenes from the movie, one scene in particular came to mind when we read a recent decision from the U.S. District Court for the District of New Jersey stemming from a Complaint Endo Pharmaceuticals, Inc. (“Endo”) filed last year against Actavis. Inc. and Actavis South Altantic LLC (collectively “Actavis”) alleging that Actavis violated the federal Lanham Act and the New Jersey Fair Trade and Consumer Fraud Acts by marketing its Oxymorphone HCl Extended-release Tablets drug products (approved under ANDA No. 079046) as “AB-rated” to Endo’s OPANA ER (oxymorphone HCl extended-release) Tablets drug products.  No, it’s not Col. Jessup’s famous “you can‘t handle the truth! ” scene that came to mind, though we did work that into the headline of this post.  It’s the scene where Capt. Ross questions Cpl. Jeffrey Barnes (played by Noah Wyle) about where the extrajudicial punishment “code red” is authorized in various Marine handbooks, and Lt. Kaffee’s cross-exam of Cpl. Barnes.  Here’s the script (you can view the video clip here):

Capt. Ross: Corporal Barnes, I hold here the Marine Outline for Recruit Training. You're familiar with this book?
Cpl. Barnes: Yes, sir.
Capt. Ross: Have you read it?
Cpl. Barnes: Yes, sir.
Capt. Ross: Good. Would you turn to the chapter that deals with code reds, please?
Cpl. Barnes: Sir?
Capt. Ross: Just flip to the page of the book that discusses code reds.
Cpl. Barnes: Well, well, you see, sir code red is a term that we use, I mean, just down at Gitmo, I don't know if it’s actually…
Capt. Ross: Ah, we're in luck then. Standard Operating Procedures, Rifle Security Company, Guantanamo Bay Cuba.  Now I assume we'll find the term code red and its definition in that book.  Am I correct?
Cpl. Barnes: No sir.
Capt. Ross: No?  Corporal Barnes, I'm a Marine.  Is there no book.  No manual or pamphlet, no set of orders or regulations that lets me know that, as a Marine, one of my duties is to perform code reds?
Cpl. Barnes: No sir.  No book, sir.
Capt. Ross: No further questions. [As Ross walks back to his table Lt. Kaffee takes the book out of his hand]
Lt. Kaffee: Corporal, would you turn to the page in this book that says where the mess hall is, please.
Cpl. Barnes: Well, Lt. Kaffee, that's not in the book, sir.
Lt. Kaffee: You mean to say in all your time at Gitmo you’ve never had a meal?
Cpl. Barnes: No, sir. Lt. Three squares a day, sir.
Lt. Kaffee: I don’t understand.  How did you know where the mess hall was if it’s not in this book?
Cpl. Barnes: Well, I guess I just followed the crowd at chow time, sir.
Lt. Kaffee: No more questions.

By way of background, the term “therapeutic equivalence” is not defined in the FDC Act or in FDA’s ANDA regulations.  The Orange Book Preface, however, states that “[d]rug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling” (i.e., bioequivalent), and that “FDA believes that products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product.” 

Pharmaceutically equivalent prescription drug products (i.e., multi-source drug products approved under FDC Act § 505) are identified in the Orange Book with either an “A” or “B” therapeutic equivalence code designation, generally, which is further defined by a one-character sub-code.  “A-rated” drug products are considered to be to therapeutically equivalent to other pharmaceutically equivalent products, because there are no known or suspected bioequivalence problems, or such problems have been resolved with adequate evidence supporting bioequivalence.  Drug products assigned an “A” rating fall under one of two categories: (1) those active ingredients or dosage forms for which no in vivo bioequivalence issue is known or suspected, and for which bioequivalence to the Reference Listed Drug (“RLD”) is presumed and considered self-evident based on other data in an application or by a showing that an acceptable in vitro dissolution standard is met; or (2) those active ingredients or dosage forms presenting a potential bioequivalence problem, but the applicant’s approved application contains adequate scientific evidence establishing (through in vivo and/or in vitro studies) the bioequivalence of the product to a selected RLD.  Drug products that fall under the first category are assigned a therapeutic equivalence code depending on the dosage form (e.g., “AA,” “AN,” “AO,” “AP,” or “AT”).   Drug products that fall under the second category are coded “AB.” 

OPANA ER is approved under two NDAs.  NDA No. 021610 covers an old formulation of OPANA ER and is no longer marketed.  It is listed in the “Discontinued Drug Product List” section of FDA’s Orange Book without a therapeutic equivalence rating, and is the NDA referenced in Actavis’s approved ANDA No. 079046.  Endo currently markets a crush-resistant version of OPANA ER approved under NDA No. 201655, for which there are currently no approved therapeutic equivalents, though ANDAs are pending.  As such, there is no therapeutic equivalence rating for the drug product in the Orange Book.  (For additional background on these products, see our previous posts here and here.)  

According to Endo’s Complaint:

Despite the fact that its Generic Oxymorphone ER Tablets are not crush-resistant and were not approved based on the current Opana® ER [NDA], Actavis is falsely marketing its Generic Oxymorphone ER Tablets as “AB Rated to Opana® ER” . . . .  Actavis’s Generic Oxymorphone ER Tablets are not and never have been AB rated to the only Opana® ER tablets sold by Endo since May 2012, i.e., the crush-resistant tablets, and those Generic Oxymorphone ER Tablets are not designed to be crush-resistant like Opana®ER.

Endo goes further in a Cross-Motion for Partial Summary Judgment, saying:

[T]he [Orange Book] listings for both the currently available Opana® ER CRF formulation and the discontinued original Opana® ER formulation state that “There are no Therapeutic Equivalents” . . . .  FDA removed the Actavis AB rating to the Discontinued Formulation of Opana® ER from the Orange Book when it moved that version of Opana® ER to the discontinued drug products list, such that Actavis’s Tablets have not been listed by FDA as AB rated to any version of Opana® ER since June 2012. . . .  Accordingly, Actavis’s implication that its oxymorphone ER Tablets are currently listed in the Orange Book as AB rated to the Discontinued Formulation of Opana® ER is incorrect. . . . [and] Actavis’s advertising is literally false. [Emphasis in original]

As such, says Endo, “Actavis’s misrepresentations concerning the nature, characteristics and qualities of the Generic Oxymorphone ER Tablets in connection with its commercial advertising and promotion of such Tablets constitutes a violation of Section 43(a) of the Lanham Act, 15 U.S.C. § 1125(a),” and the court should order Actavis to immediately cease making such representations.

Actavis filed a Motion to Dismiss the case, arguing that the federal Lanham Act cannot be used as a tool to privately enforce the FDC Act:

The courts of appeal (including the Third Circuit [in Sandoz Pharmaceuticals Corp. v. Richardson-Vicks, Inc., 902 F.2d 222 (3d Cir. 1990)]) have uniformly held that matters pertaining to the identity or bioequivalence of generic drugs are vested in FDA’s regulatory authority under the FD&C Act.  Accordingly, the courts have uniformly held that the Lanham Act cannot be used by companies like Endo as an end-run around the lack of a private right of action under the FD&C Act.

We’ve previously tackled that topic here.

After the completion of briefing in the case (see additional briefs here, here, and here), Judge Dennis M. Cavanaugh of the New Jersey District Court issued his ruling granting Actavis’s Motion to Dismiss.  Applying the doctrine of primary jurisdiction, Judge Cavanaugh said that the issue of AB-rating is one for FDA to decide.  “This Court defers to the FDA to determine whether the new formulation of Opana ER is no longer AB equivalent to the generic Actavis product. . . . [I]t would be improper for the Court to make a determination on this matter before the FDA has had an opportunity to do so,” says the opinion. 

Judge Cavanaugh did not delve into the issue raised by Endo as to whether or not “Actavis’s implication that its oxymorphone ER Tablets are currently listed in the Orange Book as AB rated to the Discontinued Formulation of Opana® ER” is literally false and violates the Lanham Act.  It’s an interesting question: Is a generic version of an RLD that is discontinued A-rated to that RLD?  As noted above, the Orange Book does not list therapeutic equialence ratings for discontinued drug products.  But is such a rating implicit?  Some might say so; thus, we come full circle to A Few Good Men and Lt. Kaffee’s cross-exam of Cpl. Barnes:

Lt. Kaffee:  How did you know where the mess hall was if it’s not in this book?
Cpl. Barnes:  Well, I guess I just followed the crowd at chow time, sir.
Lt. Kaffee:  No more questions.