By Ricardo Carvajal –

Colorado’s Department of Revenue recently published retail marijuana rules to implement that state’s Retail Marijuana Code (“RMC”).  C.R.S. 12-43.4-101 et seq.  The rules took effect on October 15, and are the culmination of a change in Colorado law that began with an amendment to the Colorado Constitution providing for the regulation of marijuana “in a manner similar to alcohol.”  Colo. Const. Art. XVIII, Section 16.  In part, that amendment states:

• Individuals will have to show proof of age before purchasing marijuana;
• Selling, distributing, or transferring marijuana to minors and other individuals under the age of twenty-one shall remain illegal;
• Driving under the influence of marijuana shall remain illegal;
• Legitimate, taxpaying business people, and not criminal actors, will conduct sales of marijuana; and
• Marijuana sold in this state will be labeled and subject to additional regulations to ensure that consumers are informed and protected.

The RMC defines “Marijuana products” to mean “concentrated marijuana products and marijuana products that are comprised of marijuana and other ingredients and are intended for use or consumption, such as, but not limited to, edible products, ointments, and tinctures” (emphasis added).  The RMC authorizes the issuance of regulations governing retail marijuana that must include certain labeling requirements.

In accord with the above, the Permanent Rules Related to the Colorado Retail Marijuana Code define a “Retail Marijuana Product” to mean “concentrated Retail Marijuana and Retail Marijuana Product that are comprised of Retail Marijuana and other ingredients and are intended for use or consumption, such as, but not limited to, edible product, ointments, and tinctures” (emphasis added).  The rules further define an “Edible Retail Marijuana Product” to mean “any Retail Marijuana Product which is intended to be consumed orally, including but not limited to, any type of food, drink, or pill” (emphasis added).  The rules require the following information to be affixed to every container holding an edible retail marijuana product:

• Ingredient List:  A list of all ingredients used to manufacture the Edible Retail Marijuana Product; which may include a list of any potential allergens contained within.
• Statement Regarding Refrigeration:  If the Retail Marijuana Product is perishable, a statement that the Retail Marijuana Product must be refrigerated.
• Serving Size Statement:  “The standardized serving size for this product includes no more than ten milligrams of active THC.”
• Statement of Expiration Date:  A product expiration date, for perishable Retail Marijuana Product, upon which the product will no longer be fit for consumption, or a use-by-date, upon which the product will no longer be optimally fresh.  Once a label with a use-by or expiration date has been affixed to a Container holding a Retail Marijuana Product, a Licensee shall not alter that date or affix a new label with a later use-by or expiration date.

The rules permit, but do not require, edible products to bear information regarding a product’s compatibility with dietary restrictions, and a nutritional fact panel that, if included, must be based on the number of THC servings within the container.

The rules include provisions that appear intended to minimize the potential for cross-contact with food products that do not contain marijuana, and to minimize consumer confusion with respect to such products.  For example, a Retail Marijuana Products Manufacturing Facility is prohibited from handling Retail Marijuana Products in a location that is operating as a retail food establishment or a wholesale food registrant.  Also, such a facility cannot label a Retail Marijuana product in a way that could cause confusion as to whether that product is a trademarked food product.   Finally, retail marijuana stores cannot sell or give away any consumable product that is not a retail marijuana product, including food products or non-alcohol beverages that are not Retail Marijuana Products.

Marijuana-infused foods have been available in Colorado for some time (see here), but were previously available only as medical marijuana.  Increased availability under the new rules is certain to give rise to ever more creative edible concoctions (see here).  It’s hard to imagine that the coming explosion of packaged marijuana-infused foods isn’t causing some discomfort at FDA, given the agency’s recent targeting of caffeinated foods.  The recently issued DOJ memorandum providing guidance on marijuana enforcement makes clear that the sale and use of marijuana and marijuana containing products remains illegal under Federal law, and that the memorandum “does not alter in any way the Department’s authority to enforce federal law… regardless of state law.”  However, the memorandum suggests that the federal government does not intend to interfere with retail marijuana operations conducted in accord with a “strong and effective state regulatory system.”  Further, the memorandum does not explicitly address applicability and enforcement of the FDC Act to such products.  The result could be odd in at least one respect: in states such as Colorado, a brownie laced with hash may be easier to come by than one containing added caffeine.

By Jennifer M. Thomas –

I have monitored the drug shortage issue over the last few years with professional interest and general concern (see here).  However, the situation was recently brought home to me when I took my four-month old in for her second round of vaccinations a few weeks ago, and was told that she would have to wait for one of her vaccinations because it was not available.  Of course, waiting won’t hurt her.  But I realized how much my anxiety and frustration would be compounded if the shortage could potentially impact my daughter’s health, or worse, if it actually did.  That unacceptable situation is faced by too many mothers and fathers every day in this country.

So it was with heightened personal interest that I read FDA’s recently released Strategic Plan for Preventing and Mitigating Drug Shortages (“Strategic Plan”), and Proposed Rule on Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products (“Proposed Rule”).  For those who lack the time to wade into these relatively lengthy documents, this post provides bullet-point highlights and a brief evaluation of each document.

Proposed Rule

• The Proposed Rule was authorized by the 2012 FDA Safety and Innovation Act (“FDASIA”).  (FDASIA: (1) expanded the FDCA’s drug shortage notification provision to all manufacturers of medically important approved or unapproved drugs – not just sole manufacturers of approved drugs – in cases of either a permanent discontinuation or a temporary interruption (FDASIA § 1001(a)); and (2) specifically authorized the Secretary to “by regulation apply [the notification requirement] to biological products . . . if the Secretary determines such inclusion would benefit the public health.”  FDASIA § 1001(a).  See our summary here);
• It requires manufacturers to notify FDA of a discontinuance or temporary interruption in manufacturing 6 months in advance, or as soon as practicable;
• It applies to all manufacturers of medically important drugs (life sustaining, life supporting, or intended to treat or prevent a debilitating disease or condition), whether approved or unapproved; and
• It expands the notification requirement to biologics.

FDA’s Proposed Rule contains few surprises, but certain elements are noteworthy.  For instance, an applicant-holder is solely responsible for notifying FDA even if it contracts out the manufacture of the product in question.  The applicant-holder is directed to work with its contract manufacturers and ingredient suppliers to develop a system of notifying FDA that avoids duplicative notifications.  This is one of the only narrowing elements of a proposed rule seemingly intended to maximize the total number of notifications submitted to the Agency. An example of that trend is FDA’s determination that for purposes of notification, a “product” refers to a specific strength, dosage form, or route of administration.  Thus, if a manufacturing disruption relates to only one strength of a particular drug or biologic, FDA must be notified even if other strengths remain available.  Further, when determining whether an interruption in manufacturing is likely to lead to a meaningful disruption in supply triggering the notification requirement, a manufacturer or applicant may only consider whether the manufacturing disruption will affect the manufacturer’s own ability to meet demand for its product – even if the manufacturer has such a small market share that its disruption is unlikely to affect the market as a whole. 

While efforts to broaden the scope of notification are consistent with FDASIA’s intent, it seems questionable whether FDA truly has the capacity to analyze and act on each of the notifications submitted pursuant to its proposed rule.  This is particularly true because, as the Agency itself acknowledges, 6 month advance notification is in most cases entirely aspirational – often only a few days advance notice is practicable, or notice may even post-date the manufacturing disruption itself.

Perhaps most importantly, FDA’s authority to enforce timely notification is limited to issuance of a public noncompliance letter.  While the Agency’s ability to publicize violations is generally one of its most powerful and well-utilized enforcement tools, it may be comparatively weak in this context, where the unfavorable publicity seems unlikely to expose a violative company to private litigation in the absence of extenuating circumstances.

Strategic Plan

FDA was required to create and submit the Strategic Plan to Congress pursuant to FDASIA § 1003.

• The Strategic Plan was mandated by FDASIA, created by FDA’s Drug Shortage Task Force, and will be submitted to Congress.
• It reflects a two-pronged FDA strategy to address drug shortages by:
  • Improving FDA’s response to shortage notifications from manufacturers:
    • Streamlining the agency’s internal process, clarifying the roles and responsibilities of various groups within FDA that are working to prevent shortages; and
    • Improving communications with the public and healthcare providers, including enhancing the drug shortages webpage and rolling out a new smartphone application to provide real-time shortages information.
  • Addressing the root causes of shortages (primarily quality and other manufacturing issues):
    • Creating an Office of Pharmaceutical Quality within FDA – a clearinghouse for manufacturer questions about how best to improve and ensure quality;
    • Providing incentives to manufacturers for making manufacturing quality improvements or for taking action to prevent or end a drug shortage; and
    • Engaging in a risk-based approach to detect early warning signals of potential shortages, so that FDA can intervene before a shortage occurs.
• It also includes suggested actions that manufacturers should consider to help prevent shortages, and mitigate the effects of shortages when they occur, including:
  • Building a robust inventory before making manufacturing changes;
  • Communicating regularly with contract manufacturers to update information about their processes, facilities, and capacities;
  • When notifying FDA of a potential shortage, including:
    • Information about proposed actions to address the current  shortage and similar shortages in the future;
    • A realistic estimate of how long the manufacturing disruption can be expected to continue;
  • Pursuing a dialogue with FDA about long-term solutions, including remediation efforts to upgrade aging manufacturing facilities; and
  • Having a plan in place to mitigate the impact of shortages

The Strategic Plan is a well-intentioned document, but seems to represent only the beginning of FDA’s analysis rather than the finished product.  For example, FDASIA directed FDA to include in the Strategic Plan “an examination of whether to establish a ‘qualified manufacturing partner program’.”  FDASIA § 1003.  However, the current Plan refers only to FDA’s continued examination of the possibility of a partner program, and the development of further information surrounding such a program.  This, despite public comments analyzing the viability of a partner program, and the existence of a potential model in the Biomedical Advanced Research and Development Authority ("BARDA") partner program. 

FDA also requested public comment about manufacturing quality metrics that would be most useful for purchasers and prescribers, and for manufacturers in choosing a contract manufacturer.  However, its Strategic Plan places the onus on purchasers by calling on them to make use of already published data (such as the manufacturer’s history of inspection outcomes and classifications, recalls, etc.)  FDA claims to be limited because “buyers ultimately decide how or whether they will use this data when they make purchasing decisions.”  However, this statement evades the question of whether FDA is making information public in a way that is readily understandable and usable by purchasers, prescribers, and other manufacturers.  For example, at least one public comment suggested a type of scoring system based on inspection history, remediation efforts, etc.  FDA’s Strategic Plan does not appear to contemplate that idea, or any other system for consolidating and reporting information about manufacturing quality.

Finally, FDA minimizes its own ability to “offer financial or other economic means to promote innovation in quality manufacturing.”  While no one would expect FDA to dole out cash rewards for quality improvements, the agency cannot fail to understand the financial impact of even its smallest indication of favor towards a company – particularly a publicly traded one.  For example, simply expediting review of new facilities for companies that have exhibited exemplary manufacturing quality standards would be a significant boon to those companies.  Expedited product review would be an even greater benefit.  Even a public scoring system, as discussed above, that incorporated the proactive measures taken by a company to improve quality, or prevent or mitigate shortages, would be a way for FDA to reward desirable behaviors.  The Strategic Plan does not analyze these possibilities.

In conclusion, while the Agency seems to be expending significant resources to address the issue of drug shortages, it remains unclear whether those efforts will produce better outcomes than have already resulted from the heightened awareness and voluntary response produced by President Obama’s 2011 Executive Order (see our previous post here).  Even FDA cannot confirm that its Proposed Rule and Strategic Plan will have a real impact on drug shortages.  When asked for concrete examples of shortages that would have been prevented or improved had FDA’s Proposed Rule or its Strategic Plan been in place a year ago, the Agency had no response.

Postponed due to the partial government shutdown, this conference will address numerous compliance and enforcement issues of interest to dietary supplement manufacturers and distributors, and will feature discussion of the anticipated impacts of FSMA implementation. Senior FDA and state officials will provide their perspectives, as will Hyman, Phelps & McNamara, P.C.’s Ricardo Carvajal. The conference is scheduled to take place in Anaheim, CA. Additional information is available here.

By Karla L. Palmer –

On Monday, November 4, 2013, the Drug Enforcement Administration (“DEA”) published a notice of proposed rulemaking (“NPR” ), proposing to place the substance  2 –((diemthylamino)methyl)-1-(3-methyloxyphenyl) cyclohexanol), and its salts, isomers, salts of isomers, and all isometric configurations of possible forms, including tramadol, in Schedule IV of the Controlled Substances Act (“CSA”).  Although not entirely unexpected given DEA’s published concerns about the abuse potential, it comes at time almost eighteen years after the drug was first marketed in the Untied States.

Trade names of the substance include Ultram® and Ultracet®.  Schedule IV controlled substances are those substances that  have a low potential for abuse relative to drugs in Schedule III, have a currently accepted medical use in the United States, and the abuse of the drug could lead to limited physical dependence relative to the drugs in Schedule III.  Tramadol was approved for marketing in 1995 as a non-controlled analgesic.  The drug was not scheduled based on information related to its low potential for abuse and very weak narcotic effect.  DEA now reports that data demonstrates, because of inadequate product labeling (which has undergone several revisions) and lack of established abuse potential, it has become known to narcotics abusers.  As a result, DEA received numerous reports of its abuse and dependence (see here).  At least 10 states have already scheduled tramadol as a controlled substance, and at least four citizen petitions to reschedule tramadol have been pending at DEA since approximately 2005.  

The CSA provides that scheduling of any drug may be initiated by the Attorney General: (1) by his own motion; (2) at the request of the Secretary of HHS; or (3) on the petition of an interested party.   The NPR states that this particular rulemaking is based on the recommendation from HHS and an evaluation of all other relevant data provided by DEA.  The scheduling of tramadol has been under review for over seven years.  In 2007, DEA submitted to HHS its request for a scientific and medical evaluation (which findings are binding on DEA), and for HHS’s recommendation on scheduling of tramadol.  In 2010, the HHS provided to DEA its scientific and medical evaluation, recommending, after completing the eight-factor analysis required in 21 U.S.C. s 811(b), placement of tramadol in Schedule IV.  DEA completed its own eight-factor review pursuant to 21 U.S.C. s 811(c) in 2011.  Those analyses are attached here and here, and are briefly summarized below:

(1) Drug’s Actual and Relative Potential for Abuse:  HHS and DEA found that since initial marketing of tramadol in 1995, the drug has been, and currently is, abused for its opioid effects.  DEA also found that individuals are taking tramadol in sufficient amounts to create a public health threat, and there is “significant” diversion of tramadol from legitimate channels.  Individuals are also taking tramadol on their own initiative, and not on the advice of medical practitioners.  Tramadol also shares several pharmacological effects similar to other scheduled opioids.  

(2) Scientific Evidence of the Drug’s Pharmacological Effects, if Known:  DEA and FDA recognized tramadol as an opioid analgesic that produced effects, including adverse, analgesic, and other effects, similar to opioids in Schedules III and IV.

(3) The State of Current Scientific Knowledge Regarding the Drug or Other Substance:  The NPR sets forth a chemical description of the substance that DEA seeks to schedule.      

(4) Its History and Current Pattern of Abuse:  Data reviewed by both FDA and DEA reveals that tramadol has been abused since 1995 “by a wide spectrum of individuals of different ages, alone and in combination with other psychoactive substances.”  From 2009-2011, more prescriptions were written for tramadol than for any other opioid other than hydrocodone and oxycodone.  Collected data from several national databases demonstrate the misuse, abuse, and diversion of tramadol in the United States.  Data concerning tramadol most closely resembles that of propoxyphene (Darvon®), another Schedule IV narcotic.  

(5) Scope, Duration and Significance of Abuse:  Similar to factor four, HHS considered 15 years of various sources of data detailing the medical and non-medical use and abuse of tramadol.  Data shows that tramadol has less abuse potential than several narcotics currently controlled in Schedule II.  As evaluated by both HHS and DEA, data shows, however, that tramadol most closely compares to propoxyphene (Schedule IV) and codeine (Schedules II, III, and V).  Thus, tramadol's similarity to other controlled opioids and clear evidence of significant non-medical use and abuse, accompanied by serious adverse events, indicates that tramadol has sufficient abuse potential and incidence of drug dependence and addiction to warrant control as a Schedule IV controlled substance.

(6) What, if any, Risk There is to the Public Health:  DEA’s analysis reveals that there are “numerous risks” the public health that may result from tramadol abuse, which adverse effects on the public health are consistent with other opioids.  The incidence of adverse events is similar to that of codeine-containing products, and emergency room visits due to non-medical use of tramadol is similar to that of propoxyphene (Schedule IV), yet lower than that of Schedule II and III opioids.  Reported exposure and death cases quadrupled from 2004 to 2011, ranking third behind oxycodone and hydrocodone combination products.  The collected data from a number of sources indicates that tramadol “presents risks to the public health,” which supports scheduling, but the data also suggest a lower schedule than Schedule III.    

(7) Its Psychic or Physiological Dependence Liability:  HHS reviewed information from clinical and pre-clinical studies, and found that repeated dosing of tramadol resulted in dependence development, and withdrawal symptoms occurred upon discontinuation of treatment.  HHS states that tramadol may produce a “modest level of physical dependence;” studies suggested a decree of dependence development consistent with other opioids in Schedule IV. 

(8) Whether the Substance is an Immediate Precursor of a Substance Already Controlled Under the CSA:  Both HHS and DEA conclude that it is not an immediate precursor of other controlled substances. 

Requirements for Handling Tramadol as a Schedule IV Controlled Substance

The NPR sets forth the requirements under the CSA and its implementing regulations for handling of a Schedule IV controlled substance.  If tramadol is placed in schedule IV, those entities that  handle tramadol will be , by the effective date of the final rule, subject to registration, security, labeling and packaging, inventory, recordkeeping, reporting (including ARCOS reporting), prescription, and import and export requirements required for substances placed in Schedule IV.  Any activity involving tramadol occurring after the effective date of the final rule that is in violation of the CSA or its regulations could result in civil, criminal or administrative sanctions. 

Written Comments and Hearing Requests

Written comments on the NPR are due within 60 days, or by January 3, 2014.  Interested persons (those “adversely affected or aggrieved by any rule or proposed rule “) may file a request for a hearing within 30 days of the date of publication of the proposed rule, or by December 4, 2013.

Effect on International Scheduling  

As a result of HHS’s findings and DEA’s scheduling action, one consideration is whether international scheduling will follow suit.  The United States is a party to both the 1961 and the 1971 Conventions on Psychotropic Substances.  Tramadol has been reviewed four times between 1992 and 2006 by the World Health Organization’s (“WHO’s”) Expert Committee for Drug Dependence (“ECDD”) for possible scheduling.  The WHO makes recommendations to the Commission on Narcotic Drugs (“CND”) for scheduling under the international treaties.  On each occasion the ECDD did not recommend scheduling tramadol based on its low potential for abuse.  This latest action in the United States could lead to a new review by the WHO and the CND.  Tramadol has been approved for marketing internationally since 1977.  Any member country can request a review for scheduling of any substance.    Tramadol’s status in other countries currently ranges from availably as an over-the-counter product availability by prescription yet non-controlled, to its scheduling as a controlled substance. 

Further commentary on the proposed scheduling will be forthcoming.  Stay tuned.

By Allyson B. Mullen –

Now that the eCopy program is well underway, it might be a good idea to review how the program works and consider a few of the common pitfalls.  Although nearly a year has passed since the final guidance document for the eCopy Program for Medical Device Submissions (the “eCopy Guidance,” we previously blogged on the guidance here) was issued, the glitches are still being worked out. 78 Fed. Reg. 102 (Jan. 2, 2013).  Earlier this month, FDA issued a revised version of the eCopy Guidance, which incorporates several minor changes to clarify the processing and technical standards for eCopies based on FDA’s experience to date with the program.  eCopy Guidance at 1.

An eCopy is “an exact duplicate of the paper submission,” and not an electronic submission.  Id. at 2.  Generally, the key things to remember when preparing an eCopy are:

• The eCopy must be submitted on a CD, DVD or flash drive along with the paper copy of the submission;
• The eCopy must be delivered together with a signed cover letter which states, either, that “the eCopy is an exact duplicate of the paper copy,” or “the eCopy is an exact duplicate of the paper copy except [specifying all differences]” (each, an “eCopy Statement”);
• If the submission is submitted by a party other than the applicant (e.g., law firm, consultant, etc.), the eCopy cover letter must be signed by the submitting party (the law firm, consultant, etc.) rather than the applicant (e.g., manufacturer);
• The eCopy must meet FDA’s technical requirements (see, eCopy Guidance Attachment 1), which can be an issue with certain media, such as flash drives that come pre-loaded with various files;
• The electronic files should be primarily in pdf format; and 
• The electronic files must be named in a specific fashion with a prefix (e.g., “001_”, VOL_001_”) depending on whether the submission comes in volumes.

It can be easy to have your submission put on eCopy hold if the eCopy does not precisely meet the requirements of the eCopy Guidance.  For example, if the files do not exactly follow FDA’s naming scheme or the submitter forgets the eCopy Statement in the cover letter, the submission can be placed on eCopy hold.  It is important to remember that FDA will not accept a submission, for which an eCopy is required, until a valid eCopy has been received.  Id. at 12.

An eCopy is required for nearly all medical device submissions, including 510(k)s, de novo petitions, PMAs, IDEs, HDEs, and pre-submissions. Id. at 3-4.  Even when an eCopy is not required by law (e.g., Master Access Files, 513(g)s and CLIA Categorization submissions), FDA still “strongly encourages” that you include an eCopy with your submission.  Id. at 5.  A trap for the unwary submitter is that the filing instructions in several of FDA’s existing guidance still instruct filers to send a certain number of hard copies rather than hard copies and an eCopy.  For example:

• FDA’s 2006 Guidance Document “Real-Time Premarket Approval
  Application (PMA) Supplements,” (the “Real-Time Guidance”) states that three copies of the supplement should be submitted to FDA for review, but makes no reference to one of those copies being an eCopy.  Real-Time Guidance at 8; and 
• FDA’s Draft Guidance “Medical Devices: The Pre-Submission Program and Meetings with FDA Staff” (the “Pre-Submission Guidance”) states that the submitter should send three hard copies of the Pre-Submission to FDA for review, and goes on to say that FDA only “strongly encourages [the submitter] to submit an electronic copy in which case [the submitter] may submit only two (2) hard copies.”  Pre-Submission Guidance at 12.

The statements in these other guidance documents are no longer operative in light of the eCopy Guidance, which requires that an eCopy be submitted with all PMAs and Pre-Submissions.  Revised eCopy Guidance at 3-4.  Therefore, submitters should remember that the eCopy Guidance trumps these other guidance documents and just because the submission-specific guidance does not articulate that an eCopy is required, FDA will still place the submission on eCopy hold until it is received.

By Jessica A. Ritsick, Jay W. Cormier & John R. Fleder –

If you have ever needed to determine whether pulling an FDA-regulated product from retail shelves is a “market withdrawal” or a “recall” you know that the line between these two terms at times is murky at best.  So, it is no surprise that there has been some buzz recently about FDA’s October 23, 2013, update to the Agency’s Regulatory Procedures Manual (“RPM”), when FDA stated that “Section 7-5-1, 2(b) ‘Notes,’ was revised to clarify the term ‘market withdrawal.’” 

As readers of our blog know, the RPM is a document that FDA uses as a guide when determining when and how to conduct domestic and foreign regulatory and enforcement actions.  RPM Chapter 7 deals with recall procedures.  FDA’s statements suggest that the RPM update “clarif[ies] the term ‘market withdrawal,’” but does it?

Let’s start, first, with FDA’s definition of a market withdrawal in its regulations.  21 C.F.R. § 7.3(j) defines “market withdrawal” as:

a firm’s removal or correction of a distributed product which involves a minor violation that would not be subject to legal action by the Food and Drug Administration or which involves no violation, e.g., normal stock rotation practices, routine equipment adjustments and repairs, etc.

A market withdrawal is not a recall, as the definition of “recall” itself points out.  See 21 C.F.R. § 7.3(g) (“Recall does not include a market withdrawal or stock recovery.”).  Before turning to the RPM, it makes sense to reflect on what a recall is.

Recall means a firm’s removal or correction of a marketed product that the Food and Drug Administration considers to be in violation of the laws it administers and against which the agency would initiate legal action, e.g., seizure.

Id.  To recap:  market withdrawals are removals or corrections of products with minor FDCA violations distributed in interstate commerce for which FDA wouldn’t initiate legal action; recalls involve more substantial violations of the FDCA for which FDA would consider initiating legal action.  The problem, for regulators and the regulated alike, is determining what constitutes a minor violation and what does not.  So it is not surprising that industry, including this blog, was excited to apparently gain additional clarity, however small, regarding this important issue based on FDA’s statement that it had clarified the definition of a market withdrawal. 

For at least the last five years or so, RPM Section 7-5-1, 2(b) “Notes,” has used an example of products that had been tampered with, but not by the manufacturer or distributor, to elucidate a distinction between “market withdrawal” and “recall.”   This version of the RPM stated that, when requested by the relevant FDA offices, companies should:

submit a Recall Recommendation for a product removal as a result of actual or alleged tampering with individual unit(s) where there is no evidence of manufacturer or distributor responsibility.  The district should recommend the action be classified as a market withdrawal as, although the situation may present a health hazard, there is no one identified as responsible for the violation.  This will allow documentation and monitoring of specific corrective actions meeting the market withdrawal definition but considered significant to the agency.

FDA, Regulatory Procedures Manual ch. 7, § 5-1, 2(b) (2007).   FDA says it has now “clarified” the term “market withdrawal.”  Let’s look at the supposed clarification:  the new RPM keeps the same language except for the last sentence (in bold), which now reads: “This will allow documentation and monitoring of the market withdrawal.”

What’s the difference?  FDA tightened up its language to make more clear what has been the case for at least the last twelve years – removal of a product that is the subject of actual or alleged tampering where the manufacturer or distributor is not responsible is a market withdrawal.  Rather than beat around the bush, FDA removed the fussy lingo from the prior RPM and decided to simply state that these situations are market withdrawals, not recalls.  However, the Agency still wants to monitor them, so industry is expected to submit a Recall Recommendation to FDA. 

This is not new, and has been the Agency’s position since at least 2001 (as far back as we researched).  FDA, Regulatory Procedures Manual ch. 7 (2001) (Responsibilities and Procedures – District Office (Monitoring District)) (“When requested by OE/DCMO or the Center, submit a Recall Recommendation for a product removal as a result of actual or alleged tampering with individual unit(s) where there is no evidence of manufacturer or distributor responsibility.  The District’s evaluation should state that the action is considered a market withdrawal.”).

So, in the end, what’s all the fuss about?  Unfortunately, not much.  For better or worse, Chapter 7 does not make major changes to the definition of “market withdrawal,” and certainly does not change the definition of “recall” or alter the distinction between a market withdrawal and a recall.  So, we are all still left wondering when, exactly, a market withdrawal becomes a recall.  We’d like to paraphrase Justice Stewart and say we know it when we see it, but that assumes there are no close calls.  In the meantime, FDA will continue to assert that it is final arbiter of these decisions, and we will keep looking for more tea leaves to help you make the right call.

By Delia A. Stubbs & Alan M. Kirschenbaum –

Yesterday, in a letter to Representative Jim McDermott, Secretary of Health and Human Services (“HHS”) Kathleen Sebelius stated that qualified health plans (“QHPs”) and other programs related to health insurance exchanges under Title I of the Affordable Care Act (“ACA”) are not “Federal health care programs” for purposes of the Federal health care program antikickback law and criminal false claims prohibitions at 42 U.S.C. section 1320a-7b.  That section defines a Federal health care program as (1) “any plan or program that provides health benefits, whether directly, through insurance, or otherwise, which is funded directly, in whole or in part, by the United States Government …” or (2) Medicaid, the State Children Health Insurance Program (SCHIP), or certain other federally subsidized state health care programs.  The letter explained that “Federal health care programs” do not include QHPs themselves, nor state or federal exchanges, cost-sharing reductions or premium tax credits to enrollees, consumer oriented and operated plans (“CO-OPs”), or federal risk adjustment, reinsurance, or risk corridor programs. 

According to Secretary Sebelius, HHS’ decision was based on a careful review of the statutory definition and consultation with the Department of Justice (“DOJ”).  The letter did not explain how HHS or DOJ had arrived at their conclusions, but presumably they did not believe that federal expenditures for operating the exchanges, subsidies to QHP enrollees, or other federal expenditures related to exchanges amount to “direct funding” of a plan. 

Although the Federal health care program antikickback law and criminal false claims penalties will not apply to QHPs and exchanges, Secretary Sebelius sought to reassure Rep. McDermott that HHS has other vehicles to ensure oversight over the ACA insurance programs – most notably the Federal False Claims Act, which, under a provision added by the ACA, applies to “payments made by, through, or in connection with an Exchange” if the payments include any Federal funds.  ACA § 1313(a)(6)(A).

By Kurt R. Karst –     

The forces backing implementation of an FDA policy under which biosimilar biological products, licensed under Section 351(k) of the Public Health Service Act (“PHS Act”) as added by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), and their brand-name reference product counterparts share the same International Nonproprietary Name (“INN”) are mustering, as the civil war for a modern day (and nonfictional) Iron Throne grows.  Meanwhile, a cold wind blows in from the icy North; and Daenerys Targaryen exclaims “Where are my DragINNs?”  (Thanks for that last one @AlecGaffney!)    

That’s the scene we envision as we watch the debate over biosimilar naming grow.  And grow it has.  For the second time in as many months – and for the third time overall – FDA has been asked in a Citizen Petition to address biosimilar naming.  The latest Citizen Petition, submitted to FDA earlier this week by the Novartis Group of companies (“Novartis”), follows a September 2013 Citizen Petition (Docket No. FDA-2013-P-1153) from the Generic Pharmaceutical Association (“GPhA”) supporting shared biosimilar and reference product INNs (see our previous post here), and a June 2013 Citizen Petition (Docket No. FDA-2013-P-0776) from the Biotechnology Information Institute saying that “FDA must assign both unique and biosimilar/(bio)generic-type non-unique names for finished products and their active agents.”  The Novartis petition, like the petition from GPhA, requests that FDA require that a biosimilar be identified by the same INN as the reference product it relies on for approval.

Novartis nicely sums up the current debate and dialogue in a single paragraph:

The BPClA is appropriately silent about the nomenclature FDA should apply to biosimilars, as such nomenclature should be self-evident from FDA’s current practice.  Nevertheless, the question of whether biosimilars should share an [INN] with their reference product has been the subject of much public debate.  Such debate has confused the concept and current utilization of INN by departing from the INN’s intended purpose of facilitating the identification of pharmaceutical substances.  Instead the current dialogue has implied that the INN is intended to facilitate the identification of a specific product.  This implication is untrue and has resulted in confusing an otherwise straightforward issue.  Many products, including biologics, currently marketed in the United States share INNs [(see Table 1 attached to the Novartis petition)].  But INNs are not, and cannot be, the only or even the primary tools used for tracking and tracing.  Indeed, despite their shared INNs, these products have been successfully traced for pharmacovigilance purposes.

The petition goes on to make several noteworthy points.  Referencing a 2006 policy paper (included as an attachment to the Novartis petition) FDA sent to the World Health Organization (“WHO”) stating, in part, that “INNs should not be used to differentiate products with the same active ingredient(s) when credible scientific data demonstrate that no pharmacologically relevant differences exist,” Novartis comments that:

assigning unique INNs to biosimilars that FDA concurs are highly similar to a reference product would imply that INNs are intended to communicate more than just molecular characteristics and a pharmacological class.  It would imply that INNs are intended to communicate an aspect of the regulatory status itself, such as interchangeability or lack thereof.

But this has not been FDA’s historical position, says Novartis:

Indeed, many biologic products on the market today share INNs even though they have never been compared directly to each other, and should a demonstration of “sameness” be required by FDA retrospectively today, many of these products would fail to meet it.  Nevertheless, and most importantly, the fact that these products share INNs has not resulted in any safety issues being identified.

Assigning different INNs to biosimilar versions of reference products would result in several problems, posits Novartis:

[It] would introduce unnecessary confusion into the health care system and could unintentionally communicate increased caution, unfounded risk, or other regulatory reservations that are purely hypothetical.  Significantly, it would put into question years of FDA’s practice of using the well-established analytical standard of high similarity to approve major manufacturing changes of originator biologic products without a parallel change in the originator INN, despite the fact that the manufacturing changes have altered, sometimes substantially, the originator biologics’ molecular structures. . . . Requiring separate INNs for biosimilars but not originator biologics would undermine FDA’s own approval decisions, which in both cases require FDA’s determination that the compared product (biosimilar or the post-manufacturing change originator biologic) produces the same clinical outcomes as its comparator (respectively, the reference product or the pre-manufacturing change biologic).

Novartis submits that imposing unique INNs on biosimilars would not improve any aspects of patient safety, pharmacovigilance or tracking, and would instead undermine the safe use of all biologics by introducing unfounded confusion into the health care system. 

The Novartis petition comes on the heels of the WHO’s 57th Consultation on INNs for Pharmaceutical Substances at which biosimilar naming was the topic du jour, as well as a recent letter from several Members of Congress supporting shared INNs for biosimilars and their reference products.  

Letters of support for shared INNs came from several sectors ahead of the WHO meeting.  Hospira’s Senior Vice President and Chief Scientific Officer, Sumant Ramachandra, M.D., Ph.D., authored a paper, titled “WHAT’S IN A NAME?  The Importance of Biosimilar Nonproprietary Names for Healthcare Innovation,” saying that “[i]t is imperative that the [WHO], U.S. Pharmacopeia (USP), the FDA and other international regulatory bodies support the use of the same nonproprietary names for original biologics and biosimilars.”  Why?  Because “using a different nonproprietary name for a biologic and the biosimilar product modeled from it will create confusion among the clinicians who rely on international and local standards to fill prescriptions for patients,“ and different INNs “may impede access to the annual $20 billion savings—in just the U.S. alone—that biosimilars have been estimated to deliver,” according to Dr. Ramachandra.  In addition, a joint letter from the American Pharmacists Association, the National Association of Chain Drug Stores, and the National Community Pharmacists Association urges the WHO to adopt a shared naming policy, saying that “[t]he use of different INNs would increase the burden of being able to distinguish which products are biosimilar and interchangeable with which reference product and may pose difficulties in recognizing the best alternative product for therapeutic use in a timely manner.  Such confusion may lead to medication errors.”

In an October 23, 2013 letter to FDA Commissioner Margaret Hamburg, six U.S. Senators (both Republicans and Democrats) share their concerns on biosimilar naming and urge FDA to adopt a shared naming policy, saying that “[i]f biosimilars are unable to share the same active ingredient name as the brand originator product, we believe the Congressional intent behind the BPCIA would be undermined as would the safely and accessibility of affordable biosimilars.”  The Senators also question the removal of the above-referenced 2006 FDA statement to the WHO from the Agency’s website:

It was brought to our attention that the FDA has removed its 2006 statement on naming from its website.  Does the removal of this statement indicate that the fDA is considering a change to its position on naming?  If so, we ask that the FDA provide a briefing for our staff on this topic in advance of any changes. In particular, we would like to know what factors led to the agency’s decision to reevaluate this policy and what outreach the FDA has done to consumers, pharmacists and others to inform its assessment.

Just a few days later, the Biotechnology Industry Organization (“BIO”) issued a statement addressing the October 23rd letter.  According to BIO, which “strongly opposes naming products in a way that will create confusion for physicians and patients and will hinder effective pharmacovigilance,” “Congress left it to the experts at FDA to make the decision about product names – as the agency does for every other product.  Reserving this to FDA will allow for thorough consideration of technical, scientific and patient safety issues involved.”

By Kurt R. Karst –      

The Generic Pharmaceutical Association (“GPhA”) held its annual Fall Technical Conference this week.  There were lots of interesting topics on the conference agenda, such as complex drugs, ANDA filing and refuse-to-receive issues (see the recent FDA guidance here), adverse event reporting, and Center for Drug Evaluation and Research (“CDER”) reorganization plans (see here).  But the big topic on the minds of those attending was FDA’s implementation of the Generic Drug User Fee Amendments of 2012 (“GDUFA”), including how the Office of Generic Drugs (“OGD”) is working to fulfill its GDUFA performance goals, which come into full force beginning in Fiscal Year 2015.

The good news is that FDA seems to be fully on top of GDUFA implementation.  (A rundown of GDUFA year 1 accomplishments was reported on earlier this week by Bob Pollock of Lachman Consultants – see here.)  The bad news, of course, is that in the effort to meet GDUFA goals, the character of the generic drug industry could be forsaken or forgotten, as we've previously opined.  A balance will need to be reached.

It was announced at the conference that the Agency has put together a steering committee to oversee GDUFA implementation – the GDUFA Steering Committee – composed of senior FDA personnel to ensure alignment across CDER components.  As shown below, the GDUFA Steering Committee is itself multifaceted, with various subcommittees.

The Generic Program Subcommittee is taking a cross-functional team approach to manage implementation, as illustrated below, and has developed interim milestones and timeframes for each of the types of submissions to FDA.  

An important aspect of this process is apparently to empower OGD Regulatory Project Managers (“RPMs”) “by delineating process steps and dependencies, associated interim milestones and goal dates, and roles and responsibilities” to ensure “the RPM manages each application appropriately, and [provides] review discipline accountability,” according to a presentation given by Manju Thomas of FDA’s Office of Strategic Programs.  The RPM empowerment initiative also seems to be an idea underlying FDA’s recent 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 [ANDAs] from the authorized representative for an applicant with an ANDA submission (the authorized inquirer) by [RPM] staff in [OGD].”  

Another significant component of the GDUFA Steering Committee is the GDUFA Policy Subcommittee.  This subcommittee, composed primarily of OGD personnel, has been tasked with recommending various policy improvements, according to OGD Regulatory Counsel Keith Flanagan.  The short list of policy improvement items are near and dear to the generic drug industry. 

For starters, there’s OGD’s prioritization policy and how to allocate resources.  The intent is to enable RPMs (and managers) to manage workflow with a balanced attack, keeping 4 goals in mind: (1) public health needs (e.g., drug shortages); (2) meeting GDUFA year 3 (Fiscal Year 2015) cohort goals (e.g., review and act on 60% of original ANDA submissions within 15 months from the date of submission); (3) not losing sight of ANDAs submitted in cohort years 1 and 2 (Fiscal Years 2013 and 2014); and (4) ensuring that the pre-GDUFA backlog of ANDAs is addressed in a balanced manner so that there is not a rush to address these submissions by the end of Fiscal Year 2017.  Under the GDUFA Performance Goals, “FDA will review and act on 90 percent of all ANDAs, ANDA amendments, and ANDA prior approval supplements regardless of current review status (whether electronic, paper, or hybrid) pending on October 1, 2012 by the end of FY 2017.”)

Also before the GDUFA Policy Subcommittee are issues such as “How to avoid multiple cycle reviews?”, “How to address industry’s lackluster response to MAPP 5200.3?” (see our previous post here), “How to provide clarity on the various GDUFA amendment tiers and what constitutes a major, minor, or delaying amendment?” and “How to provide clarity on the review of chemistry supplements?”  One thought being tossed around on ANDA qualify (i.e., “How to avoid multiple cycle reviews?”) is the establishment of a public docket seeking industry comment on best practices (and perhaps a guidance document). 

Each of these policy improvements – and particularly those that are pursued with industry input and involvement – should go a long way to make the transition from a pre- to post-GDUFA world less rocky.  Though there are still some kinks in the system that need to be worked out, and there will certainly be disputes, it is possible that we may be on the road to A Modern Utopia after all.   

By Ricardo Carvajal –

We previously reported on a case – Wilson v. Frito-Lay North America, Inc. – in which a federal district court held that statements on a food company’s website do not constitute labeling even though the labels of some products include a reference to the website.  Plaintiffs were given leave to amend, and did so – but were rebuffed again in an October 24, 2013 decision from the U.S. District Court for the Northern District of California. 

In their amended complaint, Plaintiffs alleged that Defendant’s website contains numerous statements that explain and supplement other statements about the products, and pointed to FDA warning letters in which the agency took the position that the websites at issue in those cases constituted labeling. 

The court pointed to FDA guidance stating that a website is likely to constitute labeling when the product contains a statement that refers the consumer to a website “for additional information for a claim for the product.”  In such cases, the website “supplements or explains the product and is designed for use in the distribution and sale of the product” (see here).  The court then concluded that the FDA warning letters cited by plaintiff are irrelevant:

Those letters do not address how the FDA regulations are to apply.  Instead they discuss specific websites that the FDA had independently concluded constituted labeling. The FDA has made no such specific conclusions about Defendant's Products in this case…

The court held that the products’ reference to defendant’s website address does not constitute labeling under the FDC Act because it appears below Defendant’s physical address and “not near the ingredients list or any nutritional facts.”  Further, the label does not direct consumers to the website “for more facts about the labeled product.”  The court dismissed Plaintiff’s claims about the website with prejudice.

By Delia A. Stubbs –

The amount of government activity on issues involving controlled substances last week makes the furlough seem like a figment of our imagination.  Following issuance of a press release on hydrocodone rescheduling and a court ruling on DEA’s delay on the scheduling of FYCOMPA (see prior posts here and here) on Friday, FDA announced its approval of New Drug Application (“NDA”) No. 202880 for Zogenix, Inc.’s (“Zogenix’s”) single-entity, extended-release, hydrocodone pain-killer drug, Zohydro ER.  FDA’s approval renders Zohydro ER the first U.S. approved single-entity hydrocodone product, the first extended-release/long-acting (“ER/LA”) opioid analgesic to contain hydrocodone, and the first ER/LA opioid analgesic to display new labeling proposed for that class of drugs.

Although Congress placed single-entity hydrocodone in Schedule II, when it first passed the Controlled Substances Act in 1970, Zohydro ER is the first drug subject to that rule.  Fortunately for Zogenix, this pre-determined schedule means that Zogenix need not wait to market Zohydro ER while DEA determines whether and in which schedule to place the drug.  This is in sharp contrast to the experience of manufacturers of new chemical entities (“NCEs”) with abuse-potential, who customarily agree to refrain from marketing their products until DEA issues a final scheduling order, which can take over a year, and who may lose their exclusivity rights in the interim.  (See prior posts here and here, and a challenge to FDA’s position on the start of the exclusivity clock here.)

Other than rendering it the first U.S. approved single-entity hydrocodone product, FDA’s approval of Zohydro ER marks two other important firsts: it renders Zohydro ER the first FDA-approved ER/LA opioid to contain hydrocodone and, consequently, the first drug to exhibit new labeling that FDA has proposed apply to all drugs in that class.  As previously reported, on September 10, 2013, FDA requested that all holders of NDAs, biologic license applications (“BLAs”), or abbreviated new drug applications (“ANDAs”) for ER/LA opioid analgesics submit supplemental NDAs with revised labeling that would, among other things, indicate that those drugs are for “the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.”  The affected applicant holders had 30 days to submit supplements or provide reasons for not doing so in writing to FDA.  Zohydro ER is the first opioid to display the recommended labeling.

In addition to marking several firsts, Zohydro ER’s approval has received sharp criticism by lawmakers due to its apparent departure from a movement by FDA to potentially require abuse-deterrent technology for all opioids, like hydrocodone.  Earlier this year, FDA found that Purdue withdrew its drug, OxyContin (oxycodone), for reasons of safety or efficacy in the wake of the FDA’s approval and the Company’s marketing of the same drug with that technology.  FDA declined to reach the same result for Endo’s drug, Opana ER (oxymorphone).  See FDA, CDER, Response to Center for Lawful Access and Abuse Deterrence Citizen Petition, Docket No. FDA-2013-P-0703, at 5-6 (Oct. 25, 2013) [hereinafter, “CLAAD Petition Response”].

Within hours after FDA issued its press-release announcing Zohydro ER’s approval, Congressman William Keating (D-MA) issued a letter condemning FDA’s approval of the drug without abuse-deterrent technology.  He explained:

Last year, a FDA panel questioned the medical need to have such a strong drug on the market and today, FDA not only approves this dangerous drug, but does so without requiring any abuse-deterrent features.  This is outrageous.  Abuse-deterrent technologies should not be the anomaly – they must be the norm.

The Congressman is referring to an Advisory Committee meeting held on December 7, 2012.  Congressman Keating called for support of proposed legislation, the STOPP Act, which would, among other things, require FDA to refuse to approve an ANDA that references a listed drug that utilizes abuse-deterrent technology, absent a showing of comparable tamper-resistance (see our previous post here).  

On the same day that FDA approved Zohydro ER (we told you it was a busy week!) the Agency responded to a Citizen Petition filed by CLAAD.  In that response, which mentioned the agency’s approval of Zohydro ER, FDA stated that its policy is to consider whether abuse-deterrent technology is necessary to ensure adequate safety of a drug on a “product-by-product” basis.  See CLAAD Petition Response at 5.  To illustrate that point, FDA discussed how it came to different conclusions regarding the reformulations and subsequent withdrawal from the market of the original formulations of OxyContin and Opana ER. Id. at 5-6.  It reasoned that it would be ill-advised to require such technology for all opioids at this time, in part because the “science of abuse deterrence technology is in its early stages” and those technologies “have important limitations” such as that they are not “intended or believed to have any impact on the most common form of abuse of this and many other prescription opioids-swallowing intact tablets or capsules.”  Id.  at 5.  However, FDA also stated that it strongly encourages “the development of opioids that can be expected to significantly reduce abuse,” and incentivizes that behavior by allowing companies to label their drugs accordingly.  Id.

Zohydro ER, as an ER/LA prescription opioid analgesic, is also subject to a class-wide Risk Evaluation and Mitigation Strategy.  This and other measures recently adopted by FDA do not apply to immediate-release opioids.  It is unclear yet how FDA will apply its “product-by-product” review for that class of drugs in the future.

By Kurt R. Karst – 

In a decision handed down on September 30, 2013 (but not unsealed until last Friday), the U.S. District Court for the District of Columbia rebuffed a challenge by Cumberland Pharmaceuticals Inc. (“Cumberland”) to FDA’s approval of a generic version of Cumberland’s acetaminophen overdose treatment, ACETADOTE (acetylcysteine) Injection, 200mg/mL, which is approved under NDA No. 021539.  In granting FDA’s Motion for Summary Judgment and denying Cumberland’s Motion for Summary Judgment (reply briefs here and here), the court found FDA’s November 7, 2012 denial of a May 18, 2012 Citizen Petition (Docket No. FDA-2012-P-0507) sumitted by Cumberland and simultaneous approval of InnoPharma, Inc.’s (“InnoPharma”) ANDA No. 200644 for a generic version of ACETADOTE did not violate the Administrative Procedure Act (“APA”).

As we previously reported, Cumberland sued FDA requesting that the court set aside FDA’s approval of ANDA No. 200644 and order FDA not to accept for review or approve any ANDA for generic ACETADOTE containig edetate disodium (“EDTA”).  FDA approved a formulation of ACETADOTE on January 23, 2004 containing the chelating agent EDTA with a postmarketing study commitment that Cumberland “evaluate the potential benefit of [EDTA] on the stability of the drug product.”  Cumberland conducted the evaluation, and on January 10, 2011, FDA approved a Suppemental NDA for an EDTA-free formulaton of ACETADOTE.  Cumberland then withdrew from the market the EDTA-containing version of ACETADOTE. 

In May 2011, a Citizen Petition (Docket No. FDA-2011-P-0339) was submitted to FDA requesting that the Agency make a determination as to whether the discontinued, EDTA-containing version of ACETADOTE was discontinued for reasons of safety or effectiveness.  Under FDA’s regulations implementing the FDC Act (21 C.F.R. § 314.122 and § 314.161), an ANDA for a generic version of a listed drug that has been voluntarily withdrawn from sale is to be accompanied by a petition seeking a determination as to whether the listed drug was widrawn for safety or effectiveness reasons, and FDA must make such a determination before approving an affected ANDA.  Cumberland’s May 2012 Citizen petition requested that FDA not approve any ANDAs for generic ACETADOTE containing EDTA.  Cumberland argued that the EDTA-containing version of ACETADOTE was discontinued for safety reasons.  Specifically, Cumberland alleged that “EDTA has generally been associated with adverse events, such as significant drops in serum calcium levels, which might result in fatality, hypokalemia, hypomagnesemia, or hypotension,” “EDTA has also been associated with adverse events such as syncope, and allergic contact dermatitis,” and “[a]llergic reactions to EDTA may lead to a problematic interruption of therapy that occurs while these reactions are treated.” 

FDA says in the Agency’s November 2012 petition response that available data “do not provide a reasonable basis upon which to conclude that the original, EDTA-containing formulation of Acetadote was unsafe.”   FDA further states that EDTA is a component in several currently marketed drug products – some with higher quantities of EDTA than in “old” ACETADOTE – and concludes that “although there is a theoretical safety concern with EDTA in Acetadote . . . . we have insufficient evidence to conclude that the original formulation was withdrawn for reasons of safety.”  Given FDA’s determination, as well as a waiver, granted pursuant to 21 C.F.R. § 314.99(b), of FDA’s so-called “exception excipient” regulations at 21 C.F.R. § 314.94(a)(9)(iii) for generic versions of injectable drug products that differ from the RLD in formulation (something other than a permitted difference in preservative, buffer, or antioxidant), FDA was able to approve InnoPharma’s ANDA No. 200644. 

As reflected in the more than 1,800-page administrative record, FDA’s decision on EDTA-containing Acetylcysteine Injection (captured in the Agency’s November 2012 Citizen petition response), was reached after significant debate within FDA.  FDA’s Division of Gastroenterology and Inborn Errors Products (“Gastroenterology Division”) initially recommended in a July 1, 2011 memorandum that the Agency “not accept ANDAs for acetylcysteine injection based on the discontinued formulation” because of concerns about allergic reactions and syncope.  In subsequent meetings to discuss the review of the safety of EDTA-containing Acetylcysteine Injection, representatives from FDA’s Office of Generic Drugs and Office of New Drugs raised concerns with the Gastroenterology Division’s July 2011 opinion.  Specifically, they contended that the Gastroenterology Division’s opinion “appears inconsistent with Agency precedent and potentially unsupportable” because:

(1) there was no recall of the original formulation;
(2) the amount of edetate in Acetadote is comparable to that in approved and currently-marketed propofol products;
(3) the FDA allows both propofol products that contain and do not contain edetate;
(4) there are a number of other products containing edetate in various amounts on the market; and
(5) “[t]here are concerns about drug shortages and the potential problems of having a single supplier of this product.”

Given these concerns, the Gastroenterology Division was asked to reconsider its initial opinion. 

In a subsequent opinion, the Gastroenterology Division determined that “[o]n re-examination of the electronic records of letters and reviews for this NDA, there is no definitive evidence that this [postmarketing commitment] was prompted by specific safety concerns,” and that while “[t]here are potential safety concerns . . . associated with [edetate,] . . . none of these concerns rises to the level that would enable us to conclude that the old formulation of Acetadote[] (with [edetate]) was withdrawn for reasons of safety.”  In reaching this opinion, the Gastroenterology Division acknowledged that “exclusively marketing a non-[edetate] containing product would be preferable because it would eliminate even the potential for risk from [edetate],” but the Division reasoned that “there is a risk to the U.S. population in having only a single source of Acetadote[] available for treating [the] life[-]threatening condition of acetaminophen poisoning (i.e., concerns about future drug shortages, which could be devastating in this case).”

In considering whether FDA’s determination that the original, EDTA-containing formulation of ACETADOTE was withdrawn for safety reasons violated the APA, Judge Reggie B. Walton said he was “unconvinced by Cumberland’s attempts to discredit the FDA’s determination.”  Specifically, Judge Walton wrote in his opinion: 

Cumberland’s chief argument in support of its claim that the FDA’s decision is arbitrary and capricious is that the decision is not adequately supported by the evidence before the agency.  Cumberland contends that the FDA reversed its position regarding the safety of edetate-containing Acetadote, pointing to the postmarketing commitment the FDA elicited during the approval process for Acetadote and the July 1, 2011 Gastroenterology Division opinion as evidence that the agency “had, and continues to have, safety concerns about the [edetate]-containing formulation of Acetadote” . . . .  The Court’s review of the administrative record shows that it supports the FDA’s determination that the original formulation of Acetadote was not withdrawn for safety reasons. . . .

Moreover, even if the FDA’s request for the postmarketing commitment was based on safety concerns, such a motivation is not necessarily inconsistent with the challenged determination here.  Having concerns about the safety of an ingredient and even expressing a preference for a formulation that does not contain it is not the same as definitively believing the ingredient to be unsafe or requiring a manufacturer to remove an ingredient. . . .  And, as the FDA points out, it would not have approved Cumberland’s NDA for edetate-containing Acetadote if it had significant concerns regarding the product’s safety.

Cumberland had made much ado about the “about-face” FDA made after the Gastroenterology Division’s initial July 1, 2011 memorandum.  But Judge Walton, citing his earlier decision in Graceway Pharms., Inc. v. Sebelius, 783 F. Supp. 2d 104, 113 (D.D.C. 2011) (see our previous post here), in which there was a disagreement among various FDA components, said that Cumberland’s emphasis on internal debate within FDA is misplaced:

Because the Court’s inquiry here must consider the record in its entirety, the fact that a single memo in the record recommended finding that Cumberland withdrew the original formulation of Acetadote for safety reasons is not dispositive.  Admittedly, the Gastroenterology Division’s July 1, 2011 report is at odds with the FDA’s final conclusion.  However, disagreement among agency staff during the decisionmaking process does not fatally undermine the agency’s final determination, nor does it alone justify according the agency’s final decision less deference than usual.

Cumberland also took issue with two considerations included in the Gastroenterology Division’s later opinion: (1) the possibility of drug shortages if there is only one manufacturer of Acetylcysteine Injection; and (2) FDA’s failure to recall the original formulation of ACETADOTE.  Dispensing with these arguments, Judge Walton wrote that “[w]hile this document is part of the administrative record used to assess whether the FDA’s decision was arbitrary and capricious . . .  this Court’s review of the FDA’s decision must be on the reasons stated for the decision in Dr. Woodcock’s response to the [two] citizen petitions, not other reasons given by agency staff elsewhere in the record.”

Moving on to FDA’s waiver of the Agency’s so-called “exception excipient” regulation at 21 C.F.R. § 314.94(a)(9)(iii) for generic versions of injectable drug products, Judge Walton said that “[h]aving concluded that the Court must affirm the FDA’s determination that the edetate-containing version of Acetadote was not withdrawn for reasons of safety, Cumberland’s objection to the FDA’s grant of a waiver of the regulatory requirement that a proposed ANDA drug contain identical inactive ingredients as the reference listed drug to InnoPharma must also fail.”  The court found FDA’s decision to grant a waiver to InnoPharma pursuant to 21 C.F.R. § 314.99(b) in order to permit the company’s proposed EDTA-containing Acetylcysteine Injection was in accordance with the FDC Act and applicable regulations.

Cumberland had argued that it was arbitrary and capricious for FDA to have granted a waiver to InnoPharma to market an EDTA-containing formulation of Acetylcysteine Injection when the Agency “has consistently preferred that Cumberland, if possible, reduce or remove [edetate] from its product.”  But Judge Walton did not find FDA’s actions inconsistent.  “On the contrary,” wrote Judge Walton, “the FDA is allowing InnoPharma to market an edetate-containing generic version of Acetadote, just as it permitted Cumberland to market an edetate-containing formulation of the drug.”  Seeing no inconsistency in FDA’s treatment of Cumberland and InnoPharma, Judge Walton found FDA’s grant of a waiver to InnoPharma was not arbitrary and capricious.

By Delia A. Stubbs –

Earlier this week, the U.S. Court of Appeals for the D.C. Circuit denied Eisai, Inc.’s (“Eisai’s”) petition to order DEA – in essence – to get moving on the scheduling of its drug, FYCOMPA (perampanel), which FDA approved in October 2012 under NDA No. 202834.  As previously reported here, Eisai argued that DEA’s failure to initiate a rulemaking proceeding nearly one year after FDA approved the drug (and granted Eisai five years of new chemical entity exclusivity, though the start of that exclusivity is being contested – see here) was unreasonable and asked the court to order DEA to act promptly.  In response, DEA promised in its opposition to issue a Notice of Proposed Rulemaking (“NPRM”) by the end of October.  DEA delivered on that promise by proposing to place FYCOMPA in Schedule III.  Interestingly, despite this action, the three-judge panel comprised of Judges Henderson, Griffith, and Kavanaugh still reached the merits of Eisai’s petition, and found that Eisai had not shown that the agency’s delay warranted the extraordinary remedy of mandamus.  This departs somewhat from recent rulings by the District Court in similar challenges.  See Order at 2, Prevor v. FDA, No. 11-1187 (D.D.C. May 8, 2013) (holding plaintiff’s motion to compel FDA to act timely in abeyance in light of FDA’s promise to act by a date certain).

More importantly, even in the absence of a writ, the question remains whether a better process could be crafted to more efficiently schedule NCEs.  See our prior post, here.  In its opposition, DEA explained its delay was based in part on its need to conduct an independent evaluation of FDA’s scientific and medical fact findings, despite their ultimate binding nature on the agency.  Response in Opposition to Petition for Writ of Mandamus at 1, 6, In Re EISAI, Inc., USCA Case # 13-1243, (D.C. Cir.  Sept. 4, 2013) (“Opposition”); See also Schedules of Controlled Substances: Placement of Carisoprodol Into Schedule IV, 76 Fed. Reg. 77,330 (Dec. 12, 2011).  (A copy of Eisai’s Reply Brief is available here.)  DEA reasoned that its re-evaluation ensures its conclusions are adequately founded, in case they are later challenged in court.  Opposition at 6-7.  However, this response is still inadequate if the result will continue to be that companies like Eisai lose exclusivity rights in cases where there is a significant delay between FDA transmitting its recommendations to DEA and DEA issuing the scheduling decision. 

Comments and request for hearing by interested parties on the NPRM must be filed by November 21, 2013.

By Delia A. Stubbs –

While typically not made public, today, FDA issued a statement that it intends to forward a recommendation to DEA by December to move hydrocodone combination products from their current placement in Schedule III to Schedule II.  That change would mean, among other things, stricter security controls on those drugs as well as a restriction on the amount of medication – 90 days worth – that a patient can be prescribed at one time.   

FDA’s recommendation comes as no surprise, given its advisory committee’s recommendation earlier this year that it reach this result (see our previous post here).  CDER Director, Janet Woodcock, projected that the regulations re-scheduling hydrocodone “could take effect as early as next year.” 

The development is interesting given pending legislation that would accomplish the same result, but would afford a grace period to certain DEA registrants, namely manufacturers and distributors and other “non-practitioners,” to comply with the new storage and security requirements (see our previous post here). 

The Grocery Manufacturers Association ("GMA") is presenting a webinar on GRAS self-determinations for food ingredients next Tuesday, October 29 from 1:30 to 3:00 p.m. EST.  The webinar is intended to help food businesses understand applicable requirements and avoid missteps in ingredient safety assessments, and will feature a presentation on FDA’s expectations by the Division Director of Biotechnology and GRAS Notice Review, Dr. Antonia Mattia.  For additional information and registration, click here.