On November 20th, the Food and Drug Law Institute ("FDLI") will present a webinar on the regulatory requirements that apply to health-related claims for foods.  Hyman, Phelps & McNamara, P.C.'s Ricardo Carvajal will discuss requirements applicable in the U.S.  Vicente Rodriguez, current president of the European Food Law Association, will discuss requirements applicable in the European Union.  The presenters will compare and contrast requirements applicable to nutrient content claims, health claims, structure/function claims.  Time will be provided for Q&A.  Additional information and registration is available here.

By Allyson B. Mullen – 

For many individuals, a diagnosis, be it life threatening or chronic, is scary.  However, the trial and error process that can follow the diagnosis in order to find a therapy (e.g., drug, device and/or biologic) that works best for the patient can be just as scary.  It would be wonderful if, at the time of diagnosis, or shortly thereafter, doctors could with a high degree of confidence identify what the best treatment was for that individual and avoid this process.  Many such personalized treatments are now being developed, and in the recent report “Paving the Way for Personalized Medicine – FDA’s Role in a New Era of Medical Product Development,” (the “Report”) [issued on October 30, 2013, FDA says it is preparing to address these new types of treatments from a regulatory perspective. Report at 2.

Personalized Medicine, sometimes also referred to as “precision medicine,” has been defined by the National Academy of Sciences as “the use of genomic, epigenomic, exposure and other data to define individual patterns of disease, potentially leading to better individual treatment.”  Id. at 6.  Personalized Medicine typically involves two medical products, a diagnostic test (a device) and a therapeutic.  Id. at 8.  The diagnostic is generally regulated as a medical device, and can include in vitro diagnostic assays or in vivo tests (e.g., diagnostic imaging).  Although drugs and biologics are the most obvious therapeutics where personalized medicine will be used, all types of regulated products can be therapeutics.  For example, recently three dimensional printing was used to create a personalized tracheal splint based on CT images of the patient’s airway and lungs.  Id. at 9. 

According to the Report, “the era of personalized medicine” has arrived:

• In 2011, one third of the new drugs approved had some type of genetic or biomarker data in the submission relative to efficacy, safety or pharmacokinetics;
• Since 2010, CBER has licensed seven new products which require careful matching of donors and recipients; and
• The number of submissions to CDRH’s Office of In Vitro Diagnostics and Radiological Health (OIR) involving personalized medicine has increased by more than an order or magnitude.  Id. at 54. 

The Report goes on to tout FDA and industry’s recent successes in this area.  Specifically, the Report highlights the approval of Kalydeco, the first drug to treat the underlying cause of Cystic Fibrosis, rather than the disease symptoms.  Id. at 3.  Kalydeco was an output of decades of work by the Cystic Fibrosis Foundation and Vertex Pharmaceuticals, the drug’s manufacturer.  Id.  The drug was approved in only approximately three months after its application was granted “priority review.”  Id.  FDA emphasizes that this success was a result of a “well-prepared submission, strong evidence, and a commitment on the part of all of the parties involved.”  Id. 

In achieving such a success, the Report discusses the historic and recent scientific, policy and organizational changes that FDA has made to address personalized medicine products.  Id. at 14–22.  The Report stresses that the primary challenge it needs to address related to personalized medicine is the science.  To that end, the Report enumerates a number of ways in which FDA says it is addressing the scientific challenge of personalized medicine, for example:

• Biomarker Qualification Program.  CDER is working with external scientists and clinicians to develop biomarkers with an aim of establishing a framework for encouraging development, identification and regulatory acceptance of biomarkers in drug development.
• MicroArray and Sequencing Quality Control Project.  National Center for Toxicological Research (NCTR) scientists are running this FDA-led project to “advance translational and regulatory sciences by assessing technical performance and practical utility of emerging molecular biomarker technologies for clinical application and safety evaluation.”
• Genomic Reference Library.  The National Institute of Standards and Technology (NIST) and OIR are working together to develop genomic reference material to be used in evaluating whole genome sequencing instruments.
• Clinical Trial Design and Methods.  FDA is generally working on refining clinical trial design and statistical analysis.  Specifically, the I-SPY 2 Trial, developed by the Biomarkers Consortium, which consists of FDA, the National Institute of Health (NIH), and the pharmaceutical industry, was launched in March 2010.  This trial uses an adaptive trial design to reduce the speed and cost of development for new drugs for women with high-risk breast cancer.  Id. 43–46.

However, FDA acknowledges that there are a number of other challenges that both it and industry face with respect to personalized medicine, including:

• Coordination of Multiple Products. As discussed above, personalized medicine involves two products, which raises a host of issues since each product is generally developed on its own time frame, by a different company, and each is likely subject to differing regulations (e.g., diagnostics as devices and therapeutics often as drugs and biologics and sometimes as devices);  Id. at 32–35.
• Regulation of Diagnostics.  Many of the diagnostic tests used in personalized medicine are in vitro diagnostic assays (IVDs), which can be commercialized to laboratories as a kit subject to FDA regulation as a device, or can be developed and used solely by a single laboratory as a laboratory developed test (LDT).  FDA’s efforts to regulate LDTs has been controversial (as discussed in our previous post here).  FDA has been developing a risk-based framework for regulating LDTs, although to date, nothing has been finalized. Id. at 30–32.
• Limited Understanding of Disease and Lack of Infrastructure.  With all of the new technologies, there is a mass of new data, but it is still unclear what it all means, and the infrastructure to “analyze, integrate, share, and mine” the data does not yet exist.  Id. at 56.
• Clinical Adoption of New Diagnostics.  Just as it takes FDA time to understand and accept new technology, clinicians have been slow to use new diagnostic tools, possibly due to how new the technology is, and the lack of tools to help the clinician in interpreting what the results of the tests mean.  Id. at 57.  In addition, although not mentioned in the Report, the lack of reimbursement for these new diagnostics is also a big impediment to their adoption by clinicians. 

Lastly, with all of the growth and excitement in this area, FDA says it wants to ensure that those individuals who do not have the characteristics to benefit from certain therapies are not forgotten and that all sub-classifications of disease are considered.  Id.

It is clear that advancement of Personalized Medicine through therapeutics and diagnostics is a high priority for FDA, as shown by a five-page table listing the various guidance documents that FDA has issued in this area.  Report at 24-28.  And FDA plans to issue more guidance documents in this area.  For example, CDRH’s Fiscal Year 2014 Proposed Guidance Development List includes several draft and final guidance documents related to personalized medicine, for example, a final guidance document for In Vitro Companion Diagnostic Devices, and a draft guidance for Direct to Consumer (DTC) Genetic Testing: IVDs. 78 Fed. Reg. 66746, 66746 (Nov. 6, 2013). 

In sum, there are many regulatory challenges that still face companies developing personalized therapies and diagnostics, and there is a long way for both industry and FDA to go before many of these products become realities.  There are also external factors that play a key role, such as reimbursement, health care reform, and commercial considerations.  However, the Report does describe steps FDA is prepared to take to address new therapies and technologies to help facilitate growth in the area of personalized medicine.

By Dara Katcher Levy –

A new Warning Letter issued by FDA’s Office of Prescription Drug Promotion (OPDP) suggests that FDA may want a new fight when it comes to the issue of that pesky First Amendment and the interplay with FDA-regulated products. 

In a November 8, 2013 Warning Letter, OPDP alleges that statements made by Aegerion Pharmacueticals’ CEO during broadcast interviews on a CNBC talk show, “Fast Money,” constitute evidence of a new, unapproved, intended use for its drug, Juxtapid (lomitapide) capsules.  These statements, OPDP alleges, misbrand Juxtapid, making its distribution a violation of the Federal Food, Drug, and Cosmetic Act.  

This is the first OPDP Warning Letter that takes issue with an initial broadcast of statements aimed at the financial community, rather than the re-distribution of these materials for purposes of product promotion or as part of a “media pitch” (see our previous post here).   

FDA did not cite any of the company’s marketing materials to support its allegation that Aegerion intended a new use for Juxtapid, rather, the focus is solely on the CEO’s statements made as part of the “Fast Money” interviews.  Further, OPDP did not cite the traditional statutory provisions relating to false or misleading promotional materials in its Warning Letter; the statutory violation alleged is that the drug is misbranded as its labeling fails to include adequate directions for the new intended use as expressed in statements made by the CEO.  Although OPDP makes mention in the Warning Letter that Aegerion’s CEO failed to include risk information as part of the interview, this is unrelated to OPDP’s misbranding allegations relating to the new intended use for the drug.

We are interested to see whether OPDP will be increasing its enforcement focus on investor-related materials and other materials intended for the financial community.    

By Jennifer M. Thomas –

The generic drug industry has waited with bated breath since, as we reported here and here, FDA signaled that it was “considering a regulatory change that would allow generic manufacturers, like brand-name manufacturers, to change their labeling in appropriate circumstances.”  See Amicus Brief of the United States at 15, n. 2, Mutual Pharm. Co., Inc. v. Bartlett, 133 S. Ct. 2466 (2013) (No. 12-142).  On Friday, November 8, 2013, the wait was over.

FDA’s Proposed Rule would allow generic manufacturers to independently update product labeling through the “changes being effected” (“CBE-0”) supplement process that is currently only available to branded drug manufacturers with respect to product safety labeling.  Under the Proposed Rule, generic manufacturers could unilaterally change their safety-related product labeling, and those changes could take effect simultaneous with the companies’ notification of FDA and of the branded drug manufacturer – no prior approval required.

The current regulatory scheme only permits generic manufacturers to use CBE-0 to update their labels in conformance with the branded drug (also called the Reference Listed Drug, or “RLD”) label.  See 21 C.F.R. § 314.150(b)(10).  Practically speaking, this means that the branded drug manufacturer must change its labels first, followed by the generics.  Most importantly, the Supreme Court has determined that generic manufacturers’ lack of independence with respect to drug safety labeling makes it impossible for them to comply with both Federal drug labeling requirements, and state tort law (failure to warn or design defect) requirements.  See PLIVA, Inc. v. Mensing, 131 S. Ct. 2567 (2011); Mutual Pharm. Co., Inc. v. Bartlett, 133 S. Ct. 2466 (2013) (reasoning that the only way to correct a design defect with respect to a drug that cannot be reformulated is through labeling).  Thus, state product liability suits based on use of generic drugs have generally been held preempted by Federal law.  Id.

While FDA’s stated purpose in proposing the new rule is to “speed the dissemination of new safety information about generic drugs to health professionals and patients,” (FDA Press Release), it is no mistake that the first whisperings of this rule appeared in a case involving generic preemption.  FDA’s admission that “[i]f this proposed regulatory change is adopted, it may eliminate the preemption of certain failure-to-warn claims with respect to generic drugs,” seems a ridiculous understatement.  If finalized, this rule would change the entire regulatory and liability landscape for generic drug manufacturers.

But does FDA have the authority to promulgate the Proposed Rule?  And if so, should it?  Given the serious questions surrounding it, this Proposed Rule seems as likely to go the way of the dodo as to ultimately be finalized.

Concerns about FDA’s statutory authority are unavoidable.  FDA acknowledges that its proposed new regulatory scheme would result in at least a temporary multiplicity of labels for the “same” drug, a result that the statute appears to prohibit except in enumerated circumstances.  See 21 U.S.C. § 355(j)(2)(A)(v).  Specifically, the statute requires applicants for generic drug approval to provide “information to show that the labeling proposed for the new drug is the same as the labeling approved for the listed drug . . . except for changes required because of difference approved under a [suitability petition], or because the new drug and the listed drug are produced or distributed by different manufacturers.”  Id.; see also id. at § 355(j)(2)(C).

FDA’s Federal Register notice wisely avoids addressing the statutory “sameness” point directly.  However, it does note that by waiting to actually approve a safety-related CBE-0 supplement until FDA can simultaneously approve a change in branded-drug labeling, the Agency “ensures that the approved labeling for a generic drug continues to be the same as the approved labeling of its RLD.” (emphasis supplied).  See Proposed Rule at 34.  FDA is also careful to point out that the statute requires a generic drug label to be identical to the branded drug “at the time of approval,” and that only FDA regulations have taken the position that generic drug labeling must maintain the same label as the branded drug throughout the lifecycle of the generic product.  Proposed Rule at 13.  A position the Agency now proposes to alter.

Assuming FDA has authority to issue the Proposed Rule, it will give patients an avenue for recovery from generic drug companies after suffering an injury.  But will it keep patients from harm in the first place?  The desirability of FDA’s Proposed Rule from a patient-safety perspective is certainly open to debate, and will be a point of serious contention in the coming months.  This is evidenced both by the Agency’s own admittedly changed position, and by the immediate and opposite reactions to the Proposed Rule.  See, e.g., Statement of the Generic Pharmaceutical Ass’n; Press Release: Harkin Welcomes Release of Proposed Rules to Protect Consumers Using Generic Drugs.  

FDA acknowledges its previously long-held view that the labeling of generic drugs must be identical to that of the listed drug in order to ensure patient safety, not least because a generic drug’s approval relies upon safety and efficacy studies of the listed drug.  See 57 Fed. Reg. 17,950, 17,961 (Apr. 28, 1992).  It also “acknowledges that there may be concerns about temporary differences in safety-related labeling for drugs that FDA has determined to be therapeutically equivalent.”  Proposed Rule at 18.  Nevertheless,  the Agency argues that the changing prescription drug landscape, in which 80% of the drugs dispensed are generic, has altered the risk-benefit balance between clarity and consistency on the one hand, and speedier access to safety information on the other.  Proposed Rule at 14.  FDA proposes to address the inevitable confusion regarding multiple versions of safety labeling through increased transparency – a website listing all of the pending CBE-0 supplements for safety-related labeling changes.  Proposed Rule at 19-20.  We anticipate that, particularly in the case of drug products for which there are multiple generic manufacturers, this website would be a virtual cacophony of labeling.

The comment period on FDA’s Proposed Rule will be open at least 60-days after its publication in the Federal Register – until January 12, 2014 – and likely longer.  The Docket No. is FDA-2013-N-0500. 

Hyman, Phelps & McNamara, P.C. is pleased to announce that James C. Shehan has joined the firm as Of Counsel.  Previously, Mr. Shehan served for 19 years as Novo Nordisk Inc.’s General Counsel and Corporate Vice President of Legal, Government and Quality.  His extensive experience will bolster the firm’s already deep expertise in, and inside knowledge of, the drug industry.  Specifically, Mr. Shehan’s work at the firm will focus on:

• Internal investigations and strategic handling of federal enforcement actions;
• Corporate compliance and GMPs;
• Hatch-Waxman and advertising litigation;
• Private and public transaction due diligence; and
• Drug development, biosimilars, and other areas essential to the drug industry.

At Novo Nordisk, Mr. Shehan was a part of an executive team that led one of the most successful healthcare companies in the United States.  During his years there, Novo Nordisk became the US market leader in diabetes, established other thriving therapeutic areas, went from ~ 200 employees to more than 5000, and grew sales from ~$100 million to more than $5.5 billion while achieving over 40 consecutive quarters of double-digit sales growth.

Mr. Shehan began as the sole member of the legal department and eventually managed a staff of 100.  His tenure included the approval of four blockbuster drugs, a multi-year GMP investigation, a Supreme Court Hatch-Waxman case, the successful defense of a Lanham Act false advertising challenge to the launch of a new biotech product, the partial spin-off of ZymoGenetics Inc. in what was at that time the largest private equity placement in history, and patent litigations related to human growth hormone, medical devices, and inhaled and injectable insulins.

Mr. Shehan also established Novo Nordisk’s compliance program and government affairs function.  In the latter role, he led Novo Nordisk’s efforts to shape the passage and implementation of the Affordable Care Act, particularly the provisions that allow for the first time in the US the approval of biosimilar drugs and the Sunshine provisions that require pharmaceutical and medical device companies to publicly report certain payments to physicians.  In the former role, he obtained extensive experience in the areas of health care fraud, off-label promotion and government drug price reporting and discounting.

Mr. Shehan has served on the boards of the Healthcare Institute of New Jersey, the National Association of Manufacturers and the Healthcare Leadership Council.  He was also for many years a member of the Law Section Executive Committee of the Pharmaceutical Research and Manufacturers of America and the General Counsel Committee of the Biotechnology Industry Organization.  He is Chairman of the Board of the American Friends of the Statens Museum for Kunst (Denmark’s national art gallery).

Prior to Novo Nordisk, Mr. Shehan spent five years as a regulatory attorney at Pfizer, where he worked on matters such as the approval and launch of Zithromax, Zoloft, and Procardia XL and the product liability litigation and regulatory issues stemming from the Bjork-Shiley heart valve.  Mr. Shehan began his career as a Regulatory Counsel in the Office of the Associate Commissioner of Health at FDA.  He is a recipient of FDA’s Award of Merit for his work on the implementation of the Hatch-Waxman Amendments.

Mr. Shehan is a graduate of Georgetown Law School and the Columbia University.  He is admitted to practice law in New York State.

By Etan J. Yeshua –

The Food and Drug Administration last week initiated a process that could prohibit the sale of partially hydrogenated oils (PHOs), as well as food products containing industrially manufactured PHOs, such as certain baked goods, microwave popcorn, frozen pizzas, frostings, and stick margarine.  Citing evidence that the trans fatty acids in PHOs provide no known benefit to human health and that any incremental increase in trans fat consumption increases the risk of coronary heart disease (CHD), FDA announced its tentative determination that food manufacturers should be prohibited from selling PHOs, or adding them to foods, without first obtaining FDA approval for their use.  The Agency is seeking comments on its tentative determination, including information about the costs that the move would impose on the food industry, and particularly the costs to small businesses (see here).  The deadline for submitting comments is January 7, 2014.

Current Regulatory Status of PHOs

With the exception of two oils that FDA says are not widely used (i.e., partially hydrogenated versions of rapeseed and menhaden oil), FDA maintains that it has never directly authorized the use of a PHO in food.  That is, FDA has never approved the use of a PHO as a food additive, affirmed it as generally recognized as safe (GRAS), or granted a prior sanction.  Instead, according to FDA, “commonly used PHOs… have been considered GRAS (through a GRAS self-determination) by the food industry for use in food at levels consistent with good manufacturing practice based on a history of use prior to 1958” – the year that the Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act was passed.  With last week’s notice in the Federal Register, FDA announced that it does not believe there exists a “consensus of expert opinion regarding the safety of” PHOs.  If the announced “tentative determination” is finalized, food manufacturers would effectively be prohibited from selling PHOs without first obtaining FDA approval for a specific use of a specific oil in specific amounts as a food additive. 

Health Effects of Trans Fats

Despite what it described as a significant decrease in the average consumption of industrially produced trans fatty acids in the U.S., FDA stated that “[o]n the average day, at least eight Americans die as a result of the trans fats in partially hydrogenated oils” and that “[m]ost of these deaths could be prevented by removing industrially produced trans fats from the US food supply.”  FDA cited controlled trials and observational human studies on trans fats, as well as the opinions of expert review panels from the Institutes of Medicine, the American Heart Association, the American Dietetic Association, the World Health Organization, the Dietary Guidelines Advisory Committee, and the FDA Food Advisory Committee Nutrition Subcommittee, all of which purportedly concluded that “there is no threshold intake level for industrially-produced trans fat that would not increase an individual’s risk of CHD, or adverse effects on risk factors for CHD.”  FDA also cited evidence that the trans fats in PHOs may worsen insulin resistance, increase diabetes risk, and put fetuses and breastfeeding infants at higher risk of impaired growth.  Given these findings, FDA has tentatively determined that PHOs are not GRAS for any use in food.

FDA’s Cost-Benefit Analysis

The Agency believes that “the benefits of this action would be much higher than the costs,” although it noted that “in many cases we have very limited data to support our rough estimates.”  Taking into account the cost to industry of reformulating and relabeling products and substituting ingredients, as well as the cost to consumers of changing recipes, FDA estimated the cost of its proposal to be between $12 and $14 billion (net present value) over 20 years.  On the other hand, the 20-year net benefit for removing PHOs from the food supply – including the medical costs that would be avoided, as well as the monetary value of preventing deaths and illnesses (e.g., each fatal heart attack prevented is valued at about $1.76-million) – is estimated by FDA to be between $117 and $242 billion.

Request for Comments

Comments related to FDA’s announcement can be submitted with regard to any aspect of the Agency’s tentative determination, but FDA has specifically requested input with regard to certain issues, including, among others:

• Whether there are data to support other approaches to addressing the use of PHOs in food (e.g., setting a limit on the levels of trans fats in food);
• How long it would take manufacturers to reformulate food products to eliminate PHOs from the food supply;
• What FDA could do to reduce the burden on small businesses that would result from removal of PHOs from foods; and
• Whether there are products that cannot be reformulated.

An article published in the current edition of Regulatory Focus, the flagship publication of the Regulatory Affairs Professionals Society (RAPS), and authored by Hyman, Phelps & McNamara, P.C.’s Alexander J. Varond discusses the recent trends and developments in personalized medicine, including FDA’s current thinking and new challenges facing industry.  Despite the promising potential of personalized medicine, the field is still in its infancy and there is much uncertainty.  The article surveys key issues for sponsors, including the potential effect of next-generation sequencing technology on companion diagnostics, the importance of payers in the development of personalized therapies, and new regulatory pathways being proposed to ensure companion diagnostic reviews keep pace with breakthrough therapies.

The New York Academy of Sciences will present a conference on scientific and regulatory issues pertaining to nanomedicine on November 21.  The conference will feature speakers from the U.S. and abroad so as to provide domestic and international perspectives.  Hyman, Phelps & McNamara’s Ricardo Carvajal will participate in a panel discussion on acceleration of the development of nanomedicine.  Further information and registration information is available here.  FDA Law Blog readers can use the code NANOMED25 to receive 25% off the cost of registration.

By Kurt R. Karst –      

Earlier this week, sanofi-aventis U.S., LLC (“Sanofi”) filed a Complaint in the U.S. District Court for the District of Columbia against FDA in what appears to be a first-of-its-kind lawsuit.  Sanofi alleges that FDA’s decision to make public a copy of the labeling approved on October 11, 2013 under NDA No. 020468 for the Over-the-Counter (“OTC”) use of Nasacort Allergy 24 HR (“OTC NASACORT”) for the temporary relief of symptoms of hay fever or other respiratory allergies (nasal congestion, runny nose, sneezing, and itchy nose) in adults and children ages 2 years and older violates the Administrative Procedure Act (“APA”).   

Despite having approved a prior approval supplement (S-035) under NDA No. 020468 for the prescription-to-OTC use of NASACORT nearly a month ago, despite having received four Freedom of Information Act (“FOIA”) requests to release the labeling, and despite FDA policy, the Agency has failed to post on the CDER Internet Web Page (at Drugs@FDA) a copy of the approved labeling text. 

FDA procedures have called for the prompt publication of approval information on the CDER Internet Web Page.  For example, FDA Manual of Policies and Procedures (“MAPP”) 6020.8, titled “Action Packages for NDAs and Efficacy Supplements,” directs FDA staff to promptly compile and disseminate drug approval action packages.  In particular, MAPP 6020.8 states that FDA Document Room Staff are responsible for “[e]nsuring that three copies of the action package are made and distributed according to the procedures in MAPP 4520.1, Communicating Drug Approval Information, upon notification by the project manager that the application has been approved.”  MAPP 4520.1 is currently being updated and has been temporarily removed from FDA’s website; however, the most recent version of that MAPP stated the following policy:

Approved labeling text or final printed labeling for new drugs . . . will be made available on CDER’s Web Site and the CDER Fax-on-Demand system within the time frames specified in this MAPP, a period not to exceed three working days. [(emphasis added)]

The reason for FDA’s failure to timely post the OTC labeling along with the currently-posted approval letter for the NDA supplement was not entirely clear; however, there were suspicions that Sanofi was claiming proprietary rights to the OTC NASACORT labeling until Sanofi’s consumer healthcare division, Chattem, Inc., begins making the drug available next year (see here).  Those suspicions were confirmed with the filing of Sanofi’s lawsuit.  According to Sanofi, “FDA rejected Sanofi’s requests for confidentiality and advised Sanofi that it would post the approved labeling and packaging on FDA’s website on November 12, 2013.” 

Sanofi alleges that the OTC NASACORT labeling is protected from public disclosure under FOIA Exemption 4.  That exemption protects “trade secrets and commercial or financial information obtained from a person [that is] privileged or confidential.”  According to Sanofi:

Until Sanofi’s labeling and packaging material is publicly disclosed, it constitutes proprietary information, the disclosure of which would cause substantial completive harm to Sanofi.  Accordingly, the labeling and packaging information falls within Exemption 4 to the Freedom of Information Act and the Trade Secrets Act, 18 U.S.C. § 1905 until Sanofi chooses to make the labeling and packaging public in connection with the launch of the product.

So what’s all the hubbub really about?  Competition of course!  FDA did not grant Sanofi a period of 3-year new clinical investigation marketing exclusivity for the prescription-to-OTC switch of NASACORT.  So some might say that the company’s efforts to prevent publication of the OTC labeling is a lifecycle management tactic that provides a limited period of de facto marketing exclusivity. 

As Sanofi alleges in the Complaint:

Release of Sanofi’s approved labeling and packaging materials prior to its launch of the OTC version of Nasacort Allergy 24 HR will cause substantial competitive harm to Sanofi because it will provide generic manufacturers with advance knowledge of the labeling that they must match and thereby will enable them to launch their competing products sooner than would be the case if they must wait until Sanofi launches its product

Release of this information will also permit manufacturers of competing branded products to prepare advertising and promotion materials in advance of Sanofi’s launch of its OTC product.

The FDC Act requires that the labeling of a generic drug approved under Section 505(j) – whether for prescription or OTC use – be the same as the currently approved labeling of the Reference Listed Drug.  Indeed, FDA and the Office of Generic Drugs (“OGD”) have recognized in guidance the need to promptly make labeling changes to meet these legal obligations, stating in relevant part that:

OGD believes that prompt revision, submission to the Agency, and implementation of revised labeling are important to ensure the continued safe and effective use of generic drug products.  Because the regulations state that the labeling of the generic must be the same as the innovator, the revision should be made at the very earliest time possible.

Without access to approved labeling, however, generic drug sponsors may be unable to meet relevant legal and FDA obligations.  (FDA has approved a single ANDA for a generic version of the prescription version of NASACORT – ANDA No. 078104, approved on July 30, 2009.)   Prompt approval of an ANDA labeling supplement could result in the unusual situation where a generic version of a brand-name drug is available to consumers before the brand-name drug is available.

Sanofi requests that the court set aside FDA’s decision to make public the OTC NASACORT labeling as a violation of the APA, declare that FDA’s decision to make public the OTC NASACORT labeling because of the non-applicability of FOIA Exemption 4 violates the APA, and declare that the OTC NASACORT labeling falls within FOIA Exemption 4.  In the alternative, Sanofi requests that the court remand the matter to FDA for reconsideration, and preliminarily and permanently enjoin FDA from publicly disclosing the OTC NASACORT labeling until Sanofi launches the product.  (We'll update this post once Sanofi's injunction pleadings are available.)

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.