By Riëtte van Laack –

As we anticipated, both the FTC Staff and POM Wonderful appealed the May 17, 2012 Initial Decision by the FTC’s Administrative Law Judge (ALJ).  Among other things, the FTC Staff appealed the ALJ’s conclusion that substantiation of disease efficacy claims does not require well-designed, well-conducted, double-blind, randomized, controlled clinical trials (RCTs) and the ALJ’s denial of FTC Staff’s proposed remedy to require FDA approval for all future claims that any POM product is effective in the diagnosis, cure, mitigation, treatment or prevention of a disease.  POM has also appealed the ALJ’s findings that POM contends were erroneous.

In general, the FTC has historically proclaimed that the standard of substantiation is “Competent and Reliable Scientific Evidence,” a standard that the FTC has stated is flexible.  Although consent decrees suggested otherwise, the Agency has been unwilling to specify that, with regard to health benefit claims, this standard always requires RCTs.  However, in its appeal in In Re POM Wonderful, the FTC Staff  unequivocally asserts that for so-called establishment claims, i.e., claims about the amount and type of evidence about the products specific health benefit, only RCTs are sufficiently reliable to establish a causal link between the product and the reduced risk of a disease.  In fact, according to the FTC Staff, it is “axiomatic that only [RCTs] can establish that a product is proven to treat, prevent or reduce the risk of a specific disease.”  Although it applies a different analysis, FTC Staff also concludes that for non-establishment disease efficacy claims, i.e., claims that a product treats, prevents or reduces the risk of diseases, only RCTs will do.  The FTC Staff stresses that the requirement for RCTs applies to disease efficacy claims and its statements should not be interpreted to mean that RCTs are automatically required for any health efficacy claims. 

The FTC Staff also again argues that its proposed remedy requiring FDA pre-approval for future disease efficacy claims is justified in light of POM’s past conduct, the complexity of the scientific issues, the expertise of FDA to evaluate this type of claims, and the FTC’s interest in harmonizing with FDA.  The FTC Staff asserts that this requirement provides a bright line and will protect the FTC from disputes of the kind it has encountered in previous litigated cases (e.g., Lane Labs, Inc. and Garden of Life, Inc.).

Now that the FTC Staff and POM have made their written arguments, the next step in the process is for the five FTC Commissioners to hear oral argument and make a final decision regarding whether to adopt, in whole or in part, or not at all, the ALJ’s Initial Decision.  Oral argument before the Commission is scheduled for August 23, 2012.

By Nisha P. Shah –

On July 8, 2012, Massachusetts Governor Deval Patrick signed H. 4200, which, in part, relaxes: (1) the state anti-kickback law to permit the offering of coupons for prescription drug and biological products, and (2) the marketing laws to allow prescription drug and medical device manufacturers to provide meals to health care practitioners (HCPs) consumed outside of a health care setting.   

All-Payor Anti-Kickback Law

Massachusetts is one of a few states to have an all-payor anti-kickback statute that prohibits, in part, a person from offering any remuneration (including rebates) to induce the purchase or order of any good, facility, service, or item that is paid in whole or in part by a health care insurer.  Mass. Gen. Laws ch. 175H, sec. 3.  Under this law, manufacturers have been prohibited from providing coupons or rebates that are offered by manufacturers to patients insured by any health care plan (not just Medicare, Medicaid, or other government health care program) to offset the costs or co-payments associated with prescription drug or biological products.  Manufacturers offering such coupon programs typically have excluded all residents of Massachusetts from benefiting from the coupon program.

Sections 128 to 130 of H. 4200 add an exception to the all-payor anti-kickback statute to allow, among other things, pharmaceutical manufacturing companies (as defined in the marketing law, Mass. Gen. Laws ch. 111N) to provide a discount, rebate, voucher, or other reduction in a patient’s out-of-pocket expenses (including co-payments and deductibles) on a biological product or prescription drug.  However, the law specifically prohibits a pharmaceutical manufacturer from offering such coupons for a prescription drug that has an AB rated generic equivalent as determined by FDA.  Additionally, the coupon must be given to a patient directly or electronically or through a point of sale or mail-in rebate, or through similar means.  The phrase “similar means” was not defined, and it is not clear how broadly this should be construed (for example, whether coupons could be provided to HCPs to give to patients).  This coupon exception will not apply if a pharmaceutical manufacturer excludes or favors any pharmacy in the redemption of such coupon. 

Sections 128 to 130 went into effect immediately and are scheduled to sunset on July 1, 2015.  By December 31, 2014, the Division of Health Care Finance and Policy (Division), in consultation with the Department of Public Health (DPH), must complete an analysis of the impact on health care costs of the use of such coupons for biological products and prescription drugs from August 1, 2012 to July 31, 2014.  The statute authorizes the Division to require manufacturers of biological products and prescription drugs to report on the number and types of coupons that the manufacturers have issued and that have been redeemed in Massachusetts.

Marketing Law

In H. 4200, the Massachusetts legislature also relaxed the marketing laws that prohibit the provision of meals outside of the hospital or medical office setting.  In 2008, Massachusetts enacted a law that imposes compliance and reporting requirements on pharmaceutical and medical device companies that employ a person to sell or market prescription drugs or medical devices in Massachusetts (see our blog post here).  See generally, Mass. Gen. Laws ch. 111N.  The original law prohibited a company from providing meals to HCPs that are part of a recreational event, offered without an informational presentation, consumed outside of a health care setting, or for a HCP’s spouse or other guest. 

According to Section 111 of H. 4200, manufacturers are now permitted to provide or pay for “modest meals and refreshments” in connection with non-continuing medical education (CME) presentations for the purpose of educating HCPs about the benefits, risks and appropriate uses of prescription drugs or medical devices, disease states or other scientific information, as long as the presentation occurs “in a venue that is conducive to informational communications.”  DPH must define in regulation what constitutes “modest meals and refreshments” and also determine whether companies must pay a fee to pay for the costs of administering the new requirements.  Companies must file quarterly reports detailing all non-CME educational presentations at which such meals or refreshments are provided.  The reports must include the following information: (1) the location of the non-CME presentation; (2) a description of any pharmaceutical products, medical devices or other products discussed at the presentation; and (3) the total amount spent on the presentation and an estimate of the amount spent per participant. 

Additionally, Section 111 of H. 4200 also permits the payment of reasonable expenses for the technical training on the use of a medical device.  Section 113 of H. 4200 instructs DPH to no longer require reporting by pharmaceutical and medical device manufacturers of any information that has been disclosed to the federal government that may be obtained by DPH.  This follows the federal preemption requirement under section 6002 of the Patient Protection and Affordable Care Act (PPACA) (see our blog posts here and here).  Finally, DPH will be required to make data submitted by companies in annual reports publicly available and in a searchable format on DPH’s web site not later than 90 days following receipt of the information.

By Kurt R. Karst –

FDA’s Office of Generic Drugs (“OGD”) will have a new leader beginning next week.  On July 13th, Helen Winkle, Director of the Office of Pharmaceutical Science in the Center for Drug Evaluation and Research, in which OGD is housed, announced that Gregory P. Geba, M.D., M.P.H. has been named OGD Director.  Dr. Geba will replace Dr. Keith Webber, who has served as OGD’s Acting Director since the departure of Gary Buehler in 2010.  During that time, Dr. Webber has also served as Deputy Director of the Office of Pharmaceutical Science. 

The announcement comes just days after the enactment of the Generic Drug User Fee Amendments of 2012 (“GDUFA”) as part of the FDA Safety and Innovation Act (see here).  GDUFA significantly revamps the generic drug approval process and will have wide-ranging effects on industry and on OGD.  Below is the correspondence from Ms. Winkle announcing Dr. Geba’s selection.

The Office of Pharmaceutical Science (OPS) is proud to announce the selection of Gregory P. Geba, M.D., M.P.H., as Director of the Office of Generic Drugs (OGD) effective July 15, 2012.
 
Dr. Geba has served in senior-level clinical/managerial positions in the pharmaceutical industry for the past 15 years. He most recently served as Deputy Chief Medical Officer for Sanofi US, where he provided medical and scientific leadership and managerial direction to a staff of approximately 500 multidisciplinary scientific and regulatory professionals engaged in drug development activities across all therapeutic areas, as well as to the company’s field medical group.
 
He has contributed to the registration of more than 20 currently marketed drugs or devices across multiple therapeutic areas. In so doing, he successfully employed his working knowledge and demonstrated practical application of drug manufacturing processes, current quality and risk management processes, and standards relevant to FDA’s laws and regulations. He brings extensive clinical research experience, including leading or serving as the key point in filing new drug applications, biologic license applications, and promotional studies comparing efficacy and effectiveness of novel biopharmaceuticals versus standard of care (including regimens containing branded or generic drugs), and has provided or supervised key safety updates and presentations to FDA Advisory Committees. Dr. Geba’s experience also includes leading medical affairs activities while serving in a variety of senior-level positions. His scope of responsibility in those activities included contribution to the design of experimental protocols and assessment of data from pre-clinical, animal, and first-in-human studies; design, implementation, analysis, and interpretation of phase 2a proof-of-concept and 2b dose ranging studies; and production of important comparative effectiveness and safety data when assessing benefit-risk relationships during phase 3, phase 3b, and phase 4 studies.
 
Dr. Geba received his medical degree from the University of Navarre and his M.P.H. from the Johns Hopkins Bloomberg School of Public Health. He joins OGD at an opportune time to lead our expanding generic program into a reorganization of both structure and process to improve coordination, communication, and efficiency, as well as enhance the Office’s ability to ensure that all generic drugs—which make up nearly 80 percent of prescriptions filled in the United States—are safe, effective, of high quality, and interchangeable with the brand name drug product/reference listed drug.
 
Please join me in welcoming Dr. Geba to this important position. We welcome the wealth of knowledge and experience that he will bring to the organization.

By Alexander J. Varond –

After more than three years, FDA approved a class-wide Risk Evaluation and Mitigation Strategy (“REMS”) for extended-release and long-acting (“ER/LA”) opioid analgesics on July 9, 2012.  The ER/LA opioid REMS applies to more than 20 companies and 30 products, and while it includes a shared implementation program, each opioid product REMS is to be written and approved as an individual document.

In this post, we first briefly discuss the history of the program’s development and then explain the implications of the new class-wide REMS.

A long road for a rather dull REMS.  On February 6, 2009, FDA sent letters of ER/LA opioid analgesics detailing the need for a new REMS.  During a media briefing on February 9, 2009, FDA officials expressed the agency’s ambitious plan to develop a class-wide opioids REMS and further expressed that the program was “going to be the largest risk management effort [FDA had ever] undertaken.”  Rightly so, FDA announced it was taking on an effort aimed at addressing the nation’s growing prescription drug abuse epidemic.  During the media briefing, FDA also intimated that it was actively exploring requiring mandatory training for prescribers and developing a more restrictive distribution system. 

In February 2009, FDA felt it had a “pretty good outline” of what the REMS should include but took steps to consult with stakeholders, health professionals, and patient advocacy groups about the new REMS.  After collecting information from these groups, FDA planned to write letters to manufacturers and explain the requirements for the new REMS.  Within six months of the letters’ issuance, FDA expected companies to implement the REMS.

More than two years later, in April 2011, FDA finally sent letters to manufacturers of ER/LA opioids detailing its requirements for a new REMS program.  We discussed those requirements here.

Now, more than three years after beginning the opioid REM process, the final REMS is completed and amounts to essentially a mere education and monitoring program.  Additionally, despite FDA’s statement in 2009 that “voluntary programs have not been successful in getting us where we need to go with maintaining access to legitimate patients and dramatically decreasing the serious adverse event reports,” the healthcare professional education provided by the REMS is in fact voluntary. 

It is clear that, in 2009, the agency underestimated both (1) the complexity of creating a program that did not adversely affect patients in need of pain management and (2) the difficulty associated in creating a class-wide REMS program with many manufacturers.  FDA also miscalculated its authority to create a mandatory training program (FDA later considered its ability to create a mandatory training system but decided that it would need a grant of legislative power to create such a system).

Moreover, FDA did not anticipate the resistance (here and here) it would receive from healthcare professionals and patient advocacy groups against mandatory training or restrictive distribution systems.  These groups urged the agency not to require a REMS that was overly burdensome or jeopardized patient access to ER/LA opioid analgesics.

FDA’s decision not to impose mandatory education on prescribers or patients highlights the agency’s “step-wise approach” and emphasizes the difficulty it faces in reducing prescription drug abuse while maintaining access to patients with legitimate needs.  Moreover, the approximately 41-month timeframe it took to develop the LA/ER opioid analgesics REMS program reveals the difficulty FDA faces in coordinating class-wide and shared REMS programs of this nature.

FDA’s Blueprint for a house it’s not completely satisfied with.  Under the approved REMS, drug manufacturers are required to pay accredited continuing education ("CE") companies to independently develop and provide voluntary 2-3 hour ER/LA opioid training programs to prescribers in accordance with FDA’s “Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.”

The training will focus on developing prescriber knowledge about ER/LA opioid analgesic therapy in the following categories: assessing patients for treatment; initiating therapy, modifying dosing, and discontinuing use; managing therapy; counseling patients and caregivers about safe use; general drug information about ER/LA opioid analgesics; and specific drug information.  Additionally, prescribers will be counseled on how to recognize evidence of and potential for opioid misuse, abuse, and addiction.

Manufacturers will also be expected to provide a patient counseling document for prescribers to give to patients, helping prescribers to properly counsel patients on their responsibilities for using ER/LA opioid analgesics safely and an updated one-page Medication Guide that pharmacists will include when dispensing the drug that contains consumer-friendly information on the safe use and disposal of the medicines.

The first CE programs must be offered to prescribers by March 1, 2013.  FDA also expects 25% of the nation’s estimated 320,000 prescribers to be educated by year one, 50% by year two, and 60% within three years.  The REMS includes additional assessment metrics which include the number of grants awarded to CE providers, the number of prescribers trained, patient knowledge of risk information, and the effect on access to patients with legitimate needs for ER/LA opioid analgesics.

During the announcement of the REMS, Margaret Hamburg, Commissioner of FDA, and R. Gil Kerlikowske, Director of National Drug Control Policy, expressed a desire that these efforts to curb prescription drug abuse would be bolstered by future legislation to make opioid analgesic training mandatory.

Earlier this week, President Obama signed into law the Food and Drug Administration Safety and Innovation Act (“FDASIA”) (usually pronounced “fuh-day-zha”).  In addition to reauthorizing and amending several drug and medical device provisions that were scheduled to sunset, FDASIA establishes new user fee statutes for generic drugs and biosimilars.  FDASIA also equips FDA with tools intended to expedite the development and review of innovative new medicines that address certain unmet medical needs, and with new authority concerning drug shortages, among other things.  The law significantly changes the FDC Act and the PHS Act in several respects that will have considerable short- and long-term effects on the regulated industry.

Hyman, Phelps & McNamara, P.C. has prepared a detailed summary and analysis of FDASIA.  The memorandum summarizes each section of FDASIA and analyzes the new law’s potential effects on the FDA-regulated industry. 

FDASIA includes 11 titles, the first 5 of which concern drug and medical device user fee and pediatric-related programs.  Title VI includes myriad changes to the law styled as medical device regulatory improvements.  Title VII makes significant changes to enhance FDA’s inspection authority and the drug supply chain.  Title VIII creates incentives to encourage the development of products for antibiotic-resistant infections.  Title IX expands the scope of products that qualify for accelerated approval and creates a new “breakthrough therapy” program, among other things.  Title X is intended to legislatively address the current drug shortage crisis.  Finally, Title XI reauthorizes certain provisions created by the FDA Amendments Act of 2007, provides for the regulation of medical gases, and includes several miscellaneous provisions, such as provisions on prescription drug abuse, 180-day generic drug marketing exclusivity, citizen petitions, controlled substances, and nanotechnology to name a few. 

By Douglas B. Farquhar –

In a long-awaited ruling, a federal judge has upheld FDA’s decision to grant approval to the generic version of Xibrom®, an ophthalmic product for treatment after cataract surgery (active ingredient: bromfenac).

The opinion was issued Monday by Judge James Gwin of the Northern District of Ohio (substituting for Judge Emmet Sullivan in this case, which was brought in the U.S. District Court for the District of Columbia).  The decision disposes of a challenge brought by ISTA Pharmaceuticals, Inc. to FDA’s grant of approval to an Abbreviated New Drug Application (“ANDA”) filed by Coastal Pharmaceuticals.  In the litigation, our firm represented Metrics, Inc., doing business as Coastal Pharmaceuticals, and Mylan Pharmaceuticals Inc., which markets the generic product.

Bromfenac had an unusual approval history.  After securing approval for and marketing a twice-a-day brand product, which was called “Xibrom,” ISTA sought and secured approval for a product administered once a day, called “Bromday®.”  Xibrom and Bromday have the same indication, the same active ingredient, and the same dosage strength.  Prior to the approval of Bromday, Coastal filed its ANDA seeking approval of a twice-daily product.  ISTA then filed a Citizen Petition with FDA seeking that any generics for the twice-daily product should be denied on the grounds that labeling for the new product, Bromday, replaced the labeling for the older product, Xibrom (see our previous post here).  ISTA argued that the ANDA could not be approved unless it included labeling that was identical to the current labeling of the product, and ISTA claimed that the “current labeling” for the product was the once-daily instructions for use, for which ISTA had an exclusivity period.

FDA disagreed.  On May 11, 2011, FDA granted approval to the Coastal ANDA, and denied the ISTA Citizen Petition.  FDA, in its response to the Citizen Petition, stated that Xibrom and Bromday are two different products, and, although ISTA had withdrawn Xibrom from the market, the product was not withdrawn for reasons of safety or efficacy, which would have prohibited its use as the “Reference Listed Drug” for an ANDA.

ISTA then promptly filed a lawsuit seeking a Temporary Restraining Order (“TRO”) that would have prohibited the generic product from being distributed.  Mylan and Metrics intervened as parties in the litigation.  ISTA failed to secure a TRO, and filed an Amended Complaint that added allegations related to FDA’s discussions about whether an ophthalmic product could safely treat two eyes with the same bottle, because of concerns about cross-infection if the dropper touches the eye’s surface.  Coastal’s generic product was approved in two sizes, 2.5ml and 5ml, with the larger size containing enough medication to treat two eyes twice a day for the prescribed period.
 
Judge Gwin addressed each of ISTA’s arguments in his 9-page opinion.  He pointed to ISTA’s public statements that implied that Xibrom and Bromday were two different products, and noted that Xibrom and Bromday were both on the market for a period of months.  He also found that, although ISTA argued in the litigation that Xibrom was removed for reasons of safety and efficacy, ISTA “never indicated that Xibrom was unsafe or ineffective” while the agency was considering whether to grant Coastal’s ANDA.  He noted that FDA has requested some manufacturers of ophthalmic products to “voluntarily change their labels” to address “some ongoing concerns about improper consumer usage and cross-contamination of post-operative eyes,” but FDA has not yet required such changes to be made.  Copies of the ISTA and FDA briefs are available here and here. 

By Kurt R. Karst – 

In a decision that, unless appealed, marks the end of AstraZeneca Pharmaceuticals LP’s (“AstraZeneca’s”) battle with FDA over the approval of generic versions of the company’s blockbuster antipsychotic drug SEROQUEL (quetiapine fumarate) Tablets, the U.S. District Court for the District of Columbia granted FDA’s Motion for Summary Judgment and denied AstraZeneca’s Cross-Motion for Summary Judgment.  At the heart of the case is a controversy over the applicability and scope of 3-year exclusivity based on FDA’s simultaneous approval of supplemental NDAs (“sNDAs”) that contained information on pediatric uses of quetiapine and that made changes to the drug’s labeling to add “Table 2” of the Warnings section regarding “general safety information that is not indication-specific.”

As we previously reported (here and here), the court battle with FDA started around mid-March when AstraZeneca sought to enjoin FDA from granting final ANDA approvals for generic SEROQUEL after FDA denied without comment two citizen petitions AstraZeneca submitted to FDA last year concerning labeling carve-out issues for generic versions of SEROQUEL (as well as an extended-release version of the drug, SEROQUEL XR (quetiapine fumarate) Extended-Release Tablets.  The DC District Court denied AstraZeneca’s Application for Prelimiary Injunction and dismissed the action without prejudice, saying that it was premature.  Just days later, FDA approved several ANDAs for generic SEROQUEL, and AstraZeneca filed a second lawsuit seeking to vacate FDA’s ANDA approvals and to enjoin FDA from granting any further final ANDA approvals.  The DC District Court promptly denied AstraZeneca’s Motion for Temporary Restraining Order; however, the case progressed to the summary judgment stage. 

AstraZeneca argued that under the plain language of FDC Act § 505(j)(5)(F)(iv), the company is entitled to a period of 3-year marketing exclusivity for the Table 2 information until December 2, 2012, plus 6 months if you count in pediatric exclusivity.  (FDA previously determined that such information could not be omitted from generic drug labeling.)  According to AstraZeneca, the court’s analysis should begin and end at Chevron Step One, because the plain language of the FDC Act says that “if (1) there is an approved sNDA containing reports of new clinical investigations sponsored or conducted by the applicant that were essential to the approval of the sNDA, then (2) the sNDA applicant has three years of exclusivity over a ‘change approved in the supplement.’”  And because, according to AstraZeneca, the sNDAs FDA approved for SEROQUEL on December 2, 2009 included reports of new clinical investigations that were essential to the approval of the sNDAs, the Table 2 labeling change FDA approved at that time is entitled to 3-year exclusivity.  AstraZeneca also argued that independent of the pediatric sNDAs FDA approved, Table 2 deserves exclusivity on its own merit because it “contains reports of new clinical investigations” conducted by AstraZeneca that were “essential to approval” of the labeling change “approved in the supplement.”

FDA, following the explanation provided in the Agency’s March 27, 2012 Letter Decision, primarily argued that the scope of 3-year exclusivity relates to the scope of new clinical investigations conducted by the NDA sponsor.  That is, the FDC Act sets up a “logical relationship between the change in the product for which the new clinical investigations were essential to approval of the supplement, and the scope of any resulting three-year exclusivity.”  According to FDA, “AstraZeneca reads the statute to provide for exclusivity for any labeling change, even if the change was initially submitted through general correspondence (and not a supplement), and it was unrelated to the purpose for which the supplement was submitted, and the change occurred only coincidentally and contemporaneously with the changes relating to the new clinical investigations that were the subject of the supplements.”

Finding FDC Act § 505(j)(5)(F)(iv) ambiguous, Judge Beryl A. Howell moved on to Chevron Step Two where she concluded that FDA’s interpretation of the statute – i.e., “that a substantive relationship between new clinical studies and changes in the supplement, not the format of a submission, dictates what changes receive exclusivity” – is reasonable for three reasons: “First, the administrative record shows that the pediatric supplements were approved on their own merits based upon clinical investigations unrelated to the Table 2 labeling change, which standing alone does not entitle AstraZeneca to exclusivity.  Second, the FDA’s interpretation of the statute is largely consistent with past practice, and therefore not arbitrary and capricious. Third, the FDA’s interpretation is consistent with the legislative history” while AstraZeneca’s interpretation would disrupt the careful balance Congress crafted with the Hatch-Waxman Amendments by warranting evergreening of exclusivity.

FDA did not get off scot-free, however.  Following her previous criticism that the case record “strongly suggests that the FDA has made ‘tactical decision[s]’ to prevent the plaintiff ‘from seeking judicial review of FDA’s legal position,’” and that FDA engaged in tactics of “hiding the ball” of its position on the approval of generic SEROQUEL until March 27, 2012 (which FDA objected to in footnote 17 of the Agency’s brief), Judge Howell included in her opinion comments critical of FDA’s handling of the exclusivity decision.  Judge Howell also suggested that “FDA could in the future minimize misunderstanding about which approved change warrants an exclusivity period, prompted by the ambiguity in the statute, by more carefully and precisely delineating at the time of the approval — in separate communications if necessary — those changes in an sNDA that warrant an exclusivity period and those changes that do not.”  This is not a bad idea.  After all, Orange Book exclusivity codes do not provide such depth and are only shorthand for what a period of 3-year exclusivity actually covers.

By Kurt R. Karst –      

In a rare lawsuit against FDA involving the Orphan Drug Act of 1983, as amended, K-V Pharmaceutical Company (“KV”) and its wholly-owned subsidiary, Ther-Rx Corporation (“Ther-Rx”), filed a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction in the U.S. District Court for the District of Columbia last week.  The Plaintiffs are seeking temporary, preliminary, and permanent declaratory and injunctive relief to “restore” Plaintiffs’ orphan drug exclusivity for MAKENA (hydroxyprogesterone caproate) Injection, 250 mg/mL. 

FDA approved MAKENA on February 3, 2011 under NDA No. 021945 “to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.”  Because FDA had previously designated MAKENA (formerly known as GESTIVA) as an orphan drug for the approved indication, the Agency granted KV a period of 7-year orphan drug exclusivity that expires on February 3, 2018.  (On the same day that FDA approved MAKENA, the Agency denied a Citizen Petition – Docket No. FDA-2007-P-0051 – requesting that FDA revoke the orphan drug designation.)  Orphan drug exclusivity prevents FDA from approving another company’s version of the “same drug” for the same disease or condition for 7 years, unless the subsequent drug is different from the approved orphan drug, or because the sponsor of the first approved product either cannot assure the availability of sufficient quantities of the drug or consents to the approval of other applications. 

For several years, hydroxyprogesterone caproate injection, also known as “17p,” has been made available to women at risk of preterm birth by compounding pharmacies that compound the drug.  In some cases, product is reportedly imported into the U.S.  FDA’s policy (see Compliance Policy Guide 460.200), issued in the wake of the U.S. Supreme Court’s April 2002 decision in Thompson v. Western States Medical Center, 535 U.S. 357 (2002) striking down as unconstitutional certain provisions of FDC Act § 503A concerning pharmacy compounding, is generally not to permit pharmacy compounding of drugs that are commercially available and approved by FDA. Nevertheless, in a move that stunned many (including us – see here and here), FDA issued a press release on March 30, 2011 stating, in relevant part, that “[i]n order to support access to this important drug, at this time and under this unique situation, FDA does not intend to take enforcement action against pharmacies that compound hydroxyprogesterone caproate based on a valid prescription for an individually identified patient unless the compounded products are unsafe, of substandard quality, or are not being compounded in accordance with appropriate standards for compounding sterile products.”  Within hours of FDA issuing its press release (referred to by Plaintiffs as the “Statement”), the Centers for Medicare & Medicaid Services (“CMS”) issued its own statement informing States and Medicaid payers that they “can choose to pay for the extemporaneously compounded hydroxyprogesterone caproate” notwithstanding the availability of MAKENA.  The FDA and CMS statements followed some controversy concerning the price of MAKENA that sparked interest from some members of Congress. 

FDA issued further public statements on MAKENA on November 8, 2011 and June 15, 2012 (here and here), and CMS issued an updated statement on June 15, 2012 in light of some analyses conducted on compounded 17p.  FDA also issued a “Questions and Answers” document on June 29, 2012 discussing the Agency’s risk-based approach to enforcement action against compounding pharmacies and with respect to compounded 17p.  Plaintiffs allege in their Complaint, however, that “[n]one of these statements has announced an intent to take enforcement action against unlawful compounded 17P that is not customized to meet the special needs of individual patients who have the condition for which Makena, a drug that has statutory market exclusivity, is indicated but for whom Makena is medically inappropriate.”  Moreover, Plaintiffs allege that “FDA’s Statement and policy are part of a plan . . . to make unapproved, unlawful, but cheaper, compounded versions of 17P available in the marketplace, despite the statutory market exclusivity that applies to Makena . . . .”

KV and Ther-Rx allege myriad violatations of the law by FDA, including the Administrative Procedure Act, the FDC Act, and the Due Process Clause of the Fifth Amendment to the U.S. Constitution.  Specifically, Plaintiffs allege, among other things, that FDA’s Statement and the policy it sets forth:

• “violate [FDC Act § 527(a)] by effectively nullifying Makena’s statutory seven-year period of market exclusivity by giving de facto approval to compounded versions of 17P that are intended for use to treat the same indication for which Makena is designated as an orphan drug and is approved, and that are not customized to meet the medical needs of individual patients who have the condition for which Makena is indicated but for whom Makena is not medically appropriate”;

• are contrary to the express limitations on compounding set forth in FDC Act § 503A;

• “approve, authorize, invite, encourage, and permit the introduction, and delivery for introduction, into interstate commerce of unapproved new drugs” in violation of FDC Act §§ 505(a) and 301(d), which prohibit the marketing of a new drug without an effective approval; and 

• violate FDC Act § 801(a), which requires FDA to refuse importation of any drug that appears to be unapproved in violation of the new drug approval requirements at FDC Act § 505.  The D.C. District Court recently ruled in Beaty v. FDA that FDC Act § 801(a) requires FDA to deny admission to a drug offered for import that appears to be a adulterated, misbranded, or in violation of Section 355 (see our previous post here).

Judge Amy Berman Jackson, who recently ruled against FDA in a case involving PDUFA user fees (see our previous post here), has been assigned the case.  A Motions Hearing is scheduled for August 7, 2012. 

REMINDER:  You can follow us on Twitter @fdalawblog.

By Kurt R. Karst –      

In a notice that will publish in the Federal Register later this week, FDA, citing safety concerns, will announce the Agency’s plans to take enforcement action against all unapproved single-ingredient, immediate-release human drug products containing Oxycodone HCl for oral administration, and persons who manufacture or cause the manufacture or distribution of such products in interstate commerce.  The announced move is part of FDA’s “Unapproved Drugs Initiative.”  It follows a March 2009 FDA enforcement action concerning several marketed unapproved narcotic drug products, including unapproved single-entity, immediate-release oxycodone tablets (but specifically excluding oxycodone capsules).  Since then, FDA has approved an NDA for Oxycodone HCl Capsules, 5 mg (NDA No. 200534), an NDA for Oxycodone HCl Oral Solution, 100 mg/5 mL (NDA No. 200535), and an NDA for Oxycodone HCl Oral Solution, 5 mg/5mL (NDA No. 201194). 

According to FDA, unapproved drug products containing Oxycodone HCL, a derivative of opium and a Schedule II controlled substance, “pose particular safety concerns because of their potential for addiction.”  FDA illustrates this point by citing several examples of marketed unapproved Oxycodone HCL drug products where the labeling allegedly omits “critical information,” such as information in the “Indications and Usage,” “Dosage and Administration,” and “Warnings and Precautions” labeling sections.  Moreover, says FDA, the Agency “has received reports of medication errors associated with unapproved oxycodone products and the strength of the active ingredient,” such as cases where the wrong dose of Oxycodone HCl Oral Solution was administered “due to the visual similarity of the container labels and carton labeling of the two product strengths.”

As to the legal status of unapproved single-ingredient, immediate-release drug products containing Oxycodone HCl for oral administration, FDA has determined that they are “new drugs” requiring the approval of a marketing application.  “In no case did FDA find literature sufficient to support a determination that any of these products is generally recognized as safe and effective.”  Earlier this year, Lannett Company, Inc. and Cody Laboratories, Inc. (collectively “Lannett”) submitted a citizen petition to FDA (Docket No. FDA-2012-P-0189) requesting that the Agency affirm, pursuant to the 1938 “grandfather clause” of the FDC Act, the grandfather status of certain Oxycodone HCl and Cocaine HCl drug products, including Lannett’s Oxycodone HCL Oral CONCENTRATE Solution, 20 mg/mL (see our previous post here).  On the same day FDA announced the Agency's plans to take enforcement action with respect to certain single-entity Ocycodone HCl drug products, FDA denied Lannett's petition with respect to Oxycodone HCl.  FDA's decision discusses two principal grounds for denying the petition: “First, we reject your implicit contention that oxycodone HCI products as a class are 'grandfathered' under the 1938 grandfather clause.  Furthermore, the evidence provided with your petition is inadequate to demonstrate that Lannett's Oxycodone HCI Product meets the requirements of the 1938 grandfather clause.” 

Lannett has previously challenged FDA in court on the grandfather/new drug status of another product the company marketed without approval – Morphine Sulfate Oral Solution.  In that case, the U.S. Court of Appeals for the Tenth Circuit affirmed a November 2010 decision from the U.S. District Court for the District of Wyoming granting FDA’s Motion to Dismiss the lawsuit.  In doing so, the Tenth Circuit refused to reach the merits of Lannett’s grandfather drug claim, stating, in relevant part, that “we cannot reach the merits of [Lannett’s] grandfathering claim unless the FDA has engaged in 'final agency action' under the APA. . . .  [Lannett’s] failure to avail itself of available administrative remedies [(i.e., use of the citizen petition process)] defeats its claim . . . ."  Subsequently, Lannett petitioned FDA on the grandfather status of Morphine Sulfate Oral Solution, perhaps in an effort to obtain final agency action from which to launch a new lawsuit (see our previous post here).  Although FDA has not yet substantively responded to that petition, now that Lannett has final agency action on its citizen petition with respect to Oxycodone HCl, a lawsuit challenging FDA on grandfather status might not be far off.   

With respect to when and how FDA will take enforcement action against companies marketing unapproved Oxycodone HCl drug products subject to the Agency's notice, the Agency says that it “does not expect to issue a warning letter or any other further warning to firms marketing drug products covered by this notice before taking enforcement action.”  Any drug product covered by FDA’s notice that a company (including a manufacturer or distributor) began marketing after September 19, 2011 – the proverbial “line in the sand” FDA drew in the Agency’s most recent iteration of its Marketed Unapproved Drugs Compliance Policy Guide – “is subject to immediate enforcement action.”  Products first marketed on or before September 19, 2011, that are not listed with FDA in compliance with FDC Act § 510 before July 6, 2012, and that are introduced or delivered for introduction into interstate commerce after July 6, 2012 are subject to enforcement action.  A product listed in full compliance with FDC Act § 510 that is not being “commercially used or sold” in the United States before July 6, 2012, but that is introduced or delivered for introduction into interstate commerce after July 6, 2012 is also subject to enforcement action. 

The one caveat is that FDA will exercise limited enforcement discretion for what the Agency terms a “currently marketed and listed product,” which includes a drug product covered by the notice that a company began marketing in the United States on or before September 19, 2011.  For such currently marketed and listed products, FDA says that the Agency intends to excercise enforcement discretion with respect to a product that is manufactured on or after the date that is 45 days after July 6, 2012, or that is shipped on or after the date that is 90 days after July 6, 2012.  After those dates, FDA says that the Agency will take enforcement action (e.g., seizure, injunction, or other judicial or administrative proceeding).

By Jamie K. Wolszon –

Five years ago, Congress passed the FDA Amendments Act of 2007 (“FDAAA”), requiring FDA to promulgate regulations establishing a Unique Device Identifier (“UDI”) system to facilitate adverse event and recall tracking.  Under FDAAA, the UDI regulations must require an identifier on the label of each medical device specific enough to identify the device through distribution and use, unless FDA specifies an alternative location or makes an exception for a particular device or group of devices.  The law also states that the unique identifier may include the lot or serial number. 

Until recently, FDA solicited general public comment and held public workshops, but not much more (see here).  In particular, FDA had not issued a proposed rule.  The FDA Safety and Innovation Act (“FDASIA”) requires FDA to issue a proposed rule establishing a UDI system by December 31, 2012.  FDA must publish the final rule no later than 6 months after the close of the comment period, and must implement the final regulations for implantable, life-saving and life-sustaining devices no later than two years after FDA promulgates the rule, “taking into account patient access.”  FDC Act § 519(f), as amended by FDASIA § 614. 

FDA is now ahead of schedule.  After the House and Senate had passed the legislation, but before the President had signed it, FDA unveiled a proposed rule to implement the UDI mandate. 

FDA’s proposed rule breaks the UDI into two portions: (1) a device identifier, which identifies the specific version or model of the device and the labeler, and (2) a production identifier, which includes the current production information for a device such as the lot or batch, the serial number, expiration, or date of manufacture.  FDA would require that any organization wishing to issue UDIs receive FDA accreditation. 

Each UDI must be provided in plain text and in a form that uses “automatic identification and data capture” (“AIDC”) technology, according to the proposed rule.  AIDC is any technology (such as bar code, radio-frequency identification, or near field communication) that conveys the UDI or device identifier in a form that can be entered into an electronic patient record or other computer systems via an automated process.  FDA’s proposed rule would require submission of device information into a publicly available database, the Global Unique Device Identification Database (“GUDID”).  The GUDID will not contain any identifying patient information.

For certain categories of devices, FDA would require the UDI to be placed on the device itself instead of just the labeling: That requirement is proposed for devices that are used for extended periods of time and are likely to become separated from their labeling, including an implantable device, a device that is intended for reuse, and stand-alone software devices. 

FDA is proposing to exempt several categories of devices.  The rule would exempt over-the-counter devices sold at retail establishments; devices delivered directly to hospitals and other health care facilities; class I devices exempted by regulation from the Quality Systems Requirements in 21 C.F.R. § Part 820; products used solely for research, teaching, or chemical analysis and not intended for any clinical use; custom devices; investigational devices; veterinary medical devices; devices intended for export; devices held by the Strategic National Stockpile; and devices for which FDA has established a performance standard.  The production identifier would not be required for any class I devices.  In addition to the exempt categories, a labeler may request an exception or propose an alternative that would provide for more effective identification of a device. 

FDA has provided a 120-day comment period. A final rule would be phased-in over a multi-year period based on the level of risk of the device.  UDI labeling requirements would take effect beginning one year after the promulgation of the final rule for class III devices and devices licensed under the Public Health Service Act; beginning three years after the promulgation of the final rule for class II devices; and beginning five years after the promulgation of the final rule for class I and devices that are not classified. 

The marking requirement would go into effect two years after the base UDI labeling requirement goes into effect for that device; for example, for an implantable device that was class III, the marking requirement would go into effect three years from the promulgation of the final rule.

In addition to the UDI requirements, the proposed rule also proposes requiring a standard format to use on the medical device label whenever the label contains certain dates.

By Ricardo Carvajal –

We raised this question at the recent ABA Section of Litigation Food & Supplements Second Annual Workshop as a way of commenting on emerging threads of resistance to the imposition of greater food safety-related requirements at all levels of government, but especially at the federal level.  It appears that questions are arising as to whether some requirements and restrictions proposed or imposed in the name of food safety go too far.  Sometimes the questions are raised in defense of specific foods such as raw oysters and raw milk, but they have also arisen in support of more broad based movements mounted under the banner of food freedom.  In some instances, concerns have been expressed about the attendant costs – including potential unintended consequences (e.g., destruction of wildlife habitat and a rise in allergic and autoimmune disorders as a result of efforts to eradicate pathogens from the food supply). 

We happily leave it to others to resolve any underlying scientific issues, but it seems to us that the voices of resistance are only likely to increase as implementation of FSMA goes forward and the full impact of that law is felt throughout the chain of food production and distribution.  At that point, the issue of how the government assesses progress on food safety could make a bid for center stage.  The issue is far from trivial.  Two years ago, FDA, FSIS, and CDC held public meetings to gather information on food safety metrics.  Shortly thereafter (and presumably coincidentally), CDC published a revised estimate of the toll of foodborne illness which suggested that the previous estimate of deaths associated with foodborne illness was too high – the very same estimate that was bandied about in Congressional deliberations leading up to the passage of FSMA.

Questions as to how the government assesses potential food safety risks also could sharpen.  You may recall that FSMA’s provision on preventive controls requires the owner, operator, or agent in charge of a facility to identify and evaluate known or reasonably foreseeable hazards that may be associated with the facility.  In some instances, there could be significant divergence between a manufacturer’s and the government’s assessment of whether a given hazard is reasonably foreseeable and thereby worthy of further analysis and possible mitigation.  Given the consequences that could flow from that assessment, we expect debates over the standard of “reasonable foreseeability” to be spirited. 

By Ricardo Carvajal –

In several letters issued to trade associations on June 18th (for an example, see here), FDA stated that it “will expect to enforce compliance” with the preventive controls provision in section 103 of the Food Safety Modernization Act ("FSMA") and the foreign supplier verification provision in FSMA section 301 “in timeframes that will be described in the final rules.”  Given that the proposed rules for those provisions have yet to publish, it is clear that industry will have substantial additional time to come into compliance with the requirements in those provisions.  However, that time will not be unlimited.  If the delay in publication of proposed and final rules proves too protracted, consumer advocates can be expected to put FDA’s feet to the fire. 

By JP Ellison & Jennifer M. Thomas –

If you have ever sat in a meeting, received a letter or brief, or otherwise heard an interpretation from a regulatory agency that surprised, confounded or frustrated you, then you should read the Supreme Court’s recent decisions in Christopher v. SmithKline Beecham Corp., No. 11-204, 567 U.S. — (June 18, 2012) and FCC v. Fox Television Stations, Inc., No. 10-1293 (June 21, 2012).  If you don’t have the time or inclination to wade into these decisions, we will explain why they are significant rulings for companies regulated by FDA and other federal agencies. 

Both decisions give teeth and expanded reach to the often-cited principle that the Due Process Clause of the Fifth Amendment to the United States Constitution requires that federal agencies provide “fair warning” or “fair notice” of required or prohibited conduct.  While neither decision involved an agency before which we regularly appear, the cases should have significant implications for FDA, FTC, DEA, and other regulatory agencies. 

Companies frequently battle with government agencies when: (1) A company disagrees with an agency interpretation of law that the agency put forth after the company engaged in some business practice or decision without the benefit of knowing the agency’s current interpretation; or (2) the government files an enforcement action against the company alleging violations of law, but the government did not set forth its interpretation before the company engaged in the allegedly unlawful conduct. 

In Christopher v. SmithKline Beecham Corp., the question before the Court was the interpretation of the statutory phrase “in the capacity of outside salesman” with respect to pharmaceutical detailers.  The task of interpreting that phrase was delegated to the Department of Labor ("DOL"), which had issued regulations.  Those regulations did not address how the phrase applied to pharmaceutical detailers.  In 2009, in an amicus brief, the DOL first articulated its view that pharmaceuticals detailers were not employed in the capacity of outside salespersons, and thus were entitled to overtime pay.  The agency later altered its interpretation on several occasions.  Despite acknowledging that the regulation at issue was ambiguous, and that Supreme Court precedent typically calls for deference to an agency’s interpretation of its own ambiguous regulations, the Court withheld giving the agency’s decision any deference.  The Court ruled:

Petitioners invoke the DOL’s interpretation of ambiguous regulations to impose potentially massive liability on respondent for conduct that occurred well before that interpretation was announced. To defer to the agency’s interpretation in this circumstance would seriously undermine the principle that agencies should provide regulated parties fair warning of the conduct [a regulation] prohibits or requires. 

The Court cited cases that had applied the “fair warning” principle in the context of enforcement or penalty actions brought by a federal regulatory agency.  However, notably, in Christopher v. SmithKline Beecham Corp., there was no agency enforcement action.  Instead, the issue of the agency’s interpretation arose in the context of potential  “massive liability” in a private lawsuit.  The Court also noted that when an agency announcement of its interpretation of a statute or regulation is preceded by a very lengthy period of “conspicuous inaction” in terms of government enforcement actions, “the potential for unfair surprise is acute.”  This enforcement inactivity by the government in the face of a practice that may be occurring in an entire industry suggests, according to the Court, that the practice was not even unlawful.  This is often the case in many FDA interpretations.  

In addition, the Court criticized the practice of government agencies promulgating “vague and open-ended regulations that they can later interpret as they see fit, thereby ‘frustrat[ing] the notice and predictability purposes of rulemaking.’”

The Court also warned that it “is one thing to expect regulated parties to conform their conduct to an agency’s interpretations once the agency announces them; it is quite another to require regulated parties to divine the agency’s interpretations in advance or else be held liable when the agency announces its interpretations for the first time in an enforcement proceeding and demand deference.”

The application by the Court of the “fair warning” doctrine in this context demonstrates that it can be validly raised outside the traditional enforcement context, and that various types of significant expenses could trigger “fair warning” scrutiny.  For example, a change in agency practice or position that requires additional expense in obtaining an approval might raise these same constitutional concerns.  Certainly, civil or criminal penalties, injunctions, or forfeiture actions would continue to be subject to the fair warning requirement.  We are confident that the Court’s ruling would apply in many other contexts.

FCC v. Fox Television Station, Inc. concerned whether the FCC could apply its current position — that the fleeting use of expletives violates the FCC’s indecency standards—to conduct that occurred before the FCC articulated that new policy.  The Court concluded that under the FCC’s “old” policy, fleeting expletives were not actionable.  The Court had previously concluded that the FCC’s decision to modify its policy was not arbitrary and capricious.  On its second review of the case, the Court reached the constitutional question.  The Court held that the FCC’s enforcement actions were invalid because they ran afoul of the fair notice/fair warning constitutional requirement.  The Court explained: “[a]  conviction or punishment fails to comply with due process if the statute or regulation under which it is obtained ‘fails to provide a person of ordinary intelligence fair notice of what is prohibited, or is so standardless that it authorizes or encourages seriously discriminatory enforcement.’”  In further describing the constitutional underpinnings of this doctrine, the Court explained that it was animated by “two connected but discrete due process concerns: first, that regulated parties should know what is required of them so they may act accordingly; second, precision and guidance are necessary so that those enforcing the law do not act in an arbitrary or discriminatory way.”

Significant to the Fox decision is the Court’s mandate that due process not only demands some level of clarity by the agency, but also that even if clear, the standard must be sufficiently precise as to not promote arbitrary or discriminatory enforcement.  Query whether, for example, a corporate defendant could argue that the misdemeanor provisions of the FDC Act fail to satisfy this standard for a prosecution against a regulated entity or whether responsible corporate officer facing a Park prosecution could argue that FDA’s guidance in the Regulatory Procedures Manual for a such prosecutions, does not pass constitutional muster. 

A company or individual might argue that because it is entirely within the government’s discretion whether an alleged FDC violation should result in enforcement discretion,  a warning letter, consent decree, or criminal prosecution is, in this regard,  “so standardless that it authorizes or encourages seriously discriminatory enforcement.”  Similarly, why can not companies facing these FDA actions defend by arguing that the conduct the government now claims is unlawful was not preceded by a prior clear public articulation of the government’s position?

Indeed, we expect that particularly in the context of a criminal case, a defendant facing charges now stands a much better chance of acquittal by articulating the principles set forth in these cases.  Individuals and companies will have increased incentives to take their chances at trial, much like as occurred in a decision that we explained in a recent post.     

In Fox, the Court also addressed an argument by the government that there was no constitutional violation because no penalty had been assessed against Fox, and moreover, the FCC had represented that “it would not consider the indecent broadcasts  “in any context.”  Despite this “policy of forbearance”—akin to FDA “enforcement discretion” the Court found that the constitutional issue was appropriately before the Court.  In reaching that conclusion, the Court noted that because the agency had the statutory authority to consider the conduct, its representation that it would not was “insufficient to remedy the constitutional violation.”  The Court’s analysis in this regard is important because it suggests that a constitutional “fair notice” challenge can be brought against agency action even when there is no immediate injury to the regulated person or entity, if the agency has the authority to later cite it against the company—such as when FDA recites prior 483 observations, in a later complaint for a permanent injunction.  When coupled with the Court’s decision in Sackett earlier this term regarding when allegedly non-final agency action can be challenged (see our previous post here), this aspect of Fox should provide additional support for companies seeking to challenge new or novel interpretations by regulatory agencies.

Christopher v. SmithKline Beecham Corp. and FCC v. Fox Television Stations, Inc., provide clear and dramatic support for arguments that can be brought to bear to challenge unwarranted agency action.  Because neither case involved FDA, the Court rulings’ application in the FDA context is somewhat uncertain.  However, these rulings present opportunities for companies and individuals and their counsel to carefully craft legal and factual arguments to challenge the government when it violates these Due process “fair notice” requirements.  

By Kurt R. Karst –       

Earlier this week, the Presidential Commission for the Study of Bioethical Issues (“Commission”) announced in a Federal Register notice that it is seeking comment on several ethical issues associated with the development of medical countermeasures for children.  The announcement follows an October 2011 report from the National Biodefense Science Board, titled “Challenges in the Use of Anthrax Vaccine Adsorbed (AVA) in the Pediatric Population as a Component of Post-Exposure Prophylaxis,” in which the Board recommended that the Department of Health and Human Services (“HHS”) move forward with testing AVA before a public health emergency, but only after certain ethical considerations are adequately addressed and reviewed.  Earlier this year, HHS Secretary Kathleen Sebelius asked the Commission to “conduct a thorough review of the ethical considerations of conducting clinical trials of medical countermeasures in children,” including with AVA. 

The Commission is interested in public comment on myriad issues, but specifically:

• How to conceptualize and consider risk and societal value when reviewing pediatric clinical research in general and for medical countermeasures in particular;

• The types of information, data, or facts needed to ensure evidence-based decision-making for conducting pediatric medical countermeasure research;

• Possible criteria, if any, that might classify proposed studies testing medical countermeasures for pediatric use as minimal risk;

• Ethical issues related to access to and allocation of medical countermeasures previously studied within pediatric populations in a public health emergency;

• Scientific and public health strategies that could minimize the risk or ethical concerns associated with pediatric medical countermeasure research;

• Strategies for communicating risk to prospective participants and their families; and

• The role communities play in the design and support of pediatric research and pediatric medical countermeasure research.

Over the past decade – since the anthrax attacks in late 2001 – FDA has played a key role in facilitating the development of medical countermeasures.  In addition to establishing the current Office of Counterterrorism and Emerging Threats, which, among other things, coordinates FDA’s Medical Countermeasures Initiative, FDA finalized regulations in May 2002 know as the “Animal Efficacy Rule.”  

The Animal Efficacy Rule provides that under certain circumstances, and where where human efficacy trials are not feasible or ethical, animal studies can be relied on to provide substantial evidence of effectiveness of a drug or biological product (21 C.F.R.  Part 314, Subpart I and 21 C.F.R. Part 601, Subpart H).  Evaluation of the product for safety in humans is still required, and cannot be addressed by animal studies alone.  In addition, approval under the Animal Efficacy Rule is subject to certain postapproval commitments. 

Only a few products have been approved under the Animal Efficacy Rule, beginning with the February 2003 approval of NDA No. 020414 for pyridostigmine bromide to increase survival after exposure to Soman "nerve gas" poisoning.  More recently, in April 2012, FDA approved NDA supplements for LEVAQUIN (levofloxacin) Injection, Tablets, and Oral Solution for the treatment and prophylaxis of plague due to Yersinia pestis in adults and pediatric patients 6 months of age and older. 

The lack of use of the Animal Efficacy Rule may be due to certain challenges, including the unavailability of qualified animal models that can predict efficacy of new drugs or biologics.  In 2011, the National Research Council prepared a consensus report, titled “Animal Models for Assessing Countermeasures to Bioterrorism Agents,” which addresses the challenges stemming from developing and testing medical countermeasures against biothreat agents in animal models, and that makes several recommendations.

By John A. Gilbert, Karla L. Palmer & Larry K. Houck –

The Food and Drug Administration Safety and Innovation Act (“FDASIA”) (S. 3187), which is on its way to the President for enactment after the Senate passed the bill by a 92-4 vote, may impact the scheduling of hydrocodone products, but not by the same means as Senator Joe Manchin’s (D-WV) earlier-introduced bill, S. 2297.

Senator Manchin introduced S.2297 in April of this year to amend the Controlled Substances Act (“CSA”) by legislatively rescheduling hydrocodone combination products from their current schedule III to the more restrictive schedule II.  This rescheduling would affect popular hydrocodone combination products such as Vicodin, Lortab, Lorcet, Norco, Hycodan and Vicoprofen.  (Bulk and single entity hydrocodone products have been classified in schedule II since the passage of the CSA in 1970).

Rescheduling hydrocodone combination products would impact every legitimate controlled substance handler including patients who rely on the products for pain relief.  The rescheduling would subject manufacturers, distributors, dispensers such as pharmacies and physicians, importers and exporters to more stringent regulatory requirements.  For example, schedule II substances can only be transferred between registrants via a triplicate, sequentially-numbered DEA Form 222 Official Order Form or its electronic equivalent while registrants need only document transfers of schedule III-V drugs with invoices, packing slips or other records.  Prescriptions for schedule II substances, with limited exceptions, must be written, and pharmacies must have the original prescriptions in-hand before dispensing.  Prescriptions for schedule III-V may be in a written, oral or faxed format.  Pharmacists cannot refill schedule II prescriptions; but they can, if authorized to do so, refill schedule III-V prescriptions up to five times within a six month period.  Manufacturers and distributors must secure schedule II substances in a safe, steel cabinet or vault while schedule III-V substances may be stored in a less secure controlled substance cage or other enclosure.

The legislative attempt to reschedule hydrocodone combination products quickly ran into significant and vocal opposition from numerous patient advocacy and pharmacy groups.  Several pharmacy groups including the National Association of Chain Drug Stores and the Generic Pharmaceutical Association, and the American Medical Association, have expressed concerns that rescheduling would unduly restrict legitimate patient access to needed medications and impose burdens upon pharmacies.

Thus, instead of legislatively rescheduling hydrocodone combination products from schedule III to schedule II as set forth in S.2297, FDASIA calls for the Secretary of Health and Human Services to hold a public meeting not later than 60 days after the enactment of the Act to assist the FDA with its scheduling recommendation to DEA for hydrocodone products.  If enacted, the law would require FDA to solicit input from stakeholders including patients, healthcare providers and others “regarding the health benefits and risks, including the potential for abuse and the impact of up-scheduling these products.”  Whether by legislative fiat or administrative action, the impact of rescheduling hydrocodone is significant, as noted above.

On a related note, FDA published notice of a public meeting of the Drug Safety and Risk Management Committee to be held at the FDA White Oak Campus on October 29 and 30, 2012.  77 Fed. Reg. 34,051 (June 8, 2012).  The Federal Register Notice states that purpose of the meeting is to discuss “the public health benefits and risks, including the potential for abuse, of drugs containing hydrocodone either combined with other analgesics or as an antitussive.”  The notice also states that FDA is calling for the meeting because DEA requested the Department of Health and Human Services to conduct a scientific and medical evaluation, and scheduling recommendation, for hydrocodone combination products, “in response to continued reports of misuse, abuse, and addiction related to these products.”  Interested persons can submit data, information and viewpoints orally or in writing.  Electronic and written submissions must be submitted on or before October 15, 2012.

This process may ultimately conclude with the DEA determining to reschedule hydrocodone combination products from schedule III to II pursuant to 21 U.S.C. §§ 811 and 812.  However, unlike the scuttled legislative rescheduling process, the administrative rescheduling process requires notice and public comment, and DEA’s analysis of eight statutory factors prior to rescheduling.  DEA must consider the following eight factors for rescheduling hydrocodone combination products (or any substance):  (1) Actual or relative potential for abuse; (2) scientific evidence of the substance’s pharmacological effects; (3) the state of the current scientific knowledge about the substance; (4) history and current pattern of abuse; (5) scope, duration and significance of abuse; (6) risk to the public health; (7) psychic or physiological dependence liability; and (8) whether the substance is an immediate precursor to an already controlled substance.  21 U.S.C. § 811(c).

Notwithstanding instigating an administrative process to reschedule hydrocodone combination products, FDASIA seeks to legislatively place dozens of synthetic cannabinoids in schedule I of the CSA (without the administrative notice and comment rulemaking, the eight-factor analysis or DEA’s use of emergency scheduling powers).  In a section dubbed the “Synthetic Drug Abuse Prevention Act of 2012,”  FDASIA’s enactment would place certain psychedelic/hallucinogenic dimethoxyphenethylamine drugs and synthetic cannabinoids into schedule I.  Schedule I controlled substances have a high potential for abuse and no recognized medical use in the United States.  In addition, the proposed law if passed would define the term “cannabimimetic agent,” and establish criteria for the control of similar cannabinoid compounds that meet the statutory definition.

FDASIA also seeks to double the term from 18 to 36 months DEA’s emergency authority to temporarily schedule substances in schedule I to avoid imminent hazard to the public health.  DEA exercised its emergency scheduling authority twice in the past two years to temporarily place in schedule I certain substances including some of the cannabinoids now subject to scheduling by FDASIA, in schedule I.  See DEA’s Press Release announcing the addition of 26 synthetic drugs to schedule I.