By Kurt R. Karst & Frank J. Sasinowski –      

A Senate floor amendment to the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (H.R. 2997) would establish within FDA two new review groups to recommend solutions for the prevention, diagnosis, and treatment of rare diseases and neglected diseases of the developing world.  The amendment, reportedly backed by recently-confirmed NIH Director Dr. Francis Collins, and co-sponsored by Senators Sam Brownback (R-KS) and Sherrod Brown (D-OH), was first proposed in the Senate in July, and was agreed to on August 3; however, we understand that the amendment could be further changed in Conference Committee. 

The Brown/Brownback Amendment follows recent significant discussions about how to improve the process for developing and approving products for rare and neglected diseases.  In May 2009, the National Organization for Rare Disorders (“NORD”) held a “Partners in Progress Summit” at which thought leaders, including Dr. Collins, several FDAers, and Hyman, Phelps & McNamara, P.C.’s Frank Sasinowski, discussed ways to encourage innovative research and ensure that patients have access to treatments for rare disorders.  In addition, the non-profit Kakkis EveryLife Foundation has advocated for a new Office of Drug Evaluation for Rare Biochemical and Genetic Disorders as part of a larger science driven regulatory policy approach to accelerate treatments for rare diseases.  Dr. Emil Kakkis, President of the Foundation, told FDA Law Blog that “We are pleased with the support of Dr. Collins and Sen. Brownback in advocating for practical changes at the FDA, and with the broad support we have received from others for our initiatives.”  

Under the Brown/Brownback Amendment, which is included as Section 745 in H.R. 2997, the FDA Commissioner may establish within the Agency “a review group which shall recommend to the Commissioner of Food and Drugs appropriate preclinical, trial design, and regulatory paradigms and optimal solutions for the prevention, diagnosis, and treatment of rare diseases.”  The rare disease review group would be composed of 8 FDA employees who must have “specific expertise relating to the development of articles for use in the prevention, diagnosis, or treatment of rare diseases, including specific expertise in developing or carrying out clinical trials.”

With respect to “neglected diseases of the developing world” (i.e., “tropical diseases” as defined in FDC Act § 524(a)(3) concerning priority review vouchers), the FDA Commissioner may establish within the Agency “a review group which shall recommend to the Commissioner of Food and Drugs appropriate preclinical, trial design, and regulatory paradigms and optimal solutions for the prevention, diagnosis, and treatment of neglected diseases of the developing world.”  The neglected diseases review group would also be composed of 8 FDA employees, but who have “expertise relating to the development of articles for use in the prevention, diagnosis, or treatment of neglected diseases of the developing world, including specific expertise in developing or carrying out clinical trials.”

The Brown/Brownback Amendment also requires FDA to submit a report to Congress describing the Agency’s findings and recommendations of the rare and neglected disease review groups, and to issue guidance and develop internal review standards based on their recommendations.

The Brown/Brownback Amendment appears to be a more evolved and specific version of language included in the Senate Report accompanying the version of the Agriculture/FDA Appropriations Bill introduced in the Senate (S. 1406).  The Senate Report accompanying S. 1406 stated:

Neglected Diseases.— The Committee is concerned about the challenge of increasing the number of approved treatments for diseases that, although not necessarily rare, may have few if any therapeutic options.  The Committee recognizes that the definition of a rare disease or condition under the Orphan Drug Act includes many tropical diseases or conditions that affect more than 200,000 persons in the United States.

Because the Orphan Drug Act already embraces therapies to treat many tropical diseases, the Committee urges FDA to take active steps to stimulate orphan status and support their development.  Where appropriate, FDA should engage in partnerships and collaborations to identify compounds that may be suitable to treat this subset of orphan diseases and work in a proactive way to identify compounds to treat such diseases.

Sens. Brown and Brownback have a longstanding interest in backing neglected disease product development.  They are the authors of  FDC Act § 524 – “Priority Review to Encourage Treatments for Tropical Diseases” – that was added to the statute by the 2007 FDA Amendments Act.  FDC Act § 524 provides for a transferable priority review program – the so-called “treat and trade” program – in which applicants for certain new drugs and biologics for “tropical diseases” that have received priority review may receive a priority review voucher entitling the holder to a 6-month priority FDA review of another application that would otherwise be reviewed under FDA’s standard 10-month review clock.  As we previously reported,  FDA granted the first priority review voucher earlier this year when it approved COARTEM (artemether; lumefantrine) for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least five kilograms. 

By JP Ellison –

With the seemingly endless flow of news reports announcing yet another unsealed False Claims Act (“FCA”) case, and the regular announcement of FCA settlements for what would have only a few years ago been unheard of amounts, it is easy to lose sight of the complexity of the FCA and the issues that plaintiffs and defendants must navigate in such cases.  The 1st Circuit’s recent decision in United States ex rel Duxbury v. Ortho Biotech Products serves as a reminder that prosecuting and defending FCA cases raises a host of complicated factual and legal issues.

The Duxbury case concerned allegations of unlawful promotion of the drug Procrit.  The qui tam relators alleged that the unlawful promotion included publication of an “inflated” average wholesale price (“AWP”), marketing the “spread,” offering kickbacks to providers, and promoting the drug for off-label use.

The complicated factual and procedural history of the case (and related FCA cases) implicated several provisions of the FCA.  First, the court addressed the FCA’s jurisdictional public disclosure bar, and the distinct but related issue of whether the relators fit within the original source exception to the public disclosure bar.  In resolving this issue, the 1st Circuit joined the 4th Circuit in holding that the plain language of the FCA requires a relator to provide information to the government before filing an action that is based on the information, but did not adopt more stringent requirements imposed by other circuits. 

In reaching this conclusion, the 1st Circuit discussed the alternative interpretations adopted by the 2nd and 9th Circuits (relator must be the source to entity that publicly disclosed) and the D.C. and 6th Circuits (information must be provided before any public disclosure).  In explaining the basis for its decision, the 1st Circuit examined the structure and history of the FCA along with the statute’s plain language and in the process identified several of the public policy issues raised by the FCA.

The second issue that the court addressed was whether the amended complaint met the requirement of pleading fraud with particularity as required under Federal Rule of Civil Procedure 9(b).  On this point, the Court distinguished its recent ruling in United States ex rel. Rost v. Pfizer, Inc., 507 F.3d 720, 733 (1st Cir. 2007).  See our prior postings discussing the Rost case here, here, and here.  Beyond distinguishing Rost, and ruling in Duxbury that the complaint met the fraud with particularity requirement, without identifying specific claims, the Court offered little guidance for the future.  Indeed, the Court specifically stated that it was “‘limit[ing its] holding to the facts.’”

The last issue addressed by the court was whether the FCA’s’ “first to file” bar required the dismissal of off-label allegations contained in an amended complaint.  In concluding that the off-label allegations were barred by the first to file rule, the court compared the original and amended complaints filed by the relators and also looked at another complaint filed by a different relator that had been filed after the original complaint but before the amended complaint.  Based on this analysis, the court held that the original complaint did not contain the essential facts of the alleged off-label promotion scheme, and as a result, such allegations in the amended complaint were barred by an earlier filed complaint in another action.

In light of the intensely fact specific analysis in Duxbury, the case raises more questions than it answers.  Those questions are present in many FCA cases and warrant careful attention from any counsel handling such a case.

By Susan J. Matthees –

FDA has published a new draft guidance titled Guidance for Industry: Labeling of Certain Beers Subject to the Labeling Jurisdiction of the Food and Drug Administration.  Last month we reported that the Alcohol and Tobacco Tax and Trade Bureau ("TTB") issued a ruling clarifying that certain beer drinks that are not made from both malted barley and hops (e.g., beer made with sorghum, rice, or wheat), are not malt beverages as defined by the Federal Alcohol Administration Act ("FAA Act").  As such, these products are subject to the labeling requirements of the FDC Act. 

FDA’s draft guidance is intended to help industry comply with the labeling requirements for these products.  The guidance document explains that beer must conform to the requirements set forth in 21 C.F.R. Part 101.  These requirements include a statement of identity, which FDA explains “can be similar to the statement of composition that is required for malt beverages . . . such as ‘Beer made from sorghum’ or ‘Sorghum Beer;’” the net quantity of contents; the name and place of business of the manufacturer; packer, or distributor; a statement of ingredients; and nutrition labeling, unless exempt under 21 C.F.R. § 101.9(j).  In addition, beers subject to the FDC Act must include allergen labeling pursuant to FDC Act §§ 201(qq) and 403(w)(1).  Beer must also comply with FDA requirements for food additives, color additives, and ingredients. 

FDA understands that manufactures will need time to change their labels.  FDA has stated that it will exercise enforcement discretion until January 1, 2012 to give time to manufacturers to revise their labels.  However, the Agency recommends that manufacturers change their labels at the next printing or use stickers to place on the labels in the short term.

By Ricardo Carvajal –

Last year, a New Jersey district court held in favor of federal preemption of a state law consumer fraud claim against the manufacturer of a beverage that contains high fructose corn syrup (HFCS) and is labeled as “all natural” (see Holk v. Snapple Beverage Corp., 574 F.Supp.2d 447 (D.N.J. 2008)).  Last week, the Third Circuit reversed.  According to the appellate court, neither FDA’s policy statement on the use of “natural” nor correspondence issued by FDA that addresses the use of “natural” in the labeling of foods that contain HFCS “have the force of law required to preempt conflicting state law.”  The appellate court held that plaintiff’s claims are thus not impliedly preempted (defendant waived the question of whether the claims are expressly preempted).

Earlier this year, a California district court similarly ruled that there is no federal preemption of an unfair competition claim against the manufacturer of a food that contains high fructose corn syrup ("HFCS") and is labeled as “all natural” (see our prior post here).  That court rejected as unpersuasive the reasoning relied on by the New Jersey district court in Holk to hold in favor of preemption.  Evidently, the Third Circuit also was not persuaded.   Although it’s too early to declare the issue settled, the climb for those who would argue in favor of preemption in cases such as these appears to be getting steeper.

By Ricardo Carvajal & JP Ellison –

It’s been a busy month at the Alliance for Natural Health.  In addition to suing FDA over its handling of health claims, the Alliance (in conjunction with other plaintiffs) has sued FDA to invalidate certain provisions of the agency’s Current Good Manufacturing Practice (“CGMP”) regulation for dietary supplements.  In part, the complaint maintains that FDA cannot lawfully issue a regulation under FDCA section 402(g) that deems a dietary supplement adulterated unless that supplement violates FDCA section 402(f) (under section 402(f)(1)(A), a dietary supplement is adulterated if it presents a significant or unreasonable risk of illness or injury under the conditions of use recommended or suggested in labeling, or in the absence of those conditions, under ordinary conditions of use).  The complaint takes aim at the many recordkeeping requirements imposed under the regulation, and the fact that a dietary supplement can be deemed adulterated if any of those requirements is not met.

FDA has issued other regulations that deem certain foods adulterated if specified recordkeeping requirements are not met.  Generally, those regulations are partially grounded in FDCA section 402(a)(4), which deems a food adulterated if it has been processed, packed, or held "under conditions whereby it may have been rendered injurious to health.”  FDA’s reasoning has been that appropriate recordkeeping is essential to ensure that those foods are not produced under conditions that might render them injurious to health.  By comparison, section 402(g) deems a supplement adulterated if it has been prepared, packed, or held "under conditions that do not meet current good manufacturing practice regulations.”  Section 402(g) authorizes FDA to issue CGMP regulations for dietary supplements that are “modeled after current good manufacturing practices for food.”  Thus, there is no explicit reference in section 402(g) to the potential for injury to health.  FDA can therefore be expected to argue that is has considerable discretion in fashioning GMP requirements for dietary supplements, and that those requirements need not be contingent on the potential for injury to health.

An issue likely to be central to resolution of the case is whether the CGMP requirements imposed by FDA under the authority of section 402(g) derive from the text of the statute, in which case they would pass muster under step one of Chevron USA, Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837 (1984), or are grounded in a reasonable interpretation of that text, in which case they would pass muster under Chevron step two.  The complaint appears to take the position that the CGMP regulation fails under Chevron step one.  FDA will argue that the regulatory analysis should be conducted under Chevron step two, in which case FDA's interpretation of section 402(g) would be entitled to substantial deference.

The case is Alliance for Natural Health US et al. v. Sebelius et al., No. 1:09-cv-01523-CKK (D.D.C. filed August 12, 2009)

By Michelle L. Butler – 

Today, August 14, 2009, is the anniversary of the passage of the Consumer Product Safety Improvement Act of 2008 (“CPSIA”), which means that a number of new requirements will go into effect.  It also means that the Consumer Product Safety Commission (“Commission” or “CPSC”) continues to promulgate rules and statements of policy as it continues to implement the various CPSIA requirements. 

First, the CPSIA requires the lead content of children’s products (products designed or intended primarily for use by children 12 and younger) to be reduced from 600 parts per million (“ppm”) to 300 ppm on August 14, 2009.  A draft of a final rule to address determinations that certain materials do not exceed the lead content limit was recently submitted to the Commissioners seeking their approval to publish the rule in the Federal Register.  (The Ballot Vote Sheet identified a due date of August 13, 2009 for the Commissioners to vote whether to publish the document in the Federal Register – as of now, the results have not been posted on the CPSC website.)  The draft final rule identified specific categories of materials that do not exceed the lead content limits as long as the materials have not been treated or adulterated with the addition of materials that could result in the addition of lead:  certain precious and semiprecious gemstones; natural or cultured pearls; wood; paper and similar materials made from wood; certain printing inks; textiles (excluding after-treatment applications, including screen prints, transfers, decals, or other prints) consisting of certain dyed or undyed natural fibers and certain manufactured dyed or undyed fibers; and other plant-derived and animal-derived materials.  The draft final rule also identified certain metals and alloys that do not exceed the lead content limits.  The preamble to the draft final discussed certain component parts that would not be exempt from the lead content limits, such as zippers, buttons, and other applied decorations, and which therefore would continue to be subject to the lead content limit and testing and certification requirements.  The preamble also stated that the Commission is aware that there are many questions regarding component part testing and certification and that it would address these issues in an upcoming rulemaking.

The CPSC also issued a final interpretative rule providing guidance as to what product components or classes of components are considered inaccessible such that the lead content limits do not apply.  The final rule references the accessibility probes specified in the sharp points or edges regulations, as well as the use and abuse tests for various age groups in existing regulations.

Second, the CPSIA increased the maximum civil penalties applicable to each knowing violation of the Consumer Product Safety Act (“CPSA”), Federal Hazardous Substances Act (“FHSA”), and Flammable Fabrics Act (“FFA”) from $8,000 to $100,000.  The CPSIA also increased the maximum penalty amounts for any related series of violations from $1,825,000 to $15,000,000.  These increased civil penalty amounts go into effect August 14, 2009.  The CPSIA also required the Commission to issue by August 14, 2009 a final regulation providing its interpretation of civil penalty factors in the CPSA, FHSA, and FFA.  On August 7, 2009, a Ballot Vote Sheet with a return date of August 13, 2009 was submitted to the Commissioners regarding publication of an interim final rule interpreting the factors to be considered when seeking civil penalties and withdrawal of a previously proposed interpretive rule on civil penalty factors.  The results of the vote have not yet been published on the CPSC website.  The interim final rule would be effective upon publication since the increased penalties went into effect on August 14, 2009.

The Commission also recently issued a statement of policy regarding testing of component parts for phthalates in children’s toys and child care products.  The Commission determined that the phthalate limits in the CPSIA apply to each component part of a product rather than the product as a whole.  The Commission stated that it believed this is supported by the language of the CPSIA and is more protective of public health.  The Commission also recently published a Standard Operating Procedure for the Determination of Phthalates (Test Method: CPSC-CH-C1001-09.2) in toys and child care products.

Finally, the Commission continues to request input from interested parties in a number of areas.  For example, the Commission is required by the CPSIA to examine and assess, in consultation with consumer groups, juvenile product manufacturers, and independent child product engineers and experts, the effectiveness of the ASTM toy safety standard, ASTM-F963-07.  Accordingly, in July, the Commission issued a request for comments on this topic, which are due by August 20, 2009.  The Commission will also be holding a public hearing to receive views concerning its agenda, priorities, and current strategic plan for fiscal year 2011 (which begins October 1, 2010).  This hearing will begin on August 25, 2009 at 10 am.  Participation by members of the public is invited, and requests to make oral presentations (as well as the written text of any such presentations) must be received by the Office of the Secretary no later than 5 pm on August 18, 2009. 

This is not a catalog of all ongoing activities by the CPSC, but rather provides a look at some of the activities that are keeping the CPSC so busy these days.

By Susan J. Matthees –

The Federal Trade Commission (“FTC”) recently announced that an Administration Law Judge (“ALJ”) upheld FTC’s charges against a company, Daniel Chapter One, and its officer, James Feijo, for making claims that its shark cartilage and herbal supplements prevent, treat, and cure cancer. 

The ALJ wrote that the company “did not possess or rely upon competent and reliable scientific evidence to substantiate their claims.”  The ALJ ordered the company and its officer to stop making claims that their products inhibit tumor growth, eliminate tumors, treat or cure cancel, or heal the effect of radiation or chemotherapy unless the claims are true, not misleading, and based on reliable scientific evidence.  

The FTC first charged Daniel Chapter One in September 2008 as part of the FTC’s Operation False Cures, an enforcement initiative against companies that market false cancer remedies.  In September, the FTC announced actions against 11 different companies allegedly making unsupported claims to cure, treat, or prevent cancer.  Six of the companies targeted in the sweep settled with the FTC and the remaining 5, including Daniel Chapter One, were sued.

By Ricardo Carvajal –

In conjunction with other plaintiffs, the Alliance for Natural Health has filed suit in the D.C. district court challenging FDA’s denial of plaintiffs’ petition for the use of four qualified health claims for selenium and certain forms of cancer, and FDA’s imposition of an unfavorable disclaimer on the use of a fifth claim.  Plaintiffs contend that FDA’s actions violate their First Amendment rights to communicate “scientific information vital to those who seek to reduce their risks of certain kinds of cancers through dietary means.”  Plaintiffs ask the court to declare invalid FDA’s final order denying their petition for the claims and to enjoin FDA from taking any action to preclude their use of the claims in the labeling of dietary supplements.  This is the latest in a string of actions that have been brought against the agency over its handling of health claims, some of which have been successful (see Whitaker v. Thompson, 248 F.Supp.2d 1 (D.D.C. 2002) (Whitaker I) and the cases cited therein, but see Whitaker v. Thompson, 239 F.Supp.2d 43 (D.D.C. 2003), aff'd. 353 F.3d 947 (D.C.Cir. 2004), cert denied 543 U.S. 925 (Whitaker II)).

The complaint presents a fundamental challenge to FDA’s current approach to the regulation of qualified health claims, which the agency developed in the wake of Whitaker I and its antecedents.  First, plaintiffs take issue with FDA’s refusal to consider more than 90% of the publications submitted in support of plaintiffs’ petition.  In its consideration of qualified health claim petitions, FDA routinely excludes a significant number of publications that the agency deems for one reason or another to be irrelevant.  Second, based on prior judicial opinions, plaintiffs contend that FDA can deny use of a claim only in two instances: when “no evidence” supports the claim, or when “evidence in support of the claim is qualitatively weaker than evidence against the claim – for example, where the claim rests on only one or two old studies.”  Even then, FDA must first “demonstrate with empirical evidence that disclaimers. . . would bewilder consumers and fail to correct for deceptiveness.”  Plaintiffs maintain that FDA has failed to meet this burden.  Third, plaintiffs contend that FDA is “constructively suppressing” claims through the “imposition of an onerous, value laden set of qualifications that only allow Plaintiffs to propound a false, negatively value-laden, and inaccurate claim to the public.” 

The case is Alliance for Natural Health US et al. v. Sebelius et al., No. 1:09-cv-01470 (D.D.C. filed August 4, 2009).

By Kurt R. Karst –      

On August 12th, FDA announced the publication of final regulations concerning “Expanded Access to Investigational Drugs for Treatment Use” and “Charging for Investigational Drugs Under an Investigational New Drug Application.”  Both rules will be officially published in the August 13th Federal Register.  In addition, FDA launched a new website where patients and their health care professionals can learn about options for accessing investigational drugs. 

According to FDA, the “Expanded Access” final rule “clarifies existing regulations and adds new types of expanded access for treatment use.”  In particular:

Under the final rule, expanded access to investigational drugs for treatment use will be available to:

• individual patients, including in emergencies  
• intermediate-size patient populations  
• larger populations under a treatment protocol or treatment investigational new drug application (IND) 

It is intended to improve access to investigational drugs for patients with serious or immediately life-threatening diseases or conditions who lack other therapeutic options and who may benefit from such therapies. . . .

The “Charging Rule” revises FDA’s regulation, and will, according to FDA:

• clarify the circumstances under which charging for an investigational drug in a clinical trial is appropriate, 
• set forth criteria for charging for an investigational drug for the different types of expanded access for treatment use described in FDA's final rule on expanded access for treatment use of investigational drugs, and 
• clarify what costs can be recovered.

The rule permits charging for a broader range of investigational and expanded access uses than is explicitly permitted in current regulations.

Stay tuned for additional analysis of these new regulations . . . .

By Carmelina G. Allis –

The FDA has issued a Federal Register notice announcing a program that establishes a timeframe for the submission and agency review of responses to Form FDA-483s before the agency’s issuance of Warning Letters.  This announcement is in line with our prior report regarding the new FDA Commissioner’s promises to intensify the agency’s enforcement program.

After issuance of a 483, it is not uncommon for inspected establishments to submit a written response to FDA describing their intent to correct the observations listed in the 483.  Such responses, however, which can sometimes result in numerous correspondences over a period of many months, generally help delay FDA’s issuance of a Warning Letter.  It has been the agency’s practice not to issue a Warning Letter if the company is not a serious or repeat offender, and the 483 written response appears to indicate that the company has implemented most corrective actions and shows the company’s good-faith effort to comply with FDA’s regulations.  That is, in general, FDA will not issue a Warning Letter until it has completed its review of the company’s 483 response.

That practice, however, will soon come to an end.  As of September 15, 2009, FDA will start a new program where it will allow a company 15 business days to respond to a 483 from the date of issuance of the 483.  If the response is received within those 15 business days, FDA will conduct a detailed review of the response before determining whether to issue a Warning Letter.  If the agency decides to issue the Warning Letter after reviewing the company’s timely response, the Warning Letter will recognize receipt of the response and contain a reply as to the apparent adequacy of the company’s corrective actions set forth in its response.  If FDA receives a 483 response more than 15 days after the 483 was issued, the agency will not likely delay the issuance of a Warning Letter in order to review the 483 response.

These procedures have been prompted by the efforts of Dr. Margaret A. Hamburg, the new FDA Commissioner, to step up the agency’s enforcement program.  Along with those efforts, Dr. Hamburg recently promised that the agency will issue “close-out notices” to those companies that fully correct violations.  This Federal Register notice, however, fails to explain whether FDA will implement such a program, or whether companies should expect to receive such letters after satisfactorily addressing FDA’s observations.

FDA will conduct an assessment of this program after 18 months, and will then decide whether to implement it permanently.  The announcement fails to identify the criteria that the agency will evaluate that will serve as indicators that the program has been successful.  The stated goal of the program is to facilitate the agency’s timely issuance of Warning Letters.

By Kurt R. Karst –   

Earlier this week, Astellas Pharma US, Inc. (“Astellas”) filed a Complaint and an accompanying Memorandum of Points and Authorities in the U.S. District Court for the District of Columbia requesting declaratory and injunctive relief in connection with FDA’s response to a citizen petition and approval of an ANDA for a generic version of Astellas’ PROGRAF (tacrolimus).  Astellas had previously announced in a company press release that it planned to sue FDA over the petition decision.

FDA’s August 10, 2009 decision substantially denied a September 21, 2007 citizen petition submitted by Astellas requesting that the Agency take certain actions related to orally administered immunosuppressants used in the transplant population – and in particular, PROGRAF.  Specifically, the Astellas petition requested that FDA, with respect to orally administered immunosuppressants “characterized by a narrow therapeutic index”:

(1) Require bioequivalence studies in healthy subjects be supplemented by studies performed in the transplant patient population.  (FDA’s draft guidance document for bioequivalence testing of tacrolimus recommends that bioequivalence be demonstrated in two single-dose studies in healthy volunteers.);

(2) Require additional warnings and precautions in drug product labeling that physicians must be notified whenever a substituted oral formulation is about to be provided to a transplant patient;

(3) Add to the Orange Book Preface (§ 1.8 – Description of Special Situations) a discussion of narrow therapeutic index immunosuppressive drugs for use in transplant patients that highlights the “particular risks associated with switching patients among different oral formulations of immunosuppressants, such as tacrolimus;” and

(4) Require manufacturers of substitute oral formulations to “differentiate between strengths by color of capsule and container closure, to provide prominent dosage strength information, and to clearly differentiate between sources so that patients, physicians and pharmacists know when the sourcing has changed” in order to “reduce the potential for medication errors associated with confusion regarding strengths and sourcing of different formulations.”

FDA’s August 10th petition decision substantially denied Astellas’ requests.  FDA ruled that bioequivalence studies in the transplant patient population are not justified, and that with respect to tacrolimus, “there is insufficient scientific evidence to suggest that the use of specific patient population(s) in bioequivalence studies would detect differences in formulation that might have clinical significance and that would not be detected by bioequivalence studies in healthy subjects.”  (Also, concerning Astellas’ claim that tacromilus is characterized by a narrow therapeutic index – i.e., a product with a narrow margin of safety between doses that are therapeutic and doses that are toxic – FDA notes that “[w]hile tacrolimus is a drug product that requires careful dosage titration and monitoring of patient blood levels, FDA has not made a determination whether to characterize tacrolimus as a narrow therapeutic range drug product,” but that the Agency “is confident that it has established suffcient criteria to determine bioequivalence for tacrolimus whether or not the agency subsequently decides to characterize tacrolimus as a narrow therapeutic range drug product.”)

FDA also denied Astellas’ request for labeling changes, stating that they are not needed and that “[t]he current review process for ANDAs is adequate to assure the interchangeability of generic versions of immunosuppressant drugs such as tacrolimus with their branded counterparts.”  In addition, FDA disagreed that the Orange Book Preface should be amended, and that manufacturers should be required to differentiate between product source.  FDA did agree, however, that “it is important to differentiate between strengths for immunosuppressants,” and said that the Agency “will ensure that different strengths of a generic version of these drug products are differentiated by appropriate means (e.g., the use of unique color and/or adequate documentation of dosage strength information in the labeling).” 

Astellas’ complaint challenges FDA’s decisions concerning bioequivalence study requirements, product labeling, and source differentiation, as well as FDA’s decision to approve an ANDA for a generic version of PROGRAF.  The complaint alleges that FDA’s petition denial and and generic approval decision violate the Administrative Procedure Act, the FDC Act, and FDA’s regulations, by “failing to require bioequivalence testing in transplanted patients because meeting the FDA-established bioequivalence standards in studies with only healthy volunteers will not sufficiently predict the pharmacokinetics observedwhen tacrolimus is administered to trransplant patients,” and by “failing to require that the label of Prograf and any approved generic alert physicians and patients to the risks associated with substituting formulations of tacrolimus and to any change in the source of manufacturing.”  The company requests declaratory and injunctive relief requiring FDA to revoke ANDA approval. 

UPDATES: 

• On August 12, FDA filed its opposition memorandum, and the court issued an Order denying Astellas' TRO/PI motion.  A memorandum opinion will soon follow.  An Astellas press release issued after the court's order states that the company is evaluating its options.
• The district court's Memorandum Opinion was issued on August 17th and is available here.

By Jamie K. Wolszon & Ricardo Carvajal –

FDA has published three draft guidances that instruct growers, packers, processors, transporters, retailers and others on the prevention of microbial hazards in tomatoes, melons, and leafy greens.  According to FDA’s press release, Dr. Hamburg stated that the guidances “will be made final as soon as possible after public comment, and will be followed within two years by enforceable standards for fresh produce.”  Coincidentally, the guidances were published on the heels of House passage of the Food Safety Enhancement Act (“FSEA”) of 2009 (see our post here).  Section 104 of FSEA would explicitly authorize FDA to establish by regulation science-based standards for the safe growing, harvesting, packing, sorting, transporting, and holding of raw agricultural commodities for which FDA has determined that such standards are needed to minimize the risk of serious adverse health consequences or death to humans or animals.  Although FDA has now made clear its intention to establish such standards based on its existing statutory authority, FSEA could help make it easier for FDA to fulfill the Commissioner’s commitment to establish those standards within two years by providing FDA with more explicit authority.

The three new guidances target the risks inherent to specific types of commodities.  However, all three guidances reference the agency’s 1998 draft guidance that more generally describes good agricultural practices or GAPs (see FDA’s Guide to Minimize Microbial Food Safety Hazards for Fresh Fruits and Vegetables).  Notably, section 104 of FSEA calls on the agency to update its GAP guidance.  The three new guidances also reference FDA’s Current Good Manufacturing Practices Regulations, as well as the agency’s Guide to Minimize Microbial Food Safety Hazards of Fresh-cut Fruits and Vegetables (these are minimally processed and altered in form prior to being packaged for use by the consumer or retail establishment such as ready-to-eat salad mixes).  The three new guidances complement, rather than replace, these pre-existing recommendations and requirements.
 
For each of the three guidances, the agency examined pre-existing industry guidelines on the specific commodities as a foundation for its own guidance.  The guidances recommend measures specifically crafted to ward against risks likely to occur during production and harvest, post harvest, fresh-cut processing, distribution and retail and food service.  The guidances address environmental assessments, worker health and hygiene, water quality, product tracing and records at these stages along the food supply chain.  For instance, the guidances contain suggestions for adequate toilet facilities and handwashing, convincing sick workers to stay home, ensuring that water used to wash plants is not contaminated, deterring contamination from animals or other elements on soil, ensuring the equipment and transports are not contaminated, and establishing appropriate use of gloves.

Comments on the guidances should be submitted by November 3 at www.regulations.gov using docket numbers FDA-2009-D-0346 (tomatoes), FDA-2009-D-0347 (melons), or FDA-2009-0348 (leafy greens).

FDA Law Blog welcomes back to the blogosphere our friend Scott Hensley, formerly of the Wall Street Journal (where he was the founding editor and a regular contributor to the paper’s Health Blog).  Scott will be blogging at the National Public Radio Health Blog and appearing on NPR as well.  The NPR Health Blog covers news about health and medicine, including FDA-related issues, and is written and reported by NPR’s Science Desk.

By Douglas B. Farquhar –

In an August 6, 2009 speech at an event sponsored by the Food and Drug Law Institute, Margaret A. Hamburg, M.D., the new FDA Commissioner, promised to ratchet up enforcement by speeding up issuance of Warning Letters, reducing the amount of time that industry has to respond to notices of violations, and landing on repeat violators quickly and severely.  However, she also offered a reward to cited companies who respond expeditiously and effectively, in FDA’s view.  She promised that companies which fully correct violations cited in a Warning Letter will receive a “close-out notice,” which will be posted on the FDA website, documenting that the companies have achieved a state of compliance (trumpets sound and choirs sing).  (A copy of FDA's press release announcing Dr. Hamburg's speech and enforcement vision is available here.) 

Warning Letters have traditionally been FDA’s most potent weapon against FDA-regulated industry, short of the agency seeking an injunction, initiating criminal prosecutions, or persuading state officials to shut down a company.  Hundreds of Warning Letters, which are publicly available, are issued every year to food processors, drug manufacturers or distributors, investigators in clinical trials, medical device manufacturers, pharmacies, and Institutional Review Boards (IRBs) which monitor clinical trials.  The agency routinely follows up on Warning Letters with inspections to ensure that corrective actions have been taken.  Enforcement officials at FDA have repeatedly said that if violative conditions cited in Warning Letters are not corrected, the agency will proceed to more significant enforcement measures, including those listed above, or, if available, import detentions.

Noting a “steep decline in the FDA’s enforcement activity over the past several years,” Dr. Hamburg said that many enforcement actions have been “hampered by unreasonable delays.”  She focused primarily on the issuance and resolution of Warning Letters.  Although companies routinely have, by agreement with FDA officials, 30 to 60 days to respond to inspectional reports (Form 483s) citing violations of FDA regulations, she said that, from now on, cited companies will “generally have no more than fifteen working days in which to respond,” thus speeding up the issuance of Warning Letters when responses do not satisfy FDA’s concerns.  Her speech re-emphasized past pronouncements that there will not be “multiple warning letters to noncompliant firms before taking enforcement action.”

She also said that FDA will work more closely with “local, state and international officials” who have authority to shut down companies more quickly than FDA, especially when the “public health is at risk.”

Warning Letters are very rarely retracted or withdrawn by FDA, and there is generally no public indication that a firm has corrected the violations covered by a Warning Letter.  Dr. Hamburg pledged to set up a “close-out” process so that, after a re-inspection determines that “a firm has fully corrected the violations,” the firm and the public will be informed that issues raised in a Warning Letter have been resolved.

Dr. Hamburg praised the agency for its rapid and repeated Warning Letters issued to promoters of products who promised to “diagnose, prevent, or treat” the H1N1 virus (commonly referred to as the “swine flu” virus).  She also praised the agency for its action to stop the distribution of anabolic steroids “sold under the guise of dietary supplements.”

By Kurt R. Karst & Michelle L. Butler –      

Winston Laboratories, Inc. (“Winston”) recently sued FDA after the Agency denied a waiver of the Prescription Drug User Fee Act (“PDUFA”) application fee assessed with respect to the company’s human drug application (NDA No. 22-403) for CIVANEX (civamide (zucapsaicin)) Cream, 0.075%.  Specifically, the complaint, filed in the U.S. District Court for the Northern District of Illinois Eastern Division, seeks declaratory and injunctive relief with respect to FDA’s denial of Winston’s application for waiver of the application user fee – which was $1,247,200 in Fiscal Year 2009 – under the small business waiver provisions of the FDC Act, notwithstanding the Small Business Administration’s (“SBA’s”) determination that Winston is a “small business.”  (The correspondence identified below is included as exhibits to Winston’s complaint and is available here.) 

Under the FDC Act, FDA shall grant a waiver or reduction of user fees where “the applicant involved is a small business submitting its first human drug application to [FDA] for review.”  FDC Act § 736(d)(1)(d).  The statute further provides “Rules Relating to Small Businesses” and requires that FDA shall waive “the application fee for the first human drug application that a small business or its affiliate submits to [FDA] for review."  FDC Act § 736(d)(4)(B) (emphasis added).  The statute defines a small business as “an entity that has fewer than 500 employees, including employees of affiliates, and that does not have a drug product that has been approved under a human drug application and introduced or delivered for introduction into interstate commerce.”  FDC Act § 736(d)(4)(A). 

FDC Act § 735(11) defines the term “affiliate” to mean “a business entity that has a relationship with a second business entity if, directly or indirectly – (A) one business entity controls, or has the power to control, the other business entity; or (B) a third party controls, or has power to control, both of the business entities.” 

After FDA grants a small business or its affiliate a waiver, the company or its affiliates must pay “application fees for all subsequent human drug applications submitted to [FDA] for review in the same manner as an entity that does not qualify as a small business,” and “all supplement fees for all supplements to human drug applications submitted to [FDA] for review in the same manner as an entity that does not qualify as a small business.”  FDC Act § 736(d)(4)(B)(i)-(ii).

In May 2008, in advance of the CIVANEX NDA submission, Winston requested that FDA waive the application user fee in accordance with FDC Act § 736(d)(1)(D), asserting that the company met the statutory requirements for FDA to grant the waiver.  After receiving the request, FDA requested the SBA to determine whether Winston and its affiliates met the “small business” definition.  The SBA, which does not consider those firms that are no longer in business in determining affiliates, made a formal size determination in August 2008 that Winston and its affiliates had fewer than 500 employees. 

In December 2008, FDA denied Winston’s waiver request, stating that although Winston and its affiliates have fewer than 500 employees, the company failed to meet the requirement that the marketing application must be the first human drug application that a company “or its affiliate” submits to FDA.  FDA noted that “for purposes of determining whether to grant a small business waiver, FDA considers all affiliates, even those that are no longer in existence” (emphasis added), and that according to the Agency’s records, the CIVANEX NDA is not the first human drug application submitted by Winston or its affiliates.  Specifically, according to FDA, two now defunct companies with ties to Winston through its CEO, Joel E. Bernstein, M.D. – GenDerm Corporation (“GenDerm”) and Northbrook Testing Co., Inc. (“Northbrook”) – were considered to be affiliates of Winston that previously submitted human drug applications to FDA.  In the course of making this determination FDA conducted its own analysis of whether Dr. Bernstein was affiliated with GenDerm and Northbrook. 

Dissatisfied with FDA’s decision, Winston promptly requested that FDA reconsider the waiver denial, arguing that Winston is not an affiliate of either GenDerm or Northbrook.  In February 2009, FDA affirmed its finding that Winston is a “small business,” but also confirmed its prior decision to deny the small business waiver on the basis that, given the affiliate status of GenDerm and Northbrook, Winston did not satisfy the requirement that the NDA be the first human drug application submitted by a small business or its affiliate.  In reaching this decision, FDA stated that “[t]here is no requirement in the definition of affiliate that all relevant parties be in existence at the same time.”

In April 2009, Winston appealed the decision, explaining that FDA’s interpretation of the term “affiliate” to include companies that are no longer in business is unacceptable and inconsistent with the definition of affiliation.  In June 2009, FDA issued a final decision denying Winston’s appeal and affirming its previous determination that Winston does not qualify for a small business waiver.  In that decision, FDA affirmed that Northbrook is a Winston affiliate, but found that there is insufficient evidence to conclude that GenDerm and Winston are affiliates for PDUFA user fee purposes.  In explaining its interpretation of the scope of the term “affiliate” FDA commented that:

In contrast to the [SBA’s] process for making a size determination, which require consideration of a company’s status at the time the determination is made, PDUFA contemplates that FDA examine past events in order to determine whether an NDA is the first human drug application submitted by a company or its affiliates.  Therefore, it is reasonable, indeed, arguably necessary, to consider whether companies that may no longer exist should be considered affiliates of that company and whether they have submitted applications. Given the clear purpose of this provision and the fact that the statute's plain language includes no temporal limitation to prevent the consideration of now defunct companies, it is reasonable to consider companies that are no longer in business to be affiliates of an applicant for a small business waiver.

Moreover, policy considerations support a broader interpretation of the term affiliate. Under the interpretation promoted by Winston, a company could obtain a fee waiver for its “first human drug application,” dissolve the company, establish a new company that is essentially a duplicate of the first, and obtain a fee waiver for its next NDA (which would technically be the “first” NDA of that incarnation of the company).  This cycle could be repeatedly indefinitely.  PDUFA’s emphasis that a waiver is only available for the first human drug application submitted by “a small business or its affiliate,” and not for subsequent applications, 21 U.S.C. § 379h(d)(4)(B) (emphasis added), instead of all applications submitted by a “small business,” id. § 379h(d)(1)(D), certainly suggests that Congress intended to prevent such abuse.  To adopt an interpretation that would permit companies to easily circumvent the limitation on the small business waiver put in place by Congress is not sound public policy. [(italics in original)]

Winston’s complaint requests that the court enter a judgment declaring that FDA’s refusal to grant a small business waiver of user fees violates the Administrative Procedure Act (i.e., that FDA’s interpretation of the user fee statute is arbitrary, capricious, and an abuse of discretion, contrary to law, and in excess of the Agency’s statutory authority).  Winston also requests that the court enter an injunction requiring FDA to immediately grant Winston the small business user fee waiver.