By Ricardo Carvajal –      

FDA has announced the availability of a guidance for industry titled “Substantiation for Dietary Supplement Claims Made Under Section 403(r)(6) of the Federal Food, Drug, and Cosmetic Act.”  Under certain conditions, section 403(r)(6) permits manufacturers of dietary supplements to make nutritional deficiency, structure/function, or general well-being claims in the labeling of dietary supplements, provided those claims are truthful and not misleading.  The guidance issued by FDA is very similar to a draft guidance that FDA issued under the same name in 2004, but there are some interesting differences that suggest a possible tightening of FDA's standards with respect to the types of evidence that constitute adequate substantiation. 

In addressing animal and in vitro studies, FDA has eliminated qualifying language that was present in the draft guidance.  For example, the draft guidance stated that, "Generally, without any data from human studies, the results of animal studies alone are not sufficient to substantiate a claim."  The recently-issued guidance omits the qualifier "generally."  Also, the draft guidance stated that, "The strongest in vitro evidence would be based on data that have been reproduced in different laboratories, but this evidence alone would ordinarily not be adequate to substantiate a claim."  The recently-issued guidance changes the last phrase in that sentence to state that "this evidence alone would not substantiate a claim."  These two omissions suggest that FDA is likely to demand data from one or more human studies for substantiation (but note that FDA does not address structure/function claims that include qualifying language, a point briefly addressed further below). 

As to the weight that can appropriately be given to a single study, Example 20 in the draft guidance stated that a single positive study involving a small number of subjects likely would be insufficient to substantiate a claim in the face of several high-quality studies that produce negative results.  The recently-issued guidance omits any reference to the number of subjects as a relevant factor.  This suggests that, in the absence of explanatory circumstances, FDA may view a single positive study as insufficient to substantiate a claim in the face of several unfavorable studies, even if that study involved a substantial number of subjects.

There is additional material of interest in the footnotes of the guidance.  First, FDA responds to comments raising First Amendment concerns by concluding that the statutory substantiation requirement in section 403(r)(6) is constitutional under the analysis governing commercial speech in Central Hudson Gas & Electric Corp. v. Public Service Commission of New York (447 U.S. 557 (1980)).  The guidance states that the "misleading nature of a claim made under section 403(r)(6) that is not substantiated cannot be cured by a disclaimer stating that the claim lacks support."  However, FDA sidesteps the question of whether a claim made under section 403(r)(6) that includes qualifying language can be substantiated.  Second, FDA takes the position that a study using a conventional food or a multi-nutrient supplement would not substantiate a single ingredient dietary supplement claim, and that a disclaimer wouldn’t work in such situations.  In support of its position, FDA notes that “recent scientific studies have shown that nutrients in food do not necessarily have the same beneficial effect when taken in the form of a dietary supplement,” and may either have no benefit or show “an increased risk for the very disease the nutrients were predicted to prevent.”

By Kurt R. Karst –      

FDA’s recent approval of Antisoma Research Limited’s orphan drug, oral fludarabine phosphate, with 7 years of orphan drug exclusivity for the treatment of certain adult patients with B-cell chronic lymphocytic leukemia got us thinking about the unusual case of the major contribution to patient care – the so-called “MC-to-PC” – orphan drug designation and approval. 

The FDC Act (§ 527) provides a 7-year period of exclusive marketing to the first sponsor who obtains marketing approval for a designated orphan drug.  The scope of orphan drug exclusivity is broad; it prevents FDA approval of ANDAs, “full” 505(b)(1) NDAs, and 505(b)(2) applications.  Orphan drug exclusivity begins on the date that a marketing application is first approved for the designated orphan drug. 

Once FDA approves a marketing application for a designated drug, the Agency may not approve another firm’s version of the “same drug” for the same disease or condition for seven 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.  (FDA may, however, approve a second application for the same drug for a different use.)  A drug is “different” from an approved orphan drug if it is either demonstrated to be chemically or structurally distinct from an approved orphan drug, or “clinically superior” to the approved orphan drug. 

FDA’s orphan drug regulations (21 C.F.R. Part 316) define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways:

(a) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;
(b) greater safety in a substantial portion of the target population; or
(c) demonstration that the drug makes a major contribution to patient care.

To support a claim of “clinical superiority” based on a demonstration of a major contribution to patient care, FDA has acknowledged that it will do so only in “unusual circumstances.”  In the preamble to FDA’s final orphan drug regulations, the Agency commented that:

convenient treatment location; duration of treatment; patient comfort; improvements in drug efficiency; advances in the ease and comfort of drug administration; longer periods between doses; and potential for self administration . . . when applicable to severe or life threatening diseases, might sometimes be legitimately considered to bear on whether a drug makes a major contribution to patient care.  However, this determination will have to be made on a case-by-case basis. 

As to how much superiority could constitute a “major contribution to patient care,” FDA also remarked that:

There is no way to quantify such superiority in a general way.  The amount and kind of superiority needed would vary depending on many factors, including the nature and severity of the disease or condition, the quality of the evidence presented, and diverse other factors. . .  While comparative trials are, of course, preferred and will usually be required, it is possible that, in some circumstances, a demonstration of a major contribution to patient care can be made without such trials. 

Other than the recent oral fludarabine phosphate designation and approval (see FDA’s orphan drug designation list here, which identifies the oral fludarabine phosphate designation as a MC-to-PC precedent based on a change from an intravenous to oral dosage form), we are aware of only two instances in which FDA has designated and approved an orphan drug based on a MC-to-PC demonstration: 

• In 1998, FDA determined that Novartis’ reformulated SANDOSTATIN LAR (octreotide) was “clinically superior” to a previously approved subcuteaneous dosage form of SANDOSTATIN, because “patients can be managed with one injection per month instead of sixty to ninety injections.”  
• In 2007, FDA determined that Indevus’ histrelin acetate implant drug product, SUPPRELIN LA, was “clinically superior” to SUPPRELIN on the basis that “a single histrelin subcutaneous implant could provide therapeutic blood levels for a period of 1 year versus 365 daily injections of Supprelin.” 

A MC-to-PC counter-precedent is found in Fisons’ attempt to obtain FDA approval for PNEUMOPENT (pentamidine isethionate).  On June 15, 1989 (before FDA’s orphan drug regulations were proposed), FDA approved American Pharmaceutical Partners’ aerosolized NEBUPENT (pentamidine isethionate) for primary and secondary prophylaxis of Pneumocystis Carnii Pneumonia (“PCP”).  NEBUPENT was approved for administration (300mg once every four weeks) through a nebulizer using compressed air by trained medical personnel.  Fisons subsequently sought FDA approval for PNEUMOPENT, also an aerosolized pentamidine product for the prevention of PCP.  However, PNEUMOPENT could be self-administered through a small ultrasonic nebulizer.  Fisons (and several AIDS groups) urged FDA to approve PNEUMOPENT despite NEBUPENT’s orphan drug exclusivity, arguing that PNEUMOPENT made a “major contribution to patient care” because: (1) PNEUMOPENT could be self administered at home whereas NEBUPENT required administration in an institutional setting; (2) PNEUMOPENT required about half the time per treatment as NEBUPENT; and (3) Fisons developed a unit-dose ampule for PNEUMOPENT that avoided the use of a syringe and sterile water to reconstitute NEBUPENT.  FDA reportedly did not accept that these differences established a sufficient MC-to-PC rationale.

By Ricardo Carvajal –

FDA has issued a final rule that requires declaration of the color additives cochineal extract and carmine in the ingredient statement on the label of all food and cosmetic products that contain those additives.  FDA has made no changes to the proposed rule that it published in January 2006.  The final rule is effective on January 5, 2011, but FDA states that it “will not object to voluntary compliance immediately upon publication of the final rule.”

The final rule requires the declaration of the color additives in all foods (including butter, cheese, and ice cream) and all cosmetics (including professional-use-only products and gifts or free samples).  The agency plans to initiate separate rulemaking to implement the FDC Act’s requirement for declaration of inactive ingredients in drugs (that requirement has already been implemented for OTC drugs).  Although some comments asked FDA to require label declaration of the fact that cochineal extract and carmine are insect (or animal) derived, FDA demurred on the ground that such information is not material within the meaning of section 201(n) of the FDC Act (i.e., it is a fact that is not material with respect to consequences which may result from the use of the product as labeled or customarily used).

By Kurt R. Karst –

We previously reported on the Patent and Trademark Office’s (“PTO’s”) determination that U.S. Patent #5,817,338 (“the ‘338 patent”), which covers AstraZeneca’s PRILOSEC OTC (omeprazole magnesium) Delayed-Release Tablets, is not eligible for a Patent term Extension (“PTE”) because the PRILOSEC OTC New Drug Application (“NDA”) was not the first permitted commercial marketing or use of omeprazole, and because the PTE application was not timely submitted.  (The PTE application was submitted on the 61st day after the date of NDA approval).  The PTO finalized that determination in a decision issued last month. 

Under the PTE statute at 35 U.S.C. § 156, the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, the PTE application is submitted to the PTO by the owner of record within 60 days of NDA approval (specifically, the statute states that a PTE application “may only be submitted within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use” (emphasis added)), and if “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred.”   In recent PTE memoranda, the PTO has heavily relied on decisions by the U.S. Court of Appeals for the Federal Circuit in Fisons v. Quigg, 8 U.S.P.Q.2d 1491 (D.D.C.1988), aff’d 876 F.2d 99 U.S.P.Q.2d 1869 (Fed.Cir.1989), Pfizer Inc. v. Dr. Reddy’s Labs., 359 F.3d 1361 (Fed. Cir. 2004), and Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392, 13 USPQ2d 1628 (Fed. Cir. 1990) to support the Office’s interpretation of the term “product” in 35 U.S.C. § 156(a)(5)(A) to mean “active moiety” (i.e., the molecule in a drug product responsible for pharmacological action, excluding any salt, ester, or other non-covalent derivative) rather than the entire molecule (i.e., the active moiety in a drug product, including any salt, ester, or other non-covalent derivative).  FDA has apparently accepted this interpretation.  PhotoCure is currently challenging this PTO interpretation in the context of a PTE denial for METVIXIA (see July 28, 2008 FDA Law Blog post).

In October 2004, FDA determined that AstraZeneca’s PTE application for the ‘338 patent covering PRILOSEC OTC was “timely within the meaning of 35 U.S.C. 5 156(d)(l),” and that the PRILOSEC OTC NDA approval “represents the first permitted commercial marketing or use of the product. . . .”   Despite this initial determination, an April 2008 letter from the PTO to FDA reverses course and states that “it is the position of the [PTO] that the subject [PTE] was not timely filed based on a plain reading of the statutory language of 35 U.S.C. § 156(d)(1) and the [PTO’s] implementing regulations at 37 C.F.R. § 1.720(f),” and that because of the previous approval of PRILOSEC (omeprazole), PRILOSEC OTC “does not represent the first permitted commercial marketing or use of the ‘product’ . . . .”  In May 2008, AstraZeneca petitioned the PTO to have the April 2008 letter withdrawn and to prevent the PTO from retroactively applying “an apparently new method of determining timeliness that has not yet even been announced to the public.”  According to AstraZeneca, “[f]rom at least 1986 until relatively recently, the PTO had consistently applied to numerous other PTE applications the Original Method for determining timeliness,” under which the 60-day statutory filing deadline was calculated beginning on the date after product approval.  In October 2008, FDA issued a letter retracting the Agency’s October 2004 determination.  AstraZeneca has criticized FDA’s retraction decision.

On December 16, 2008, the PTO issued a denial of a PTE for the ‘338 patent.  With respect to the first permitted commercial marketing or use PTE criterion, the Office concluded that PRILOSEC OTC is not the first permitted commercial marketing or use of the product, because the term “product” in the PTE statute ultimately means “the underlying molecule or ion (excluding those appended portions of the molecule that cause it to be a salt or ester) responsible for the physiological or pharmacological action of the drug.”  And because FDA previously approved PRILOSEC, which contains omeprazole, PRILOSEC OTC, which contains omeprazole magnesium, does not represent the first permitted commercial marketing or use of omeprazole. 

With respect to the 60-day PTE application submission criterion and AstraZeneca’s May 2008 petition alleging application of a new counting method, the PTO acknowledges a change in the Office’s counting methodology, but nevertheless denies the PTE application as untimely.  The PTO states that AstraZeneca:

is correct that the USPTO has changed the way in which it makes the timeliness count between 2004 and 2008.  The agency has done so because it realized that it was erroneously beginning the sixty-day count on the wrong day.  By not counting the date of FDA approval as one of the sixty days included in the time period for filing a PTE application, the USPTO was failing to comply with section 156 and case law. . . .  If the USPTO treated [AstraZeneca’s] late filed PTE application as timely filed, as [AstraZeneca] requests, the agency would perpetuate an erroneous application of section 156(d)(1); the USPTO cannot do so.

The PTO’s PRILOSEC OTC decision also has implications on a PTE request concerning another AstraZeneca drug product; namely a PTE application for U.S. Patent No. 5,674,860 (“the ‘860 patent”), which covers the drug product SYMBICORT (budesonide; formoterol fumarate dihydrate) Inhalation Aerosol.  As we previously reported, in June 2008, the PTO denied a PTE for the ‘860 patent because the SYMBICORT NDA was not the first permitted commercial use of budesonide or formoterol fumarate dihydrate, and also because the PTE application was not submitted within the 60-day statutory period.  On December 16, 2008 (the same day the PTO issued its PTE denial for PRILOSEC OTC), AstraZeneca submitted a request for reconsideration of the PTO’s June 2008 decision.  Presumably the PTO will deny the request, perhaps using reasoning similar to that in the PRILOSEC OTC decision.  Litigation over the PRILOSEC OTC and/or the SYMBICORT PTE decisions seems a likely possibility given the importance of the drug products to AstraZeneca.  And indeed, the PTO seems to have set itself up for litigation.  Typically the PTO provides an opportunity for an applicant to submit a request for reconsideration of a final determination of PTE ineligibility.  The PTO’s PRILOSEC OTC decision, however, makes no such offer and notes that the December 16, 2008 decision “IS CONSIDERED A FINAL AGENCY DECISION.”

Kurt R. Karst of Hyman, Phelps & McNamara, P.C. (and co-chief blogger of FDALawBlog.net) will be speaking at two upcoming conferences on various Hatch-Waxman Act product lifecycle management issues.  The first conference is the Center for Business Intelligence’s Premier Bio/Pharmaceutical Summit on Legal & Regulatory Product Lifecycle Strategies, January 20-21, 2009, at the Hilton Baltimore in Baltimore, Maryland.  Information on the conference is available here.  Conference sessions include: 

• Advice from the FTC on how to structure a compliant lifecycle strategy;
• Patent portfolio management in a global environment, including emerging economies;
• A panel discussion on alternative pathways for exclusivity such as targeted therapeutics, superior molecules, and niche populations;
• Repurposing “old” drugs;
• A core workshop on key US laws and regulations pertaining to ANDA patent challenges and PTO patent reform proposals; and 
• Labeling carve-outs, their impact on generic approvals and affect on therapeutic equivalence ratings (Our favorite!  Mr. Karst will present on this topic.).

For more information or to register for the conference, please contact the Center for Business Intelligence toll-free by phone at 1-800-817-8601 or via e-mail at cbireg@cbinet.com.

The second conference is a Thompson Publishing Group audio conference, titled “New Drug Exclusivity Provisions: How They’ll Impact Your Product Lifecycle Management,” and will take place on January 13, 2009 from 1:00 PM – 2:30 PM.  Information on the audio conference is available here.  This conference will explore the “old” antibiotic and enantiomer exclusivity provisions recently added to the FDC Act, as well as recent issues concerning 180-day generic drug exclusivity and patent term extensions.  Learning points and questions to be answered during the audio conference include:

• What are “old” antibiotics and what is the new law permitting Hatch-Waxman benefits?
• Enantiomer exclusivity – what are the new rules permitting 5-year exclusivity? 
• How is FDA interpreting the 180-day exclusivity forfeiture provisions and when is FDA expected to issue proposed regulations on the forfeiture provisions? 
• What patents are eligible for a patent term extension? 
• What if I miss the 60-day patent term extension application period?  What is the status of legislation permitting an extension of the 60-day period? 
• When are multiple patent term extensions available? 
• How is the “regulatory review period” calculated for a patent term extension?

For more information or to register for the audio conference, please contact Thompson Publishing Group toll-free by phone at 1-800-925-1878.

By Jeffrey N. Wasserstein, Michelle L. Butler, and Jamie K. Wolszon –

On December 18, 2008, the Advanced Medical Technology Association (“AdvaMed”) announced the release of a newly revised version of the “Code on Ethics on Interactions with Healthcare Professionals,” which is a voluntary code focusing on the industry’s interactions with healthcare professionals as they relate to the marketing of products.  The revised Code will take effect on July 1, 2009.  The “updated and more rigorous Code of Ethics reflects the medical technology industry’s ongoing commitment to openness, transparency and high ethical standards,” AdvaMed chairman Michael Mussallem, chairman and CEO of Edwards LifeSciences, stated in a press release.

The revised Code is more restrictive than the 2005 version of the Code.  The revised Code also includes some of the new restrictions incorporated in the recently revised Pharmaceutical Research and Manufacturers of America (“PhRMA”) “Code on Interactions with Healthcare Professionals” (see our previous post) including a prohibition on the distribution of promotional non-educational items (e.g., pens adorned with a company or product logo), and a complete prohibition on entertainment and recreational activities.

The revised AdvaMed Code also includes new or expanded provisions related to evaluation and demonstration products; consulting agreements and royalties as compensation; compliance certification; support for third-party educational conferences; company-conducted training and education for health care professionals; research and education grants; and reimbursement assistance.  Hyman, Phelps & McNamara, P.C. has prepared a memorandum summarizing the most significant changes to the revised Code.

By Kurt R. Karst –

Last week, ViroPharma Inc. announced that the company filed a complaint in the U.S. District Court for the District of Columbia alleging that FDA has “wrongfully withheld agency records requested by [ViroPharma] by failing to comply with the statutory time limit for the processing of [ViroPharma’s] FOIA request, resulting in constructive denial of that request, and by continuing to withhold response records” in connection with the approval requirements for a generic version of the company’s antibiotic drug product VANCOCIN (vancomycin HCl) Capsules.  The lawsuit is the latest salvo in a long-running debate over the approval of generic VANCOCIN Capsules.

On March 17, 2006, ViroPharma submitted a Petition for Stay to FDA requesting that the Agency stay the approval of any ANDA or 505(b)(2) application citing VANCOCIN Capsules as the listed drug until certain requirements are met.  In particular, the petition requested that FDA not approve an application for a generic version of VANCOCIN Capsules based solely on in vitro bioequivalence testing.  According to ViroPharma, prior to March 16, 2006, FDA concluded that “in vivo clinical trials would be the basis for determining bioequivalence for generic vancomycin hydrochloride capsules,” and that on March 16, 2006, it became public knowledge that FDA “was modifying its bioequivalence standard for oral Vancocin capsules and would accept the submission of in vitro dissolution testing data as a surrogate measure of in vivo bioequivalence.”

ViroPharma submitted a FOIA request seeking the administrative record related to FDA’s March 2006 bioequivalence recommendations for generic VANCOCIN.  FDA did not immediately provide records in response to the FOIA request.  According to the ViroPharma complaint, when FDA was threatened with litigation earlier this month, an agency official noted that “FDA would soon be releasing information regarding Vancocin that could ‘vitiate the need’ for filing [a] FOIA action.” 

On December 16, 2008, FDA issued a Federal Register notice announcing the availability of a draft product-specific bioequivalence recommendation – “Bioequivalence Recommendation for Vancomycin HCl.”  Supporting documents for the draft recommendation are available here and here.  According to FDA, the draft recommendation “further clarifies its recommendations on the design of BE studies to support ANDAs for vancomycin HCl capsules.”  Specifically, FDA provides bifurcated bioequivalence testing recommendations based on the formulation of the proposed generic drug product:

If the test product formulations are qualitatively (Q1) (i.e., contain all of the same inactive ingredients) and quantitatively (Q2) the same as the reference listed drug (RLD) with respect to inactive ingredients, bioequivalence (BE) of all capsule strengths may be established based on comparative dissolution. . . .

If the test product formulations are not Q1 and Q2 the same as the RLD with respect to inactive ingredients, BE should be established by conducting an in vivo study with clinical endpoints in patients with Clostridium difficile Associated Diarrhea (CDAD). 

FDA’s bifurcated approach is similar to the approach the Agency announced in May 2008 for generic versions of PRECOSE (acarbose) Tablets.  Comments on FDA’s draft vancomycin HCl bioequivalence recommendations are due by February 17, 2009; however, ViroPharma has requested an extension of the comment period.

FDA’s December 16, 2008 Federal Register notice also alludes to a forthcoming (but don’t expect anything soon) response to ViroPharma’s 2006 petition: 

Comments on this draft guidance will also be considered by FDA as it addresses the complicated issues raised in Viropharma, Inc.’s PSAs.  FDA will carefully consider such comments before responding to the petition and finalizing its BE recommendation for vancomycin HCl.  Because of the lengthy history of FDA’s consideration of bioequivalence methodologies for vancomycin HCl capsules, the pendency of the PSAs, and the complexity of the issues involved, the availability of this draft guidance is being announced in a drug product-specific notice, and the recommendations include a significant amount of background information and explanation of the reasons for the bioequivalence recommendations.

Dissatisfied with FDA’s December 16, 2008 announcement, ViroPharma filed its complaint.  ViroPharma states that “the Draft Guidance does not include the administrative record for FDA’s March 2006 decision to change bioequivalence methods for vancomycin . . . or the data supporting that change,” and “in no way vitiates the need for FDA to respond to ViroPharma’s FOIA request.”  Moreover, ViroPharma alleges that the draft bioequivalence recommendation “confirms that FDA failed to engage in any public process before its 2006 decision . . . .”  ViroPharma alleges that the company has a statutory right to the FDA records it seeks, as well as a statutory right “that FDA not review ANDAs that seek to copy Vancocin based on FDA’s changed interpretation of its bioequivalence regulations. . . .”

Given the importance of VANCOCIN to ViroPharma and the company’s unhappiness with FDA’s December 2008 bioequivalence recommendations, it seems clear that the current FOIA litigation is intended to obtain information that could be used in future litigation in the event FDA denies ViroPharma’s 2006 petition and approves generic versions.  Stay tuned for more as this interesting story develops. 

By Jamie K. Wolszon –

FDA’s recent decision to require a Risk Evaluation and Mitigation Strategy (“REMS”) for two prescription oral sodium phosphate (“OSP”) products raises questions regarding the impact the agency’s evolving application of its new REMS authority will have in instances where both prescription and OTC products are available that contain the same active ingredient.

On Thursday December 11, FDA issued a press release announcing that it was adding a Black Box warning to two prescription OSP products, Visicol and OsmoPrep, to address the kidney injury, acute phosphate nephropathy.  FDA directed the companies to develop a REMS.  The Agency also required the firms to distribute a Medication Guide and to conduct a clinical trial to further assess the risk.   

FDA also observed that the Agency had similar concerns regarding OTC products used at higher dosages for bowel cleansing, but that “the available data show no risk of acute kidney injury when OTC products are used at the lower dosages as laxatives.”  FDA recommended “that consumers not use OTC OSP products for bowel cleansing,” and promised to amend the labeling conditions for OTC OSP products. The press release specifically mentioned Fleet Phospho-soda’s OSP product.      

Consistent with the press release, FDA also issued two responses on the same day to citizen petitions related to OSP products.  The agency denied C.B. Fleet of Lynchburg, Virginia’s (“Fleet”) 2003 petition requesting professional labeling for OTC sodium phosphates oral solution for bowel cleansing.  In the wake of FDA’s statement, Fleet announced that it would voluntarily cease marketing its product.

FDA also responded to a citizen petition submitted by food and drug attorney Natasha Leskovsek on behalf of an unnamed client.  FDA denied the petitioner’s request to remove all prescription OSP drugs from the market; however, the Agency granted the petition’s request to apply a black box warning to the prescription OSP products; and granted the petition’s request to amend the Tentative Final Monograph to remove the professional labeling for OSP products. 

Although not mentioned in the press release, along with the Black Box warning and Medication guide, the REMS requires the two makers of Visicol and OsmoPrep to develop a communication plan targeted at gastroenterologists, surgeons, primary care physicians, and other healthcare providers who are likely to prescribe or dispense OSP products or perform follow-up assessments of patients following bowel cleansing. 

In order to invoke its REMS authority, FDA must determine that, without a strategy, the benefit of the drug would not outweigh its risk.  Meanwhile, a product cannot be marketed OTC if the drug “because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such a drug.”  An OTC drug also must be safe and effective for use in self-medication. 

FDA’s new statutory REMS authority applies to new drugs that the agency approves under the new drug or abbreviated new drug approval provisions and that require a prescription.  FDA thus cannot impose REMS on OTC monograph drugs, but the agency has the means to address specific risks for OTC monograph drugs through labeling warnings or restrictions. 

There are multiple other examples of active ingredients that are marketed, albeit at different dosages or indications, both as a prescription and OTC product.  For instance, aspirin, while marketed OTC, also has professional labeling for the cardiovascular and rheumatologic indications. The professional labeling allows the maker of an aspirin product to detail the professional labeling to health care providers.  Prilosec OTC (omeprazole magnesium) is marketed with a shorter course of treatment than the prescription version and unlike the prescription version is solely marketed for treatment of heartburn. 
  

By John R. Fleder & Kurt R. Karst –

On December 10, 2008, the United States District Court for the Northern District of Illinois in Chicago dismissed a federal False Clams Act qui tam action in U.S. ex rel. Kennedy v. Aventis Pharmaceuticals, Inc. involving allegations of off-label use sales concerning the drug LOVENOX (enoxaparin sodium).  The plaintiffs (Relators) are former Aventis sales representatives.  The court had earlier allowed the Relators to take discovery in order to develop evidence to identify specific false claims that could be tied to Aventis’ supposed illegal scheme.

First, the court ruled that any claims filed as a result of the alleged off-label use scheme were not “material” to the amount the government paid for treatment of a given patient.  The government’s reimbursement was based on a diagnosis group code that was tied to a patient’s diagnosis and age, and was not dependent on the particular services rendered to a patient.  As a result, the court ruled the claims could not have been “false.”

Second, the court examined whether the Relators’ third amended complaint satisfied the requirement of Fed. R. Civ. P. 9(b) that the fraud be pleaded with particularity.  The court ruled that although it had allowed Relators the opportunity to take discovery, they had failed to identify any specific claim that was actionable.

This decision is yet another example in which a federal court has rejected a False Claims Act qui tam lawsuit against a drug manufacturer alleging unlawful off-label promotional practices.  As we previously reported, in September 2008, the United States District Court for the Middle District of Florida (Tampa Division) dismissed similar claims in United States ex rel Hopper and Hutto v. Solvay Pharmaceuticals, Inc.  The court in that case adopted a report and recommendation from a magistrate judge concluding that the relators had utterly failed to comply with the requirements set forth in Fed. R. Civ. P (9)(b) to include specific allegations of actual false claims that were submitted to the government.  We note, however, that where the government has intervened in qui tam suits alleging off-label promotion, the government has had a greater likelihood of success in extracting a settlement from the defendant than in those cases where the government has declined to intervene.

Hyman, Phelps & McNamara, P.C.’s John Fleder was recently featured in a Washington Legal Foundation YouTube video discussing qui tam actions involving off-label promotion allegations, and wrote an article for the Food and Drug Law Institute’s Update magazine on the same topic.

By Diane B. McColl & Ricardo Carvajal –

FDA has issued “no questions” response letters to the GRAS notices submitted by Cargill and Whole Earth Sweeter Company for rebaudioside A, described as “a highly purified component of the stevia plant.”  The letters (available here and here) note that the GRAS notices are for “use of a specific purified component of stevia” and that the agency’s response does “not necessarily apply to the uses of other stevia products.”  The letters also include a § 301(ll) disclaimer, such that the response letters can not be construed as “a statement that foods that contain rebaudioside A, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).”

Cargill’s GRAS self-determination encompasses “use as a general-purpose sweetener in foods, excluding meat and poultry products, provided that food standards of identity do not preclude such use, at levels determined by current good manufacturing practices.”  Whole Earth Sweetener Company’s GRAS self-determination encompasses “use as a sweetener in a variety of food categories [cereals (oatmeal, cold cereal, cereal bars), ready-to-drink teas, fruit juice drinks, diet soft drinks, energy drinks, and flavored waters], as well as use as a table top sweetener….”

Contrary to characterizations in the popular press, the issuance of a “no questions” response letter does not constitute an “approval.”  As noted in such response letters, FDA does not make its own determination regarding the GRAS status of the substance at issue, and places on the notifier the “continuing responsibility” of ensuring the safety of the substance and its compliance with all applicable legal requirements.

By Riëtte van Laack –

On October 21, 2008, the National Resource Defense Council (“NRDC”) petitioned FDA to issue a regulation to prohibit the use of Bisphenol A (“BPA”) as a food additive.

Currently, BPA is approved as a chemical for use in the production of polycarbonate polymers and epoxy-based enamels and coatings.  See, e.g., 21 C.F.R. §§ 175.300(b)(3)(viii), 177.1440, 177.1580,and 177.2280.  The safety assessments concerning the use of BPA date from the 1960s.  These safety evaluations focused on carcinogenicity and on genetic toxicity as an indicator of carcinogenicity.  However, recent research has raised concerns about the potential effects of BPA on the endocrine system. 

The release, in 2007, of two government sponsored reviews of BPA has resulted in a debate about the safety of residues of BPA in food contact substances.  Based on its review of existing data, the National Toxicology Program (“NTP”) concluded that there was “minimal concern” about the reproductive and developmental effects of BPA. In contrast, in the “Chapel Hill” report, a group of 38 experts raised serious concerns about the safety of BPA.  In August 2008, based on these reports, amendments thereto, and additional sources of information, FDA determined in its draft safety assessment that “an adequate margin of safety exists for BPA at current levels of exposure from food contact uses.” 

NRDC disagrees with FDA’s draft safety assessment, which NRDC claims relied on two-industry funded studies.  According to NRDC, “in light of the data suggesting that BPA is harmful to human health, and in response to well-founded concerns of experts in the field, FDA must prohibit BPA from use in food and food packaging [and] revoke all regulations permitting the use of any food additive that results in BPA becoming a component of food.”

NRDC’s petition was submitted shortly before a subcommittee of the FDA Science Board Advisory Committee released its review of FDA’s draft safety assessment.  The subcommittee also disagreed with FDA’s draft safety assessment and concluded that the margins of safety for BPA are inadequate.  However, the subcommittee indicated that “this does not mean that exposures are not acceptable.”  According to the subcommittee, the acceptability of exposures is a question of policy, and this decision lies with FDA. 

In response to the subcommittee review, FDA acknowledged in a statement the existence of “uncertainties” about BPA and that “additional research would be valuable.”  The Agency is “moving forward with [additional] research to address the potential low dose effects of [BPA].”  FDA’s statement also pointed to “the present consensus among regulatory agencies in the United States, Canada, Europe, and Japan . . . that current levels of exposure to BPA through food packaging do not pose an immediate health risk.”

By Diane B. McColl & Ricardo Carvajal –

On December 15, Cargill issued a press release in which it announced a “broad-based national integrated marketing campaign” to promote its sweetener Truvia™ (Truvia™ is Cargill’s preparation of rebiana, or rebaudioside A, one of the sweetening components that can be extracted from Stevia rebaudiana). According to Cargill, “the tabletop version of Truvia™ natural sweetener is now available nationwide, wherever groceries are sold.”  Previously, Cargill had filed a voluntary GRAS notification with FDA (GRN #253) setting out Cargill’s determination that its rebiana is safe for use as a general purpose sweetener.  FDA has yet to respond to that notification.

Under § 201(s) of the Federal Food, Drug, and Cosmetic Act ("FDC Act"), many food ingredients are not subject to approval and regulation by FDA as food additives if the use of those ingredients in foods is generally recognized, among experts qualified by scientific training and experience to evaluate their safety, as having been adequately shown through scientific procedures or common use in foods, to be safe under the conditions of their intended use.  Self-determination that the use of an ingredient is GRAS can be made independent of FDA, and requires neither FDA approval nor FDA notification.  Use of a self-determined GRAS ingredient carries with it the risk that FDA will disagree with the self-determination of GRAS status and take action against the substance as an unapproved food additive.  For this reason, potential users often demand that ingredient developers voluntarily notify FDA of their GRAS self-determinations.  If FDA has no questions about the notifier’s GRAS determination, FDA issues a letter stating so (a so-called “no questions” letter).  A notifier can accept the risk that FDA will disagree with its notified GRAS determination, and proceed to market without first receiving a “no questions” response letter from the agency. 

In the case of Stevia-derived sweeteners, proceeding to market without a GRAS notice “no questions” letter from FDA may carry some added risks.  As recently as August 2007, FDA issued a warning letter to the manufacturer of a tea product in which the agency took the view that Stevia rebaudiana is an unapproved food additive that renders a food adulterated under FDC Act § 402(a)(2)(C).  Additionally, the Center for Science in the Public Interest ("CSPI") issued its own press release on December 15, the same day as the Cargill press release, in which it contends that additional tests are needed to demonstrate the safety of Stevia and rebaudioside A, and that “FDA should immediately order those products off the market until all the safety testing has been done.”  Also, there is pending before the agency a citizen petition contending that the addition of steviol glycosides (the sweetening components that can be extracted from Stevia) to food is prohibited by FDCA § 301(ll) (see Docket No. FDA-2008-P-0542).

By Ricardo Carvajal & John R. Fleder –

At the invitation of the U.S. Supreme Court, the federal government has recently filed a brief as amicus curiae in the case of Albertson’s, Inc. v. Kanter (No. 07-1327) in which the government argues against preemption of California law.  The case was brought by California consumers of farmed salmon who alleged that grocers engaged in false advertising and unfair and deceptive trade practices (among other things) when they failed to disclose the presence of color additives in their salmon, in alleged violation of California’s Sherman Food, Drug, and Cosmetic Law (“Sherman Law”).  The Sherman Law sets out food labeling requirements that are identical to those imposed under federal law.  Albertson’s argued that federal law preempts the private lawsuit brought by consumers under the Sherman law.  The trial court agreed and dismissed the lawsuit on preemption grounds.  That dismissal was upheld by the California Court of Appeal, but reversed by the California Supreme Court (see out previous post here).  Albertson’s then filed a petition for a writ of certiorari with the U.S. Supreme Court, which prompted a request by the Court for the Solicitor General’s views on the matter.

In part, the government’s brief argues that the language of FDC Act § 403A “strongly suggests” that States are free to adopt requirements identical to federal requirements, and notes that NLEA section 6(c)(1) explicitly limits the preemptive effect of the NLEA.  The federal government further argues that nothing in § 403A suggests Congressional intent to “limit the States’ authority to prescribe the remedies for violations of the state requirements permitted by [section 403A].”  For support, the brief draws on the Court’s prior holdings interpreting other FDC Act statutory provisions in Medtronic, Inc. v. Lohr, Riegel v. Medtronic, Inc., and Bates v. Dow Agroscience LLC.

The government also argues in its brief that the California action is not preempted by FDC Act § 310, which provides that proceedings for enforcement, or to restrain violations, of the FDC Act must be by and in the name of the U.S. (with the exception of certain actions brought by States in conformance with certain procedural requirements).  According to the government, “[a]ctions to enforce state laws that impose requirements identical to those under the FDCA are not actions to enforce the FDCA itself.”  The government’s brief further argues that this section does not preempt state law claims that “parallel” FDC Act requirements.  Moreover, the federal government stated that even when state-law claims are predicated on violations of the FDC Act, they remain state-law claims that are not preempted by federal law.

The accolades keep rolling on in . . . .  

USPharmD has named the FDA Law Blog one of the “Top 50 Medical Ethics Blogs.”  According to them, we will help you “[s]tay on top of current legal issues in the medical field.”  And all this time we were just trying to spell the big words correctly.

The USPharmD top blogs list is the second such list we’ve made in the past few months.  In September, RNCentral.com named FDA Law Blog to their “100 Best Health Care Policy Blogs.”

By Ricardo Carvajal –  

According to a recently-issued Letter to Manufacturers, FDA “feels it is imperative to remind its constituents that front-of-package symbols can at times constitute nutrient content claims” that are subject to FDA’s regulatory requirements at 21 C.F.R. 101.13 and Subpart D of Part 101.  A nutrient content claim is one that expressly or impliedly characterizes the level of a nutrient in a food (e.g., low fat, 100 calories).  Manufacturers are making increasing use of front-of-package symbols to convey information about the nutritional attributes of their products in a simplified, consumer-friendly format.  FDA has been aware of the trend, and held a public hearing on the subject in 2007.  But it appears that some manufacturers have been making express or implied nutrient content claims without adhering to the regulatory requirements that attach to such claims.  FDA states that it “will notify manufacturers when we see any front-of-package symbols that are explicit or implied nutrient content claims that are not consistent with current requirements or where such front-of-package symbols are used in a manner that is false or misleading.”  Although not noted in FDA's letter, it is permissible to include a statement in labeling about the amount or percentage of a nutrient present in a food if the conditions specified in 21 C.F.R. 101.13(i) are met.