By Ricardo Carvajal –

While calling for further research on bisphenol A ("BPA"), a chemical used in the manufacture of some plastics, FDA has acknowledged that it has "some concern about the safety of BPA:" 

At this interim stage, FDA shares the perspective of the National Toxicology Program that recent studies provide reason for some concern about the potential effects of BPA on the brain, behavior, and prostate gland of fetuses, infants and children.  FDA also recognizes substantial uncertainties with respect to the overall interpretation of these studies and their potential implications for human health effects of BPA exposure.  These uncertainties relate to issues such as the routes of exposure employed, the lack of consistency among some of the measured endpoints or results between studies, the relevance of some animal models to human health, differences in the metabolism (and detoxification) of and responses to BPA both at different ages and in different species, and limited or absent dose response information for some studies.

FDA is pursuing additional studies to address the uncertainties in the findings, seeking public input and input from other expert agencies, and supporting a shift to a more robust regulatory framework for oversight of BPA to be able to respond quickly, if necessary, to protect the public.

In addition, FDA is supporting reasonable steps to reduce human exposure to BPA, including actions by industry and recommendations to consumers on food preparation.  At this time, FDA is not recommending that families change the use of infant formula or foods, as the benefit of a stable source of good nutrition outweighs the potential risk of BPA exposure.

The agency is directing consumers to a list of "reasonable steps families and parents can take to minimize exposure to BPA" issued by the Department of Health and Human Services ("HHS").  According to HHS, domestic manufacturers have largely abandoned the use of BPA in the manufacture of bottles and cups for infants.  With respect to liquid infant formula sold in cans, HHS made clear that "[i]nfant formula in this packaging can offer important health advantages for some infants, and the proven benefit of good nutrition outweighs the potential risk of BPA exposure."  With respect to powdered infant formula mix, HHS noted that it "typically has no detectable level of BPA."

FDA's statement that it is "supporting a shift to a more robust regulatory framework for oversight of BPA" is of special interest to manufacturers.  The current food contact uses of BPA were approved through the issuance of food additive regulations before the advent of the notification process currently used for food contact substances.  Food additive regulations are not specific to manufacturers; thus, any manufacturer can use BPA consistent with an approving regulation without notifying the agency.  Further, amending or revoking a food additive regulation requires FDA to engage in rulemaking.  In contrast, food contact notifications are specific to manufacturers, and FDA can deem a food contact notification to no longer be "effective" upon written notice to the notifier and publication of a Federal Register notice – a mechanism that is much less burdensome than rulemaking. 

By Susan J. Matthees –

In July 2008, we blogged about the U.S. District Court for the Central District of California’s decision that found Purely Juice, Inc. liable under the Lanham Act for false advertising related to its pomegranate juice product.  Last month, the U.S. Court of Appeals for the Ninth Circuit affirmed the lower court’s decision, meaning Purely Juice must pay POM Wonderful damages of over $1 million, attorneys fees of over $600,000, and a disgorgement of profits of over $300,000. 

Purely Juice’s appeal contended, in part, that the district court’s standard for purity interfered with the authority of FDA.  The Ninth Circuit stated “POM did not sue to enforce the FDCA, and the facts show no encroachment on the FDA’s authority.”  The Ninth Circuit also held that the district court did not err by finding the Purely Juice had the requisite knowledge that its product was not 100% pure pomegranate juice and without sugar added, and that the president and founder of Purely Juice was personally liable. 

By Susan J. Matthees & Anne Marie Murphy –

On January 13, FDA announced the availability of a new draft guidance document titled, Guidance for IRBs, Clinical Investigators, and Sponsors: IRB Continuing Review After Clinical Investigation Approval.  Pursuant to FDA regulations 21 C.F.R. §§ 56.108(a) and 56.109(f), IRBs must have written procedures for, among other things, continuing reviews (at least annually) of IRB-approved clinical trials and  determining which of those studies require more frequent review.  The new guidance document outlines how IRBs can carry out these responsibilities and provides guidance on what information should be provided to the IRB to assist with continuing reviews.  In 2006, FDA announced an initiative to update its 1998 Information Sheets, which provide guidance to IRBs, Sponsors, and Investigators.  When finalized, the new guidance will supersede FDA’s Information Sheet, Continuing Review After Study Approval.  
  
To assist IRBs with their reviews, the draft guidance document includes a list of information that FDA recommends IRBs consider during the continuing review, e.g., summaries of subject withdrawals, summaries of complaints, and the current version of the protocol and informed consent documents in use.  For multi-center studies, “FDA recommends that sponsors provide IRBs directly with information from the entire study, data monitoring committee reports, and any other information about the test article.”  FDA also states that IRBs may have written procedures to delegate among individual IRB members portions of the IRB continuing reviews so that the workload is sufficiently distributed to allow efficient review. 

With regard to expedited procedures for continuing review, the document provides a discussion of two of the nine categories (published in the Federal Register, see 63 Fed. Reg. 60353, 60356 (Nov. 9, 1998)) of research eligible for the expedited review set forth in 21 C.F.R. § 56.110(b).  These two categories, categories (8) and (9), are the only categories that apply to continuing reviews.  Category (8) provides for expedited continuing review where the research is  permanently closed to new subjects, where no subjects have been enrolled and no additional risks have been identified, or where the remaining research is limited to data analysis.  Category (9) provides for expedited review where the research is not being conducted under an investigation new drug (IND) application or an investigational device exemption (IDE), expedited review categories (2) through (8) do not apply to the research, and the IRB has documented “that the research involves no greater than minimal risk to the subjects and no additional risks have been identified.” 

Pursuant to 21 C.F.R. §§ 56.108(a)(2) and 56.109(f), IRBs must determine the appropriate frequency of continuing reviews, i.e., identify studies that should be reviewed more frequently than annually.  The guidance document provides a list of factors that FDA recommends IRBs consider when determining the frequency of reviews.  These factors include the risks involved in the trials, vulnerability of the study population, experience of the investigators, the IRB’s history with the sponsor and/or investigator, and whether the studies involve novel therapies.   FDA recommends that IRBs “establish written procedures for informing investigators of the FDA’s regulations and the IRB’s own policies and procedures on continuing review requirements.” 

Other Clinical Trial-Related Developments:

On December 29, 2009, FDA announced a proposed rule that would amend the Agency’s informed consent regulations.  The Food and Drug Administration Amendments Act (FDAAA) § 801(b)(3)(A) amended the Public Health Service (PHS) Act to require that FDA promulgate regulations that would require the informed consent forms for “applicable” clinical drug trials  include a statement that clinical trial information has been or will be submitted to NIH/NLM for inclusion in the clinical trial registry databank (i.e., clinicaltrials.gov).  Although FDAAA § 801(b)(3)(A) requires this change for applicable drug trials only, FDA’s proposed rule would extend the change in the informed consent form requirements to applicable device trials as well. 

In October 2009, FDA announced the availability a guidance document titled, Guidance for Industry:  Investigator Responsibilities - Protecting the Rights, Safety, and Welfare of Study Subjects.  The guidance document provides information to investigators on how they can meet their responsibilities under 21 C.F.R. Parts 312 and 812 to both protect study participants and ensure the integrity of study data.  The guidance document covers topics such as delegation of study-related tasks among the trial staff, training of trial staff, supervision of the trial, investigators’ oversight responsibilities, medical care made available to study participants, and investigator responsibilities towards protocol violations that represent unreasonable risks.  This guidance document finalizes a draft guidance that was published in May 2007.  

By Peter M. Jaensch –
 
On January 14, 2010, the United States District Court for the District of Columbia issued a decision in Smoking Everywhere, Inc. and Sottera, Inc. d/b/a NJOY v. United States Food and Drug Administration, et al., in which the court granted the plaintiffs’ motion for a preliminary injunction, thereby enjoining FDA from regulating electronic cigarettes as drug-device combination products.  E-cigarettes, which are packaged to look and feel like real cigarettes, are intended to replicate smoking by vaporizing a nicotine liquid that the user then inhales – a process users call “vaping.”

The case arises from detentions imposed by FDA on the import of electronic cigarettes, which FDA contends are drug-devices under the FDCA and therefore subject to FDA regulation. The court concluded that treating e-cigarettes as drug-device combination products, rather than tobacco products, was unlawful, absent a showing that the products are intended to assist in treating nicotine addiction or to “affect the structure or function of the body in a way distinguishable from ‘customarily marketed’ tobacco products.” The court believed that doing so would frustrate Congress’ clear intent to distinguish FDA’s regulation of drugs and devices from its regulation of tobacco products.

The court did not opine whether FDA could regulate e-cigarettes under the Family Smoking Prevention and Tobacco Control Act, which was signed into law after the FDA detention had been imposed.  It would appear that FDA lacks such authority until it issues a regulation bringing e-cigarettes under its jurisdiction as tobacco products.

The decision holds out the potential for a far wider significance with regard to all products regulated by FDA.  In footnote 8, the court analyzes and rejects FDA’s position that its import decisions are unreviewable by courts. The ruling on this point will undoubtedly suggest that other importers of a variety of products regulated by FDA will sue FDA to challenge import decisions or at least use the threat of a suit as leverage to get FDA to allow imported products into the U.S.

By Kurt R. Karst –      

As we reported yesterday, the Federal Trade Commission (“FTC”) held a press conference on January 13, 2010 announcing the release of a report, titled “Pay-for-Delay: How Drug Company Pay-Offs Cost Consumers Billions,” on the effects of pay-for-delay deals in the drug industry over the past 6 years.  FTC Chairman Jon Leibowitz and Commissioner J. Thomas Rosch issued separate statements (here and here) about the report.  The FTC also announced the creation of a new pay-for-delay website providing information about the FTC’s work in the area of branded and generic drug competition.

The report, which has been timed to urge Congress to include pay-for-delay provisions in the Health Care Bill, estimates that pay-for-delay agreements “cost American consumers $3.5 billion per year – $35 billion over the next 10 years.”  The report concludes that “a legislative solution offers the quickest and clearest way to deter these agreements and obtain the benefits of generic competition for consumers.”  

The FTC report notes that although the U.S. Court of Appeals for the Sixth Circuit  held in 2003 that such agreements were per se illegal (In re Cardizem CD Antitrust Litigation, 332 F.3d 896 (6th Cir. 2003)), subsequent appellate court decisions upholding such agreements (Schering-Plough Corp. v. Fed. Trade Comm’n, 402 F.3d 1056 (11th Cir. 2005); In re Tamoxifen Citrate Antitrust Litigation, (2d Cir. 2006); In re Ciprofloxacin Hydrochloride Antitrust Litigation, 544 F.3d 1323 (Fed. Cir. 2008)) have led to their increasing use, as shown in the following table from the report:

(Information in the table above is based on submissions made to the FTC required by the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (“MMA”).  The MMA requires pharmaceutical applicants – both brand and generic – to file with the FTC and the Assistant Attorney General certain agreements executed on or after January 7, 2004.  Since the enactment of the MMA, the FTC has published summaries of these agreements.  Copies of previous summaries are available here.)

The FTC reportedly has “multiple investigations underway,” and has filed complaints opposing pay-for-delay arrangements concerning generic ANDROGEL (testosterone gel) (Fed. Trade Comm’n v. Watson, No. 09-cv-00598 (N.D. GA Feb. 9, 2009) (transfer order)) and PROVIGIL (modafinil) (Fed. Trade Comm’n v. Cephalon, No. 08-cv-2141-RBS (E.D. Pa. May 8, 2008) (transfer order)), respectively. 

Other findings discussed in the report include the following:

• “Agreements with compensation from the brand to the generic on average prohibit generic entry for nearly 17 months longer than agreements without payments, where the average is calculated using a weighted average based on sales of the drugs.”

• “From FY2004-FY2009, 66 final agreements involved some form of compensation from the brand to the generic combined with a delay in generic entry.”

• “Out of the 66 agreements that combined compensation from the brand to the generic with deferred generic entry, 51 agreements (77%) were between the brand pharmaceutical company and the generic company that was the first to seek entry prior to patent expiration for the relevant brand-name drug.”

• “From FY2004-FY2009, pharmaceutical companies filed a total of 218 final settlement agreements involving brand and generic companies. Seventy percent of those patent settlements – 152 – did not involve compensation from the brand to the generic combined with a delay in generic entry.”

• “About 25% of patent settlement agreements from FY2004-FY2008 that were with first-filer generics involved an explicit agreement by the brand not to launch an AG to compete against the first filer, combined with an agreement by the first-filer generic to defer entry past the date of the agreement.”

By Cassandra A. Soltis –

The Federal Trade Commission ("FTC") made clear in a recent opinion that the Federal Food, Drug, and Cosmetic Act ("FDC Act") is not binding on the Commission in its enforcement of Sections 5 and 12 of the Federal Trade Commission Act (FTC Act).  The Commission also addressed some First Amendment issues and described the type of substantiation necessary when making certain health-related efficacy claims.

The FTC upheld charges against Daniel Chapter One and James Feijo (the "Respondents") for unsubstantiated claims that the Respondents’ dietary supplements would prevent, treat, or cure cancer or tumors and other serious illnesses.  In the Matter of Daniel Chapter One and James Feijo, No. 9329 (Dec. 18, 2009), at 1.  The Commission disagreed with the Respondents’ argument that the claims made for the products were protected by the First Amendment because they were ideas or opinions about the products’ efficacy, stating that “Respondents made assertions not just about what they believed those products might do, but represented that the [dietary supplements] would in fact treat or cure cancer, prevent or shrink tumors, and ameliorate the side effects of radiation and chemotherapy.”  Id. at 12.  Furthermore, the FTC noted that the representations “constituted commercial speech, not simply practicing religion or engaging in ‘charitable solicitations,’” as the Respondents suggested.  Id. at 13.  The Commission indicated that because the speech in question was commercial in nature and false or misleading, it is not afforded First Amendment protection.  Id. at 14. 

The Commission also disagreed with the Respondents’ claim that the representations made for the dietary supplements were immune from FTC challenge because they were structure/function claims, as defined in the Dietary Supplement Health and Education Act ("DSHEA"), which amended the FDC Act.  Id. 16.  The FTC stated that the representations were not structure/function claims, and even if they were, DSHEA requires that they be truthful and not misleading and supported by adequate substantiation.  Id.  The Commission concluded that “even if the [FDC Act] departed from the FTC Act and its relevant case law, Respondents offer no authority that it would be binding on the Commission.”  Id.

According to Dr. Dennis Miller, who was the FTC’s expert and a board-certified pediatric hematologist/oncologist, in order to support a claim that a product “treats, cures, or prevents cancer, the products’ efficacy and safety must be demonstrated through controlled clinical studies (tests on humans).”  Id. at 18.  Dr. Miller also indicated that studies performed on animals or in test tubes are insufficient and that “the need to substantiate a claim by clinical studies (i.e., on humans) was the same whether the purported agent was a herbal medicine or a more conventional pharmaceutical agent.”  Id.

Dr. Miller concluded that the reference materials relied on by the Respondents “did not constitute competent and reliable scientific evidence that any of the [dietary supplements] prevent, treat or cure cancer; that most of those materials were not peer-reviewed papers but instead consisted of author opinions and literature reviews; that many of the studies involved in vitro or animal studies, not studies on humans; that [other reference materials] relied on the efficacy or safety of ingredients of the [dietary supplements] rather than the products themselves” and that, without evidence that the dietary supplements “contained exactly those ingredients in the proportion tested, those studies were not probative; and that there is no competent and reliable scientific evidence that the [dietary supplements] are effective, either alone or in combination with” the other products sold by the company.  Id. at 18-19.  For those reasons and others, the Commission denied the Respondents’ appeal and issued a final Order requiring the Respondents to cease certain practices. 

By Kurt R. Karst –      

Over the past several weeks, proponents of a ban on so-called pay-for-delay settlements have put a full-court press on Congressional leaders to include provisions in the final Health Care Bill.  The House bill  includes a provision (§ 2573) sponsored by Bobby Rush (D-IL) that would amend the FDC Act to add section 505(w) – “Protecting Consumer Access to Generic Drugs” – to, among other things, make it unlawful for any person from being a party to any agreement resolving or settling a patent infringement claim in which an ANDA applicant receives anything of value, and the ANDA applicant agrees not to research, develop, manufacture, market or sell the generic drug that is the subject of a patent infringement claim.  The Senate bill does not include a pay-for-delay provision sponsored by Sen. Herb Kohl (see our previous post here).

In late December 2009, several Senators wrote a letter to Senate leaders asking for the final Health Care Bill to include the House bill’s ban on pay-for-delay settlements.  “By adopting this provision, conferees can significantly address the rising costs of prescription drugs.  These ‘pay for delay’ agreements between brand name and generic drug companies deny consumers the benefits of generic drug competition,” according to the letter. 

On January 11, 2010, the American Antitrust Institute (“AAI”), among several other organizations, wrote a letter to Senate Majority Leader Harry Reid (D-NV) and House Speaker Nancy Pelosi (D-CA) encouraging inclusion of the Rush amendment in the final Health Care Bill, as well as the Drug Price Competition Act of 2009, which was introduced last year by Sen. Bill Nelson (D-FL), and in the house by Rep. Alcee Hastings (D-FL).  That bill would amend the definition of “first applicant” at FDC Act § 505(j)(5)(B)(iv)(II)(bb) with respect to 180-day exclusivity eligibility so that certain subsequent ANDA applicants could trigger and be eligible for exclusivity (see our previous post here).  According to the AAI letter:

[Pay-for-delay] payments are anticompetitive and should be considered per se illegal: they prevent any generic manufacturer with a legitimate challenge to a patent from potentially entering the market. . . . 

Expanding the exclusivity period is vitally important, since it removes the barrier to entry that has protected collusive settlements between brands and first-filing generics. Including this language in the final health reform legislation would provide a strong complement to Representative Rush’s per se ban on these payments.

Now it is the Federal Trade Commission’s (“FTC’s”) turn to put on the pressure.  On January 12, 2010, the FTC announced that it will hold a press conference at the Rayburn House Office Building on January 13, 2010 “to announce an FTC staff analysis showing that pay-for-delay deals between brand and generic drug companies are costing American consumers billions a year, and to encourage inclusion of the House-passed pay-for-delay provision in the final version of the health care reform bill.”  The FTC – and FTC Chairman Jon Leibowitz in particular – has made no bones about its opposition to pay-for-delay settlements.  In June 2009, Chairman Leibowitz said in a speech that eliminating “pay-for-delay” settlements could save consumers $3.5 billion annually.

By Ricardo Carvajal –

Californians won’t have to contend with this warning in their grocery stores – for now.  A California appellate court has upheld a lower court’s ruling that the Federal Meat Inspection Act (FMIA) preempts Proposition 65 point-of-sale warning requirements for meat.  The suit was filed by trade associations for the meat industry in response to notices of violation sent to meat processors and retailers by a California citizen.  Proposition 65 requires that such a notice be provided before the filing of a citizen suit to enforce that law.  The notices contended that certain meat products containing dioxins and PCB’s, both of which have been identified as carcinogens under Proposition 65, were being sold without a Proposition 65 warning (PCB’s are also listed as reproductive toxins).  Proposition 65 requires that a “clear and reasonable” warning be provided before consumers are exposed to a chemical “known to the state to cause cancer or reproductive toxicity.”  The trade associations sought a declaratory judgment that Proposition 65 is preempted by the FMIA.
 
The trial court granted summary judgment for the trade associations, and ruled that Proposition 65 was impliedly preempted by the FMIA.  The appellate court upheld the grant of summary judgment on the ground that Proposition 65 is expressly preempted by the FMIA.  The appellate court decision is worth reading for its extensive discussion of the scope of “labeling” as that term is used in the FMIA, FDCA, and FIFRA.  Based on its reading of those statutes and applicable judicial precedents, the appellate court concluded that the FMIA expressly preempts a Proposition 65 point-of-sale warning requirement because that warning would constitute “labeling” that is in addition to, or different than the FMIA's labeling requirements.  The appellate court relied on the definition of "labeling" in FDCA section 201(m), as interpreted by the United States Supreme Court in Kordel v. United States, 335 U.S. 345 (1948) (material constitutes labeling if it bears a “textual relationship” to the product, “supplements or explains” the product, and is “designed for use in the distribution and sale” of the product).  No word yet on whether there will be an appeal.

By Peter M. Jaensch –

On January 4, 2010, the Washington Legal Foundation (“WLF”) filed an amicus curiae brief in support of Ortho Biotech Products’ petition for a writ of certiorari in the Supreme Court of the United States, urging review of the decision in United States, ex rel. Mark Eugene Duxbury v. Ortho Biotech Products, L.P., 579 F.3d 13 (1st Cir. 2009).

As discussed in our earlier post, the underlying case asserted qui tam claims under the False Claims Act (“FCA”) against Ortho Biotech that were based on certain of the company’s product promotion activities, alleging promotion of off-label use, marketing the “spread” and providing “kickbacks” to providers in the form, among others, of free product samples.  The District Court dismissed all of the claims, citing multiple grounds.  On appeal, the First Circuit reversed in part, reviving only those claims attributable to Duxbury based on kickbacks.  Ortho Biotech petitioned for certiorari to the Supreme Court on December 3, 2009.  Such petitions are formal pleadings requesting the Court to exercise its discretion to review a lower court's decision, and are rarely granted.

As an amicus in support of Ortho Biotech’s petition, WLF argues that the FCA is meant to combat fraud, not legitimate product promotion, and that it cannot have been Congress’ intent to permit private suits against pharmaceutical and medical device companies for their truthful promotional activities absent the identification of any fraudulently-filed claim.  Ultimately, WLF argues the specific allegation of an actual false claim is a “threshold issue” without which Federal Rule of Civil Procedure 9(b) is dispositive, and requires dismissal of Respondent’s claims.  This argument is buttressed with a warning that, if unreviewed, the Duxbury decision threatens the ability of drug and medical device manufacturers to discuss freely and truthfully their products’ off-label uses and to distribute drug samples – activities which are beneficial to doctors and their patients.

By Dara Katcher Levy –

On December 23, 2009, FDA filed a Motion To Dismiss the First Fishery import matter that we previously blogged about back in late October.  In short, First Fishery had filed suit seeking declaratory judgment and injunctive relief with regard to its product’s placement on Import Alert 99-08 – Detention Without Physical Examination of Processed Foods for Pesticides.  First Fishery alleged that a finding of pesticide in its product was subject to an exemption under the Federal Food, Drug, and Cosmetic Act, and that there had been no final determination by FDA that the sampled product was violative before placing the product on Import Alert..

In its Motion to Dismiss, FDA acknowledges that in November, after correspondence with First Fishery and with the EPA (and after the First Fishery lawsuit was filed), FDA voluntarily released the detained entry and on December 3, 2009, removed the product from Import Alert.  Because of these actions, FDA asserts there is no remaining case or controversy and moves to dismiss.

This case is a prime example that, although FDA may have broad discretion over imports, an appropriate legal challenge in the correct circumstance may force FDA to rein itself in. 

By William T. Koustas –

In yet another twist in the debate regarding FDA’s use of Risk Evaluation and Mitigation Strategies (“REMS”), Kaiser Permanente (“Kaiser”), which is the largest private integrated health care delivery system in the U.S., submitted a citizen petition on December 22, 2009 requesting FDA take several actions in order to mitigate concerns it has with FDA’s implementation of REMS, specifically Elements to Assure Safe Use (“ETASU”). 

In its citizen petition, Kaiser notes that § 505-1 of the Federal Food, Drug and Cosmetic Act (“FDCA”) requires FDA to obtain input from health care providers, patients, etc. with regard to ETASU in order to ensure that a REMS is not unduly burdensome to the patient and to minimize the burden on the health care system.  However, with the exception of REMS for extended-release opioids, Kaiser claims that FDA has not publicly sought input from patients or health care providers on the implementation of REMS as required by § 505-1.  Kaiser further claims that REMS, especially those with ETASU, can add a significant burden to the delivery of health care and thus potentially increase the cost of REMS such that it outweighs the benefits.  As a consequence, Kaiser believes that health care providers and insurers should be consulted before a new REMS with ETASU is implemented.

Kaiser discusses five actions it would like FDA to take in order to minimize the burden of ETASU on health care providers as well as ensuring that they have a voice in the implementation of REMS.  First, Kaiser requests that FDA “increase transparency and opportunity for public comment in the development, implementation and assessment of REMS programs.”  As such, Kaiser would like FDA to provide increased opportunity for public comment on all REMS with ETASU; however, Kaiser also envisions FDA establishing an advisory committee dedicated to the review of ETASU.  In the interim, Kaiser suggests that advisory committees (with a health care provider member) reviewing drugs that will likely receive ETASU also have input on the ETASU itself.  Kaiser argues that this type of input before an ETASU is implemented could reduce the likelihood that the program will need to be altered later as well as lessening the burden on the health care system.

Second, Kaiser would like FDA to make de-identified data collected through the use of ETASU publically available, which would permit health care providers, and other parties, to identify the effectiveness of REMS. 

Third, Kaiser requests that FDA evaluate the effectiveness of ETASU that have been in effect for at least one year and extend that evaluation process to all ETASU on an annual basis.  Kaiser argues that this will ensure that the benefits of the REMS will continue to outweigh the cost to patients and the health care provider while also ensuring its success. 

Fourth, Kaiser’s citizen petition raises the issue of manufacturers using ETASU to limit access of a drug to certain health care providers.  Kaiser acknowledges that an ETASU may require that some drugs only be dispensed by certified pharmacies, but it argues that manufacturers have used this requirement to prevent or limit some health care providers from using their own facilities by refusing to certify them despite the fact that these pharmacies are otherwise qualified to dispense the drug.  According to the citizen petition, some manufacturers have refused to certify a Kaiser pharmacy for no reason other than the fact that the manufacturer has “contracted” with a specialty pharmacy, thus permitting manufacturers to dictate who can prescribe and dispense a drug with ETASU. 

Finally, Kaiser would like FDA to ensure that REMS are implemented in a way to protect patient health information.  Specifically, Kaiser expresses concern that patient enrollment forms for REMS include an authorization for disclosure of such information to third parties and some enrollment forms make receiving the drug contingent on patients accepting this.  Kaiser suggests that this concern could be alleviated if manufacturers were required to identify all entities they distribute patient information to as part of the regular REMS assessments.

By Alan M. Kirschenbaum –

On January 5, 2010, FDA released a “Guidance for Industry on New Contrast Indication Considerations for Device and Approved Drug and Biological Products.”  The primary purpose of the Guidance is to establish a process that allows imaging device manufacturers to obtain approval of new indications for use of a device with an already marketed contrast or radiopharmaceutical imaging drug (a “new contrast indication”), where the drug is not labeled for that indication.  FDA’s publication of the Guidance fulfills one of the Agency’s performance commitments under the Medical Device User Fee Amendments of 2007.  A draft version of this guidance was issued in September 2008, and FDA held a stakeholder meeting on the draft guidance in August 2009. 

Under the Guidance, if a new imaging device modification involves the use of an approved imaging drug in a manner consistent with the latter’s approved labeling, a submission from the device sponsor alone will be sufficient in most cases, without need for a change in the drug labeling.  Conversely, if a new imaging device modification requires a use of the approved imaging drug that is not consistent with the drug’s approved labeling, submissions will be required from both the drug and device sponsors to ensure consistent labeling – a situation that precludes a device manufacturer from implementing a modification unilaterally.  The final guidance provides a number of examples illustrating when a device submission alone would, or would not, be sufficient to support a new contrast indication for the device.  It appears from the examples that FDA will be restrictive in permitting new contrast indications for imaging devices without corresponding changes in the drug labeling.  Moreover, the Guidance requires device manufacturers who seek a new contrast indication modification to submit clinical study support similar to what would be required in an NDA supplement.  In light of these barriers, the Guidance is most likely to facilitate new device modifications for use with contrast only where the drug is used consistent with the indications, dosage, and rate and route of administration in the already approved drug labeling and where the new use does not raise new questions of safety and efficacy.

By David B. Clissold –

Acting on cross motions for summary judgment, a Federal District Court in Kentucky has struck down some provisions of the Family Smoking Prevention and Tobacco Control Act (“Tobacco Act”) as unconstitutional, and upheld others.  As we had reported earlier, the plaintiffs originally argued that portions of the Act violated their free speech rights under the First Amendment; their due process rights under the Fifth Amendment; and effected an unconstitutional “taking” of property under the Fifth Amendment.  For reasons that are not clear, the plaintiffs apparently abandoned most of their Fifth Amendment claims during the course of the proceedings.  Thus, the decision primarily concerned free speech.

Unconstitutional As A Violation Of Free Speech Under The First Amendment

The Tobacco Act provides that labeling or advertising for cigarettes or smokeless tobacco must use only black text on a white background.  The court held this portion of the law unconstitutional since “images of packages of their products, simple brand symbols, and some uses of color communicate important commercial information about their products” such as who makes the product.  In addition, the Tobacco Act's “blanket ban” on all uses of color and images was too broad since it also precluded use of “innocuous images and colors – e.g., images that teach adult consumers how to use novel tobacco products, images that merely identify products and producers, and colors that communicate information about the nature of a product . . .”

The Tobacco Act prohibits any statement in labeling or through the media suggesting that the product was approved by FDA, that FDA deems the product to be safe, or that FDA endorsed the use of the product.  The court held that these prohibitions were reasonable.  However, the law also banned statements suggesting that “the product is safe or less harmful” because it was regulated or inspected by FDA or that it was in compliance with FDA regulations.  This was held to be unconstitutional since it banned “journalists, doctors, scientists, politicians, and numerous other groups and individuals” from making statements about the effect of the FDA regulation of tobacco products.

Too Early To Tell Whether Constitutional Under The First Amendment

The Tobacco Act bans all “outdoor advertising for cigarettes or smokeless tobacco, including billboards, posters, or placards, . . . within 1,000 feet of the perimeter of any public playground or playground area in a public park . . ., elementary school, or secondary school.”  However FDA must issue a regulation “in light of governing First Amendment case law,” explaining how this ban will be enforced before it can take effect.  The court held it could not examine this issue until FDA had issued the final regulation.

Constitutional Under The First Amendment

The Tobacco Act requires tobacco companies to print new government warnings for cigarette packages that occupy the top 50% of the front and rear panels of packaging and include “color graphics depicting the negative health consequences of smoking to accompany the label statements.” Similar warnings, occupying 30% of each of the two principal display panels, are required for smokeless tobacco products.  For all categories of tobacco products, the new warnings must occupy 20% of any advertisements.  The court held that such requirements were reasonable in part because Congress “relied on the international consensus reflected in the World Health Organization’s Framework Convention on Tobacco Control” and also reviewed “the use of a nearly identical warning requirement in Canada.”  The court also noted that even with the warnings, a substantial amount of area remained for use by the manufacturers.  However, the court ruled that the plaintiffs’ takings claim under the 5th Amendment needed to be brought in the Court of Federal Claims, and so the court lacked jurisdiction to decide that issue.

Manufacturers can not promote their brands through sponsorship of “athletic, musical, artistic, or other social or cultural event[s]” and FDA must reissue regulations that prohibit the sponsorship of athletic, social, and cultural events “in the brand name” of a tobacco product.  The court found because such events “glamorized” smoking and that many children were exposed to the events, the limitations on sponsorship were permitted.  The law also directs FDA to reissue regulations that prevent a tobacco manufacturer from distributing items such as caps and t-shirts that bear the name or logo of a tobacco brand.  The court agreed that it was impossible to limit the distribution of these items to adults only and noted that even if it was, the wearers would become “walking advertisements” conveying the notion “that tobacco use is widely accepted.”  Accordingly, the court held that the ban on such items was constitutional. With respect to the law's ban on free samples, gifts with purchase, and marketing tobacco products with non-tobacco products, the court held that these provisions restricted distribution, but did not implicate free speech rights.

The Tobacco Act’s Modified Risk Tobacco Products (“MRTP”) provision prohibits the labeling, or advertising of a tobacco product from suggesting that the product is less harmful than other tobacco products, and prohibits manufacturers from taking any action that would be reasonably expected to result in consumers believing that the tobacco product or its smoke may be less harmful than other tobacco products, without prior FDA approval of the product as “modified risk.” The plaintiffs had already lost a motion for a preliminary injunction in November 2009 that this law violated free speech.  None of the arguments presented subsequently were enough to change the court’s mind.

Conclusion

Both sides can claim at least partial victory under this decision, and it is not yet clear whether any of the parties will appeal any portion of the ruling.  In upholding many of the challenged provisions of the Tobacco Act, the court relied on Congressional findings and reports from the Institute of Medicine, World Health Organization, National Cancer Institute, and other organizations that focused on the effect that tobacco advertising may have on underage smoking.  The court agreed that preventing children from smoking was a “substantial” government interest, and found that most of the Tobacco Act’s provisions controlling the advertising and promotion of cigarettes and smokeless tobacco were directly related to promoting that interest.  Aside from any appeal in this case, the next significant challenge is likely to be whether FDA’s regulation to control outdoor advertising passes constitutional muster.

By Kurt R. Karst –      

Following FDA’s decision, reflected in the October 2009 Orange Book Cumulative Supplement (page A-28), to grant 5-year New Chemical Entity Exclusivity (“NCE”) for EMEND (fosaprepitant dimeglumine) Injection, the Agency has issued an exclusivity determination explaining its decision.  Fosaprepitant is a phosphamide derivative (a type of covalent derivative) and a pro-drug of the previously-approved active ingredient in EMEND (aprepitant) Capsules (NDA No. 21-549).

Under the FDC Act, FDA grants 5-year exclusivity for NCEs.  An NCE is a drug that contains no “active moiety” that has been approved by FDA in another NDA.  An “active moiety” is defined in FDA’s regulations at 21 C.F.R. § 314.108(a) to mean “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.”  In addition, FDA stated in the preamble to the Agency’s 1989 proposed regulations implementing the Hatch-Waxman Amendments that “[a] compound (other than an ester) that requires metabolic conversion to produce an already approved active moiety is considered a ‘new molecular entity,’ . . . and will be considered a new chemical entity entitled to 5 years of exclusivity. 

Thus, for purposes of determining whether a particular drug product is eligible for 5-year NCE exclusivity, FDA’s Exclusivity Summary completed for each NDA approval asks the following about the chemical structure of a drug:

Has FDA previously approved under section 505 of the Act any drug product containing the same active moiety as the drug under consideration?  Answer “yes” if the active moiety (including other esterified forms, salts, complexes, chelates or clathrates) has been previously approved, but this particular form of the active moiety, e.g., this particular ester or salt (including salts with hydrogen or coordination bonding) or other non-covalent derivative (such as a complex, chelate, or clathrate) has not been approved.  Answer “no” if the compound requires metabolic conversion (other than deesterification of an esterified form of the drug) to produce an already approved active moiety.

According to FDA’s exclusivity determination memorandum, which was added to the Summary Basis of Approval for EMEND (NDA No. 22-023):

Emend for Injection under FDA’s interpretation of 21 CFR § 314.108 should have been classified at the time of approval as an NCE. . . .  Fosaprepitant dimeglumine is a pro-drug phosphoramide derivative of aprepitant.  A phosphoramide is a compound in which one or more of the OR groups of phosphoric acid have been replaced with covalent bonds to an amino or substituted amino group.  Fosaprepitant dimeglumine is neither an ester, salt (including a salt with hydrogen or coordination bonds), nor other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule aprepitant.  It is a covalent phosphoramide derivative.  As a non-ester covalent derivative of aprepitant, under 21 CFR § 314.108, fosaprepitant dimeglumine is a new chemical entity entitled to 5 years of exclusivity.

Fosaprepitant is not the first instance in which FDA has reversed an exclusivity decision.  In October 2004, FDA informed the sponsor of VITRASE (hyaluronidase) Injection that contrary to the Agency’s earlier decision to grant 3-year exclusivity for the product, “[a]fter reviewing information and data regarding hyaluronidase drug products . . . the Agency has decided that 5-year exclusivity is appropriate because we have inadequate information to determine whether any active moiety in Vitrase is the same as any previously approved active moiety.”

By Kurt R. Karst –      

A recent Impact Report (subscription required) from the Tufts Center for the Study of Drug Development (“CSDD”), titled “Drug approvals for neglected diseases increase along with more R&D funding,” concludes that new products to treat neglected diseases (such as malaria, kinetoplastids, diarrheal diseases, roundworm, bacterial pneumonia and meningitis, and typhoid and paratyphoid fever) have received marketing approval from regulatory agencies at a steadily increasing rate in the past several years as research and development  funding for neglected diseases has dramatically increased.  The report is based on research conducted by CSDD Senior Research Fellow Joshua P Cohen.  

Among other things, CSDD found that:

• The annual rate of new product approvals for neglected diseases increased from an average of 1.8 in 1975-1999 to 2.6 in 2000-2009;

• Between 1999 and 2008, annual funding for neglected diseases rose from less than $100 million annually to more than $2.5 billion today, and today government research and development funding accounts for 69% of all neglected disease product development funding, with non-profit organizations and the drug industry contributing 21% and 10%, respectively;

• Vaccines have displaced drugs as the primary products being developed for neglected diseases, and products to treat HIV/AIDS and malaria accounted for 81% of negelected disease approvals from 2000-2009;

• Public-private partnerships for new product development accounted for 46% of all approvals to treat neglected diseases in 2000-2009, which is up from 15% in 1975-1999.

A provision included in the Agriculture, Rural Development, FDA, and Related Agencies Appropriations Act of 2010, Pub. L. No. 111-80, could also lead to a greater number of products approved to treat neglected diseases in the coming years.  As we previously reported, § 740 of the law requires FDA to 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.”  FDA is also required to submit a report to Congress on the review group’s findings and recommendations, and to issue guidance and develop internal review standards based on those recommendations.