FDA Issues Warning to Mylan Over CGMP Violations

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On November 22, 2011, the U.S. Food and Drug Administration (FDA) published a Warning Letter to Mylan, Inc. Found here, the October 13, 2011 Warning Letter cites Mylan for “significant violations of current good manufacturing practice regulations.” The Warning Letter came as a result of inspections of Mylans Puerto Rico plant, which took place in January and February of 2011. While the Warning Letter came roughly seven months after the inspections uncovered these deficiencies, Mylan was unable to demonstrate to the Agency that it was otherwise compliance with applicable requirements under the law.

FDAs Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals are set forth in 21 C.F.R. part 211. These regulations provide the minimum standards for which manufacturers must follow and cover a range of manufacturing activities, including required personnel, standards for sanitation of buildings and equipment, as well as recordkeeping requirements and laboratory controls. In the present case, Mylan was cited for various CGMP violations, including failure to establish required laboratory controls. In particular, FDA cited the company for failing to test each patch of its drug product to ensure that it conforms to final specifications for the drug product, as provided by 21 C.F.R. § 211.165(a).

While the violations cited in the Warning Letter were observed upon FDA inspections of Mylans plant earlier this year, the Letter was issued only recently after the company failed to demonstrate to the FDA that it has taken all necessary corrective actions. In addition to notifying the particular firm, FDA Warning Letters notify the public that a particular firm has allegedly violated federal law. Thus, given the bad publicity that these letters generate, it is advantageous for firms to correct possible violations even before the FDA issues Warning Letters.

For more information about CGMP requirements or FDA enforcement action please contact us at contact@fidjlaw.com.

Hill Dermaceuticals Sues FDA Following Approval of Generic Derma-Smoothe

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On November 4, 2011, Hill Dermaceuticals, Inc. (Hill), a Florida-based drug manufacturer, sued the U.S. Food and Drug Administration (FDA). Hill brought suit in connection with the FDAs recent approval of three Abbreviated New Drug Applications (ANDAs) submitted by Identi Pharmaceuticals (Identi). Hill, the manufacturer of Derma-Smoothe, an FDA-approved skin treatment, alleges that FDAs recent approvals of the generic formulations of its drug violate the Federal Food, Drug and Cosmetic Act (FDCA).

Found here, Hills Complaint alleges that the FDAs approvals of Identis ANDAs were arbitrary and capricious. In short, Hill alleges that in approving the ANDAs, FDA treated Identi differently and in contravention of the FDCA by foregoing certain testing to show that the drugs are safe for consumers. Because Derma-Smoothe is a topical treatment derived from peanut oil (a major allergen), FDA required Hill to perform testing to show that the refined oils in the drug contained only trace amounts of amino acids. Still required to test every batch it produces, Hill claims that it has “invested more than $1 million to license and develop a proprietary amino-acid analysis.” Because the methods Hill uses to test its products are proprietary, Hill alleges based on information and belief that FDA has approved Identis applications without requiring such testing or verification that Identis drugs have similarly low levels of amino acid.

Further, because Hill is required to declare that Derma-Smoothe has undergone such testing on the label of each product, Hill claims that Identis products cannot be approved as a generic form of Derma-Smoothe because the drug cannot contain such a declaration in product labeling. Under FDA regulations, generic formulations of drugs undergo approval through an Abbreviated New Drug Application (ANDA). Unlike a New Drug Application (NDA), an ANDA requires the manufacturer to demonstrate that its drug is bioequivalent to a drug approved via an NDA. This showing generally requires the generic to demonstrate that it contains the same active ingredients, is used in the same manner and will bear largely the same labeling. Thus, assuming the Hill case survives a motion to dismiss filed by the FDA, the Hill case will confront the extent of the differences that are permissible in product labeling in order for the Agency to make a finding of bioequivalence under the FDCA.  

Fuerst Ittleman will continue to monitor the developments of the Hill case. For more information regarding the ANDA generic drug approval process or for any questions regarding how your company can maintain FDA regulatory compliance, please contact us at contact@fidjlaw.com.

10th Circuit Dismisses Claims against FDA for Failure to Exhaust Administrative Remedies

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On November 3, 2011, the U.S. Court of Appeals for the Tenth Circuit affirmed the findings of the District of Wyoming, granting the dismissal of the lawsuit filed by Cody Laboratories, Inc. (Cody) and Lannett Co., Inc. (Lannett) and finding in favor of the U.S. Food and Drug Administration (FDA). Finding that the companies had failed to exhaust administrative remedies, the Tenth Circuit found that it was without jurisdiction to decide the merits of the companies claims. The Tenth Circuit decision may be accessed here.

The lawsuit ultimately arose from two FDA Warning Letters that were issued to Cody and Lannett in 2009. Found here and here, the Warning Letters contain directives from the FDA to cease all manufacturing of unapproved morphine sulfate products, finding that they did not constitute grandfathered drugs under the Federal Food, Drug and Cosmetic Act (FDCA). Grandfathered drugs are those that entered the market prior to the enactment of the FDCA in 1938 and its 1962 amendments and are exempted from the requirement to show effectiveness. Finding that the products were not grandfathered drugs, the FDA concluded that the products were new drugs under the FDCA, thus requiring NDAs. In response to the companies challenge to the lawfulness of the warning letters, the District Court for the District of Wyoming found that because warning letters did not constitute final agency action, it lacked the jurisdiction to entertain the suit.

On appeal, the Tenth Circuit held that the companies claims were not reviewable because the companies had failed to exhaust their available administrative remedies. In particular, the Tenth Circuit found that the failure to utilize the citizen petition procedure provided by the FDA rendered the companies claims unreviewable. 21 C.F.R. § 10.30 provides a citizen petition procedure which affords interested parties the opportunity to receive FDA review of an otherwise unfavorable Agency decision or action. Because Cody and Lannett failed to complete this internal agency review in connection with the decision that the products constituted new drugs under the FDCA, the Tenth Circuit affirmed the district courts decision that it was without jurisdiction to consider the merits of the companies claims.

Warning letters are generally the Agencys first course of action upon discovery of a violation of the FDCA and/or FDA regulations. These letters provide formal notification to offending parties of the specific violations that FDA has observed and gives them the opportunity to respond. If after receiving a FDA Warning Letter the offending party takes all necessary measures to correct such violations, the FDA will typically take no further action. However, because these letters and the suggested corrective measures therein do not technically bind named parties to a specific course of action, courts have found that FDA Warning Letters do not constitute final agency action for the purpose of judicial review. This is so even though it is the practice of FDA to post all warning letters onto its website and thereby subject the offending party to public criticism.

A citizen petition is initiated by an interested party and seeks some form of relief from FDA action. In holding that the companies did not exhaust their administrative remedies because they failed to file citizen petitions, the court appears to have overestimated the efficacy of this process. For instance, citizen petitions are often thought to be an ineffective means for challenging FDA action because FDAs regulations allow for the FDA to indefinitely delay decision-making with little recourse for the interested party. In particular, 21 C.F.R. § 10.30(e)(2) provides that the FDA may respond within 180 days by either approving, denying, or withholding a final decision of a citizen petition. Where a final decision is withheld upon conclusion of the 180 day time period, the FDAs reasoning may be that it has not had the opportunity to render a decision because of other Agency priorities, thus prolonging the timeframe for obtaining final agency action. Thus, because the FDA is not forced to provide a final decision within a definitive timeframe, citizen petitions are often viewed as a woefully ineffective means of obtaining relief.

For more information concerning the FDCA or FDA regulations, please contact us at contact@fidjlaw.com.

FDA Issues SOP Aimed at Standardizing Data Requirements for Premarket Submissions

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On November 9, 2011, the U.S. Food and Drug Administration (FDA) published “SOP: Decision Authority for Additional or Changed Data Needs for Premarket Submissions.” The document sets forth limitations to the data requirements that agency reviewers may request when reviewing various types of premarket submissions for medical devices. Found here, the document details how reviewers will be limited in the information they request by requiring managements approval, or “concurrence,” in order to seek new or additional data from those seeking agency review.

Prior to the SOP, there was no written policy in place serving to limit reviewers data requests. Thus, device sponsors often found data requests onerous and irrelevant to the safety and efficacy of medical devices. Hopefully, limitations to such data requests will benefit device sponsors by increasing the predictability and efficiency of the premarket review process.

For more information regarding the FDA premarket review process, contact us at contact@fidjlaw.com.

FDA Withdraws Approval of Breast Cancer Indication from Avastin Label

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On November 18, 2011, the U.S. Food and Drug Administration (FDA) announced its decision to revoke the approval of the breast cancer indication for Avastin. Because Avastin will still be approved for its other uses, including the treatment of brain, kidney, lung and colon cancer, the drug will remain on the market despite this recent decision. The FDA initially approved Avastin for the treatment of breast cancer based on evidence showing that the drug may restrict tumor growth. However, according to the FDAs decision to revoke its approval, further clinical data has shown that the drug may only marginally limit tumor growth.

Found here, the decision of FDA Commissioner Margaret Hamburg details the procedures whereby Avastin gained approval for this indication and the reasoning for its recent revocation. In 2008, FDAs Center for Drug Evaluation and Research (CDER) approved Avastin for the treatment of breast cancer through the Agencys accelerated approval process. Set forth in 21 C.F.R. § 601.40-46, this process allows biological products to secure approval for the treatment of life-threatening diseases upon showing some evidence that the drug may provide clinical benefit. However, as a condition to accelerated approval, manufacturers are required to continue clinical testing and report their findings to the FDA. Under 21 C.F.R. § 601.43(a), the FDA may withdraw approval where the required postmarketing testing “fails to verify clinical benefit,” where applicants are noncompliant in performing such testing, and where applicants otherwise fail to comply with other postmarketing restrictions.

Because FDA determined that further studies did not verify the level of clinical benefit that prompted the original approval, CDER proposed its withdrawal of approval for this indication in December 2010. Thereafter Avastins sponsor, Genentech, Inc., was afforded an opportunity to show the FDA why this approval should not be withdrawn. This opportunity for hearing is mandated by 21 C.F.R. § 601.43(b). Genentechs arguments were unavailing, and the FDA ultimately withdrew its approval for the breast cancer indication.

While this indication is no longer permitted in product labeling, doctors may still prescribe the drug for use in the treatment of breast cancer. Although manufacturers are limited to marketing drugs for the indications approved in product labeling, FDA regulations do not prevent doctors from prescribing drugs for other uses, a practice known as “off-label” use. Thus, despite the revocation of this indication in product labeling, Avastin may continue to be used to treat breast cancer.

For more information regarding the FDAs drug approval process, please contact us at contact@fidjlaw.com.

FDA Approves First Blood Product for Stem Cell Therapy

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On November 10, 2011, the U.S. Food and Drug Administration (FDA) announced its approval of the first blood product derived from cord blood indicated for treatment as a stem cell therapy. HEMACORD, the hematopoietic progenitor cell-cord (HPC-C) blood product, is intended for use in HPC transplant procedures for individuals affected with various blood disorders.

FDA has recently begun requiring HPC-C manufacturers to submit license applications or investigational new drug applications in order to market these products. Having issued a guidance document detailing the regulatory requirements in 2009, FDA instituted a two-year phase-in period for HPC-C manufacturers. According to the FDA’s press release detailing the approval, found here, HEMACORD marks the first approval of a license application for cord blood as the Agency’s two-year phase-in period for HPC-C manufacturers comes to a close. The phase-in period ended on October 20, 2011.  While the regulatory environment surrounding HPCs and stem cells in general has proven cumbersome to manufacturers, with approvals being scarce since the regulations were promulgated in 2001, the approval may be the first of many in the coming years.

We question, however, whether this “product” approval will ultimately benefit anyone. Doctors have been treating their patients using cord blood for more than 20 years, and more than 20,000 patients have been successfully treated in that time. More information about the history of cord blood transplantation may be found here.

For more information about the FDA regulations or the FDA approval process, contact us at contact@fidjlaw.com.

Bill Aims to Increase Number of Grandfathered Dietary Ingredients

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On November 4, 2011, a Bill was introduced before the U.S. House of Representatives that proposes to restrict the definition of “new dietary ingredient” (NDI) under the Federal Food, Drug and Cosmetic Act (FDCA). Introduced by Representative Dan Burton, the “Dietary Supplement Protection Act of 2011” seeks to alter the current definition of NDI by changing the applicable dates for which a dietary ingredient must have previously been marketed in the United States.

Currently, a NDI is defined under the FDCA as “a dietary ingredient that was not marketed in the United States before October 15, 1994 and does not include any dietary ingredient which was marketed in the United States before October 15, 1994.” 21 U.S.C. § 350(b). Those dietary ingredients that are not considered NDIs are commonly referred to as “grandfathered” ingredients. Under the FDCA, only grandfathered ingredients are “generally recognized as safe” (GRAS) for human consumption and may be used as ingredients in dietary supplements without prior FDA notification. On the other hand, if an ingredient is considered a NDI, manufacturers must notify the FDA prior to marketing any product containing such an ingredient. Under 21 C.F.R. § 190.6, manufacturers of dietary supplements containing NDIs must submit a premarket notification, demonstrating that these ingredients are safe for human consumption, at least 75 days before marketing their products.

Found here, the Bill proposes to amend the FDCA “by striking ‘October 15, 1994’ each place it appears and inserting ‘January 1, 2007’.” According to the Bill, Congress believes that the definition of grandfathered ingredients is too narrow based on current knowledge on a range of dietary ingredients and their safety for human consumption. Thus, the Bill will limit the definition of NDI, while at the same time expanding the scope of ingredients that are considered grandfathered under the Act.

For more information about the FDCA or FDA regulations, please contact us at contact@fidjlaw.com.

WTO Finds Country of Origin Labeling a Technical Barrier to Trade

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On November 18, 2011, the World Trade Organization (WTO) published its report on the ongoing Country of Origin Labeling (COOL) dispute. Implemented in 2008 as part of the Farm Bill, U.S. manufacturers began requiring country-of-origin to be designated in labeling of meats and other goods regulated by the U.S. Department of Agriculture (USDA). Found here, the WTO report details the complaints raised by Canada and Mexico, including the contention that the labeling requirements constitute Technical Barriers to Trade (TBT), in violation of international treaties between the countries.

Ultimately, the WTOs decision was mixed. While the COOL requirements were generally found to pose technical barriers to trade by discouraging imports from Canada and Mexico, the U.S. did not lose out completely. Rather, WTO decided that although the COOL requirements must stop generally, there are certain exceptions to its findings, including meat. Thus, country of origin labeling will continue to be declared on meat products in the United States without further issue from Canada or Mexico. In addition, because the decisions of the WTO are not technically binding, it is possible for the COOL program to continue in the United States with only informal action, such as tariffs, etc., available as recourse.

For more information about USDA labeling requirements, contact us at contact@fidjlaw.com.

FDA Appeals Finding that it Lacks Power to Prohibit State-Licensed Veterinary Compounding

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On November 11, 2011, the U.S. Food and Drug Administration (FDA) appealed a recent decision issued by the District Court for the Middle District of Florida, finding that the FDA lacked the authority to prohibit state-licensed veterinary compounding. The September 12, 2011 decision being appealed details the longstanding practice of pharmacy compounding in the context of veterinary medicine.

Compounding is commonly defined by state law as the practice of filling prescriptions through individualized preparation, as opposed to the manufacturing of drugs in bulk. Unlike the compounding of human drugs, over which the FDA acknowledges it lacks full regulatory control if the compounding pharmacy meets certain requirements, the FDA maintains that it possesses the authority to regulate veterinary compounding.

The case originated after the accidental death of 21 polo horses that received compounded drugs from Franck’s Lab, Inc. (Franck’s), an incident that was ultimately linked to a mathematical error in the issuing veterinarian’s prescription. In addition, Franck’s had received FDA Warning Letters in 2004 and 2005, alleging that Franck’s was impermissibly manufacturing drugs in violation of the Federal Food, Drug and Cosmetic Act (FDCA). In response to the Warning Letters, Franck’s argued that “[s]tate law and good compounding practices . . . allow bulk compounding as long as there is a valid patient physician (veterinarian) relationship.” Because the FDA permits compounding of drugs for human use, Franck’s argued that the FDA must allow the same for veterinary compounding. The FDA, however, rejected this argument and brought suit against Franck’s in April 2010 seeking injunctive relief to stop Franck’s from compounding and distributing animal drugs.

In its order, the District Court found for Franck’s and held that because the states have traditionally exercised authority over pharmacy compounding, the states likewise have the authority to regulate the compounding of animal drugs. By filing its notice of appeal, the FDA has signaled that it is not willing to concede the issue of its authority to regulate veterinary compounding.

Fuerst Ittleman will continue to monitor the Franck’s case. For more information, please contact us at contact@fidjlaw.com.

Update: Court Issues Preliminary Injunction Blocking FDA’s Graphic Smoking Warning Labels From Going Into Effect

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On November 7, 2011, Judge Richard Leon of the United States District Court for the District of Columbia granted a preliminary injunction on behalf of five tobacco companies challenging the implementation of the FDAs new graphic cigarette warning labels. As a result of the injunction, the FDAs new cigarette labeling requirements, which were scheduled to take effect in September 2012, are now blocked from taking effect until fifteen months after resolution of the plaintiffs claims on the merits. A copy of the Courts opinion can be read here.

As we previously reported, on June 21, 2011, pursuant to the authority granted to it by the Family Smoking Prevention and Tobacco Control Act to regulate tobacco, the FDA released nine new graphic warning labels that were required to appear on every pack of cigarettes sold in the US and in every cigarette advertisement starting no later than September 2012. In response to the FDAs new rule, five tobacco companies (R.J. Reynolds Tobacco Company, Lorillard Tobacco Company, Commonwealth Brands, Inc., Liggett Group LLC, and Santa Fe Natural Tobacco Company, Inc.) filed a complaint in the United States District Court for the District of Columbia alleging that the FDAs new cigarette labeling rules violated the First Amendment and the Administrative Procedure Act.

The five companies also sought an injunction to prohibit the rules from going into effect until fifteen months after a final decision has been rendered on the merits of their case. More background information involving this case can be read in our prior report here. In order for a court to grant a preliminary injunction, it must determine the following: 1) whether there is a substantial likelihood of success on the merits for the moving party; 2) whether the movant will suffer irreparable harm if the injunction is not granted; 3) whether the injunction will substantially injure other interested parties; and 4) whether the public interest would be furthered by the injunction. See Mova Pharm. Corp. v. Shalala, 140 F.3d 1060, 1066 (D.C. Cir. 1998). However, “the party seeking a preliminary injunction need not prevail on each factor.” R.J. Reynolds Tobacco Company, Inc. v. U.S. Food and Drug Administration, 11-1482, at 9 (November 7, 2011 D.D.C.). Rather, the court “appl[ies] the factors on a sliding scale.” Id. As a result, “if the arguments for one factor are particularly strong, an injunction may issue even if the arguments in the other areas are rather weak.” Id.

More specifically, the tobacco companies alleged that the requirement to place graphic images on its labels unconstitutionally compels speech. Generally speaking, compelled speech is presumptively unconstitutional and will only be upheld if it passes “strict scrutiny,” i.e.: 1) the government has a compelling interest it seeks to protect; and 2) the regulation is narrowly tailored to achieve that interest. However, as explained by the Court, narrow exceptions apply in the area of commercial speech. The government may require disclosure of only “purely factual and uncontroversial information” to protect consumers from “confusion or deception,” unless such a disclosure is “unjustified or unduly burdensome.” A lower level of scrutiny applies in cases where government- compelled speech meets this narrow exception.

In this case, the Court determined that the FDAs rule did meet the narrow exception for compelled commercial speech for several reasons. First, the Court found that the images could not be considered purely factual because must were either digitally enhanced or manipulated to depict the negative consequences of smoking. Second, the Court found that the FDAs argument that the images chosen by the rule were uncontroversial and purely factual was undermined by the fact that the FDAs selected graphic images were designed to evoke viewers emotions. Finally, the Court found that when the graphic images were combined with the textual warnings and the mandatory display of the 1-800-QUIT-NOW smoking cessation hotline, the goal was to induce the viewer to quit or never start smoking. Thus, the Court found that the FDAs labels were neither purely factual nor uncontroversial. Therefore, strict scrutiny and not a lower, more-deferential level of scrutiny applied.

In evaluating whether the FDAs labeling rule passed constitutional muster, the Court found that regardless of whether the governments interest in providing information to consumers is compelling, the FDAs rule is not narrowly tailored to achieve such a purpose. The Court noted that the size and display requirements of the rule — the top 50% of the front and back panels of all cigarette packages and the top 20% of printed advertising — is not narrowly designed to achieve an informative purpose. Rather, the Court found that such dimensions promote a government sponsored anti-smoking message. Additionally, the Court found that the graphic warnings when combined with the textual messages and the 1-800 number result in the FDA “conscript[ing] tobacco manufacturers into an anti-smoking brigade.” Thus, the Court found that the tobacco manufacturers have a substantial likelihood of success on the merits because the FDAs labeling requirements are likely to be found violative of the First Amendment.

The Court also found that the plaintiffs satisfied the other prongs necessary to be granted a preliminary injunction. The Court found that because of the plaintiffs likelihood of success on the merits and the fact that litigation would likely continue well beyond the September 2012 effective date, the plaintiffs would suffer irreparable harm if an injunction was not issued. Additionally, the Court found that injunctive relief would not harm any interested third parties because, based on the record, Congress did not demonstrate that such rules were urgent. In so finding, the Court noted that the Tobacco Act established a mutli-stage timeline in which the FDA was given two years to promulgate a Final Rule and a 15 month implementation period before the Final Rule took effect. Therefore, the Court found no prejudice to other third parties. Finally, the Court found that the “public interest will be served by ensuring that plaintiffs First Amendment rights are not infringed before the constitutionality of the regulation has been definitively determined.” As such, the Court granted the tobacco companies injunction.

Although the preliminary injunction is effective as of the Courts order, the government does have the ability to file an interlocutory appeal challenging the Courts decision. If the government does appeal and is successful, then the District Courts preliminary injunction will be vacated. A similar situation arose in Sherley v. Sebelius, a case involving a challenge to federal funding for stem cell research. In that case, the plaintiffs were granted a preliminary injunction to prevent the NIH funding guidelines from taking effect. However, as we previously reported, the D.C. Circuit vacated the preliminary injunction on appeal and remanded the case to the district court for resolution on its merits.

The practical effect of a successful government appeal would be that, although tobacco companies would still be able to challenge the FDAs rule on the merits, the companies would still have to comply with the FDAs new labeling requirements starting September 2012.

Fuerst Ittleman will continue to monitor the progress of this lawsuit and the FDAs regulation of tobacco products and advertising. For more information, please contact us at contact@fidjlaw.com.