FDA Lawyers Blog

by Andrew S. Wasson

On August 18, FDA denied Valeant Pharmaceutical's request that FDA prevent generic applications from referencing its first-generation diazepam rectal gel product. The first-generation product contained diazepam gel in fixed-dose syringes; however, Valeant subsequently developed a product using a dial mechanism to accommodate a varying amount of gel (marketed as Diastat® AcuDial™). Valeant coordinated the introduction of the AcuDial™ product with the withdrawal of the fixed-dose product. While at least one generic manufacturer hoped to reference the first-generation product, Valeant, in turn, petitioned the FDA to prevent any such approvals.

FDA determined that generic manufacturers could properly reference the first-generation product. While FDA acknowledged that it counseled Valeant to avoid overlap between the marketing of first- and second- generation products, FDA maintained that it did not force Valeant to withdraw the fixed-dose product. FDA also determined that the concerns motivating the extensive educational effort at the introduction of the AcuDial™ product would not be necessary now because patients, pharmacies and prescribers were familiar with the AcuDial™ product, having used it for five years. Finally, while Valeant argued that generic manufacturers would have to elaborately supplement the fixed-dose prescribing information (ANDA filings only allow very minimal revisions to generic prescribing information.), FDA found that such changes would be unnecessary given the simple fixed-dose delivery mechanism and because Valeant failed to present any evidence that confusion would occur.

Therefore, FDA determined that the fixed-dose product was not withdrawn for reasons relating to safety or effectiveness and that generic applicants could reference such a product.

by Erin A. Lawrence

On August 23, Judge Royce Lamberth of U.S. District Court of District of Columbia issued a preliminary injunction against federal funding for stem cell research in which a human embryo is destroyed. Judge Lamberth ruled in favor of the two researchers working on alternatives to the cells, who filed the lawsuit and argued that it violated a law passed in 1996 (section 128), which prohibited federal money for research where an embryo is destroyed. The Obama Administration signed an executive order that attempted to distinguish between the destruction of embryos and research that used already destroyed embryos. Judge Lamberth stated that "the two cannot be separated" because the research "necessarily depends on the destruction of a human embryo."

The consequences of Judge Lamberth's decision are unclear. On its face, Judge Lamberth's decision appears to even outlaw President Bush's restrictive policy allowing stem cell research on 21 already established stem cell lines. The Obama Administration expanded the number of cell lines to 75 so far. Stem cell advocates are calling on the government to appeal the decision and have the preliminary injunction nullified. The Obama Administration plans to appeal Judge Lamberth's ruling. Congress is also being urged to take up this issue by Rep. Diana DeGette when it reconvenes in a month. DeGette believes that Congress action could resolve the issue faster than the courts. DeGette's proposed legislation only allows research on embryos set to be discarded after in-vitro fertilization and only with the permission of the people that created the embryos.

Privately-funded research on human embryonic stem cells still remains legal as long as specific guidelines are followed. Privately funded researchers must be careful not to use NIH-funded equipment. Additionally, the decision does not affect companies performing experiments on adult stem cells or induced pluripotent stem cells.

Frommer Lawrence & Haug Partner Brian J. Malkin will Chair the upcoming FDA Boot Camp Conference in San Francisco from August 25 to 26. Beyond chairing the conference, Mr. Malkin also will act as a speaker on non-patent exclusivity, to help participants become better life sciences products litigators and patent attorneys. The Boot Camp will drill down into the FDA basics, including the approval process, pre-approval concerns, product labeling, clinical trials, adverse events reports, patent concerns and exclusivity. The Boot Camp will include top FDA and Regulatory attorneys from across the U.S. For more information, click here.

by Brian J. Malkin

On August 19, the President's Council of Advisors on Science and Technology (PCAST) recommended a targeted federal investment of $1 billion per year until certain key areas in flu vaccine development and production are improved to develop a more rapid response to flu outbreaks. Significant delays during the 2009-2010 H1N1 pandemic flu outbreak catalyzed the President to request this review.

PCAST's report identifies five key areas that could lead to a faster response time: (1) surveillance - Centers for Disease Control to identify emerging pandemic viruses earlier, so vaccine production may begin earlier; (2) seed viruses - National Institutes of Allergy and Infectious Diseases (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA) to develop a collection of stock viral "backbones" to facilitate developing vaccine strains; (3) sterility testing - FDA and BARDA to develop faster and more reliable vaccine sterility tests; (4) potency test reagents FDA and BARDA to develop faster and more reliable vaccine potency tests; and (5) FDA and other federal agencies in collaboration with industry to enlarge capacity and modernize equipment used in final vaccine production including vial filling.

In addition, PCAST's report recommends encouraging industry to develop more technologically-advanced vaccines. PCAST recommends that HHS, NIAID, and BARD work with industry to develop methods for making flu viruses using mammalian cell culture systems rather than chicken eggs. Currently, chicken eggs are the only approved method in the U.S. for making inactivated or live attenuated flu viruses, yet cell cultured and recombinant DNA methods are used to make other vaccines more rapidly and with less chance of contamination or allergies.

by Brian Malkin

On August 19, Health and Human Services (HHS) Secretary Kathleen Sebelius announced a long-term plan to infuse $1.9 million into the public health infrastructure to help develop medical countermeasures to combat medical threats caused by both naturally-occurring and terrorism-driven events. Sebelius acknowledged that despite an increased awareness of new or potentially weaponized medical threats, the public health system has been slow to respond with new products and rapid manufacturing capabilities. For example, during a two-stage outbreak of H1N1 pandemic flu in 2009-2010, it took 26 weeks to develop the initial vaccine doses and 38-weeks to have sufficient doses for half of the population, when the second wave occurred already at 18 weeks.

HHS's medical countermeasures focus on five key areas: (1) strengthening regulatory science at FDA, so it has the resources to create clear regulatory pathways and analyze new technologies faster by developing action teams for high priority products; (2) developing flexible manufacturing, so domestic facilities can change current manufacturing platforms to manufacture surge capacity for medical countermeasures; (3) utilizing the National Institutes of Health's (NIH's) resources to identify and nurture promising countermeasure technologies; (4) upgrading the current flu vaccine manufacturing process to include live attenuated strains, cell culture, and other technologies for more rapid vaccine development and production (see related blog); and (5) continue developing incentives for strategic partners to invest in new countermeasure technologies, such as more flexible contracting procedures.

Initial funding for the countermeasures comes from funding for the H1N1 flu pandemic and amount to: (1) $170 million for improving FDA's regulatory science; (2) $678 million to set up at least one private facility to work under government contract with small firms to make new products, develop new manufacturing processes, and help to produce vaccines during peak demand periods; (3) $33 million for new teams at NIH to identify promising research; (4) $822 for upgrades top speed development of pandemic flu vaccine; and (5) $200 million fund to invest in small companies that develop promising technologies.

by Mark P. Walters

Some biotech startups are looking beyond follow-on biologics and banking on "biobetters," drugs that are similar but perform better than branded biopharmaceuticals. While there is no abbreviated approval path for a bio-better drug, the strategy seeks to capitalize on demonstrated therapeutic and commercial success of a branded drug. By following in the footsteps of the innovator, proponents of this strategy hope to enjoy a decreased risk of failure than with most new biopharmaceutical drugs. A recent article by Wall Street Journal Venture blogger Brian Gormley focused on three companies hoping to capitalize on biobetters.

Femta Pharmaceuticals hopes to achieve biobetter success with Fm101, a rheumatoid arthritis drug that blocks the interleukin-6 (IL-6) protein instead of inhibiting the IL-6 receptor, as done by Genentech's Actemra. According to Femta Chief Scientific Officer Peter Emtage, it takes much less antibody to block IL-6 than it does to block the receptor. Femta hopes to establish itself as a "best in class" monoclonal antibody company by improving upon the effector functions of known monoclonal antibodies while maintaining favorable safety and pharmacokinetic profiles.

Itero Biopharmaceuticals Inc. has a business vision to develop bio-betters . For now, it has licensed to Watson Pharmaceuticals Inc a biosimilar preclinical-stage treatment for female infertility, recombinant follicle stimulating hormone (rFSH).

PolyTherics Ltd. is another company placing a "bio bet," betting on a biologic using a pegylation technology that it says enables site-specific pegylation of any protein or peptide. Pegylation is the addition of polyethylene glycol for the improvement of a drug's duration of action. PolyTherics is betting that it can develop a better version of treatments such as interferon alpha and interferon beta. Its lead product is designed to be an improved version of interferon alpha-2a, a treatment for hepatitis.

by Charles J. Raubicheck

A Federal judge has ruled that a USDA decision allowing the planting of genetically-modified sugar beet seeds cannot stand, until this Federal agency prepares an environmental impact statement ("EIS") adequately addressing the possible effect of this genetically-modified organism ("GMO") crop on other agricultural foods. The lawsuit brought by the ruling came in a lawsuit filed by the Center for Food Safety and other environmental organizations.

Sugar beets provide half the nation's sugar supply. Seeds that are genetically modified allow the crop to withstand the effects of the weed killer Roundup®.(active ingredient glyphosate). The court decision permits harvesting and processing of sugar beets grown in 2010, but prohibits planting of GMO seeds in the next growing season. Growers voice concern that the supply of sugar beets will be jeopardized in 2011, because the demand for conventional sugar beet seeds has been limited, given the availability of the GMO variety.

The challenge for USDA is to expeditiously produce an EIS that will pass muster in court, to assure a full sugar beet crop next year.

by Brian Malkin

On August 3, Senator Michael Bennet from Colorado introduced the Drug Safety and Accountability Act of 2010 (S. 3690), which was referred to the Committee on Health, Education, Labor, and Pensions. The Bill seeks to strengthen industry standards to ensure the quality and safety of drugs made for the U.S. market and to improve certain FDA oversight functions, such as improved tracking of foreign manufacturing sites and the power to order a drug recall (currently available for medical devices). In the end, the Bill could make U.S. drug manufacturers more diligent in monitoring the sources of the ingredients used in their drug products designed for U.S. consumers.

According to the Bill, the proposed legislative changes are required to address recurring manufacturing quality problems. Some of these problems include more than 1.3 million over-the-counter (OTC) children's medications recalled in 2010 for quality issues and up to 149 Americans dying in 2007 and 2008 from taking contaminated heparin from China. In addition, the Bill acknowledges that up to 80 percent of the active ingredients used in U.S. drugs come from overseas sources, where regulatory oversight standards differ from products made in the U.S.

The Bill seeks to provide FDA with better investigative tools for monitoring drug quality and safety. FDA would be granted the authority to assess civil penalties for violations of the Federal Food, Drug, and Cosmetic Act and to subpoena documents and witnesses. The Bill provides measures to facilitate the exchange of information between FDA and other regulatory bodies through mutual recognition agreements and improve the agency's ability to inspect non-U.S. manufacturing facilities that make drugs for the U.S. market. The Bill provides new or improved oversight for OTC drugs that have typically been considered a lower risk priority for the agency. In addition, the Bill provides measures to protect industry "whistleblowers", so they can provide FDA with additional regulatory information.

On the industry side, the Bill requires companies to establish quality management plans to ensure the quality and safety of their drugs. For example, companies would be required to better document the entities involved in producing the ingredients used in their drug products.

by Brian Malkin

On September 17, FDA will hold a public meeting to obtain input on a human generic drug user fee program. FDA announced the meeting in a Federal Register Notice that the agency published on August 9, which included a request for public comments by October 17.

FDA explains that it is considering user fees for human generic drugs to provide additional revenues to hire more staff and improve the review process. FDA acknowledged that the number of abbreviated new drug applications (ANDAs) waiting for FDA to review them, as well as median review times, has increased from 17 months to over two years. FDA has requested generic drug user fees in the past several years, but FDA's requests have not been addressed by Congress nor endorsed by the generic industry generally.

FDA said that would like to hear from industry whether the human generic drug user fee program should be similar or different that other user fee programs FDA has implemented over the years following Congressional action (e.g., prescription drug user fees for NDAs). In particular, FDA raised questions whether the Office of Generic Drugs should have performance goals and whether applicants should pay a tiered-fee structure, where more complex products pay higher fees, FDA also asked how the current backlog should be treated following the initiation of user fees and whether the user fees should support post-marketing safety concerns.

by Brian Malkin and Jennifer A. Hardy

On August 3, FDA sent Dendreon Corporation an untitled letter stating that the company had overstated the benefits and minimized the risks of groundbreaking oncology vaccine Provenge® in promotional materials. FDA's letter requested that Dendreon cease using the materials and provide the agency with a response within ten (10) days.

Provenge® gained FDA approval in April 2010 after being denied approval in 2007, which we reported here. Provenge® is specifically indicated for the treatment of advanced prostate cancer.

In the letter, FDA stated that the promotional materials "are false or misleading because they omit and minimize the risks and overstate the efficacy of Provenge®." Specifically, FDA found that the promotional kit presents a "misleading product timeline" for what sterility test information is available at the time of infusion, which directly contradicts the Warnings and Precautions section of the FDA approved labeling. According to FDA, the promotional materials overstate efficacy by not providing adequate contextual information related to the variability of the survival rate estimates.

by Erin A. Lawrence

On July 30, FDA lifted the clinical hold on Geron's Phase I trial of human embryonic stem cell therapy (hESC)--the first human studies using embryonic stem cells. The trial experiments are directed to treating patients with subacute thoracic spinal cord injuries with GRNOPC1 cells. FDA's clinical hold was originally imposed on the trial last year when Geron's preclinical results showed a higher frequency of small cysts in animals. Geron's current results from preclinical animal studies, however, showed a lower numbers of cysts and was enough to convince FDA to permit Geron to move forward with clinical trials.

Scientists hope that injecting the hESC stem cells into patients will allow them to regrow damaged nerve cells and may at least partially heal paralyzed patients. In animal studies, researchers were able to get paralyzed rodents with spinal injuries to walk again. Geron is building off of Hans Kierstead's ground-breaking work at the Univesity of California at Irvine.

Geron's CEO, Thomas Okarma, said that they hope this technology goes well beyond the treatment of acute spinal cord injury. Okarma acknowledged Geron's ability to manufacture any cell in the human body and that in theory there are no diseases or injuries that are beyond the reach of this technology. Okarma stated that their next battle is to convince Congress to spend more funds on their innovations. Geron has been working with Representatives. Diana DeGette (D-Colo.) and Michael Castle (R-Del.) on legislation to create grants and tax credits. Lawmakers plan to introduce the bill this fall.

by Brian Malkin

On August 4, Senator Sherrod Brown introduced legislation to provide additional "priority review voucher" incentives to develop innovative treatments for tropical and rare pediatric diseases. The bill, S. 3697, entitled the "Creating Hope Act of 2010" amends the Federal Food, Drug, and Cosmetic Act under section 524 (21 U.S.C. § 360n) and builds upon a similar measure added in the Food and Drug Administration Amendments Act of 2007 that only included priority review vouchers for tropical diseases and described in this guidance. The bill has been currently referred to the Committee on Health, Education, Labor, and Pensions.

Priority review vouchers entitle manufacturers to receive expedited review of another drug produced by the same manufacturer. A manufacturer, therefore, could speed FDA review of a "blockbuster" new drug, which provides a strong incentive for the development of treatments for tropical and rare pediatric diseases, including pediatric cancer. Moreover, there is no limit on the number of times a priority review may be transferred to another manufacturer before the voucher is used.

The bill defines "rare" similarly as in the Orphan Drug Act, i.e., affects less than 200,000 people or the cost of development would exceed revenue. Chagas disease was specifically added to the list of neglected tropical diseases. Whereas the 2007 measure only designated a product as qualifying for a voucher at the time of FDA approval, the new bill's process would permit sponsors to seek a designation for eligibility for the voucher prior to submitting a new drug application. Companies must submit a statement of good faith intent to market the eligible drug and a report that outlines the demand and distribution of the product. Companies, however, cannot receive a voucher for tropical disease products that they already market in other countries.

by Charles J. Raubicheck

FDA has rejected a citizen petition filed by Sandoz, Inc. that would have required generic versions of LYRICA (pregabalin), a prescription drug approved for neuropathic pain, neuralgia and seizures, that would have barred generic applicants from carving out the pain and seizure indications to avoid infringing two Orange Book patents covering these uses.

Sandoz argued that the carve-outs would remove entire paragraphs of safety information essential for prescribing physicians (risk of suicidal thoughts or behavior for the pain use, and risk of peripheral edema for the seizure use).

However, FDA ruled that the omissions were proper because they would not render generic versions less safe. The risk information, the agency explained, could adequately be communicated by modified wording that would alert doctors but not infringe the claims of the patents. The petition and ruling are unusual because (i) Sandoz does not hold the approved NDA for LYRICA, and (ii) FDA itself suggested the non-infringing wording.

by Brian Malkin and Kyle Deighan

On July 29, the Senate Appropriations Committee approved a spending bill that included a measure aimed at restricting settlement agreements between brand and generic pharmaceutical companies--settlements opponents call pay-for-delay agreements. The measure, included within the Financial Services and General Government Appropriations Bill (S. 3677), is similar to an amendment the Senate stripped from the War Funding Bill (H.R. 4899) earlier this month. The two measures each parallel the "Preserve Access to Affordable Generics Act" introduced last year in connection with the Health Care Reform Bill.

S. 3677

The amendments are an attempt to curb pay-for-delay agreements, which typically involve a brand drug company paying an allegedly infringing generic to settle patent infringement litigation. In exchange for payment, the generic agrees to stay off the market for a specified period of time, allowing the brand to retain market exclusivity. According to the U.S. Federal Trade Commission ("FTC"), a record 21 pay-for-delay deals have been made between brand and generic companies so far this fiscal year. The number of these deals struck per year has continued to rise, with 19 made in 2009, 16 in 2008, and 14 in all of 2006 and 2007. The FTC has estimated the 21 deals so far this year shelter $9 billion in prescription drug sales.

The proposed amendments would allowed the FTC to "initiate a proceeding to enforce the provisions of [the] section against the parties to any agreement resolving or settling, on a final or interim basis, a patent infringement claim, in connection with the sale of a drug product." The agreements would have been "presumed to have anticompetitive effects and be unlawful if--(i) an ANDA filer receives anything of value; and (ii) the ANDA filer agrees to limit or forego research, development, manufacturing, marketing, or sales of the ANDA product for any period of time." The presumption could have been rebutted "if the parties to such agreement demonstrate by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects."

by Andrew S. Wasson

Sanofi-Aventis ("Sanofi") and partner Debiopharm were foiled by the United States District Court for the District of Columbia in their attempt to force FDA to rescind approvals for generic oxaliplatin products. While the District Court of New Jersey entered a judgment that the generic applicants did not infringe one of the Orange Book patents (U.S. Patent No. 5,338,874), the Federal Circuit later vacated and remanded the district court ruling. In the meantime, based on the district court ruling of non-infringement, FDA approved several generic oxaliplatin applications.

Sanofi sued FDA, arguing that FDA inappropriately applied the provision of the Hatch-Waxman Act to lifting of the "30-month stay." The Hatch-Waxman Act prevents FDA from approving a generic application that challenges a patent listed in the Orange Book until thirty months elapses from the date that notice is provided by the generic challenger of its challenge (the "30-month stay"). 21 U.S.C. § 355(j)(5)(B)(iii). The 30-month stay may be lifted if "the district court decides that the patent is invalid or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity)." 21 U.S.C. § 355(j)(5)(B)(iii)(I). Here, Sanofi and Debiopharm argued that even though the district court entered a judgment that the patent was not infringed, the 30-month stay should be put back into place because the Federal Circuit vacated the district court opinion.

The United States District Court for the District of Columbia disagreed with Sanofi and Debiopharm. Analyzing the issue under the rubric of the Administrative Procedures Act and Chrevron deference, the court found that FDA's decision to approve generic applicants was neither arbitrary, capricious, nor an abuse of discretion. In particular, the court noted that the provision for the 30-month stay stands in stark contrast to other provisions in the Hatch-Waxman Act which specifically reference an appellate action. The court therefore concluded that the, "plain language of the statute dictates that the thirty-month stay terminate upon the entry of judgment by a district court that a patent is invalid or not infringed, regardless of any subsequent appeal, and that the FDA was bound to follow this directive."