FDA Lawyers Blog

By Andrew S. Wasson

Multiple sources indicate that FDA is close to releasing an initial draft guidance on biosimilar products. Last Friday, Reuters reported that Janice Soreth, deputy director of the FDA's Europe office in London, stated that FDA might release the guidance "as early as the next few weeks, maybe even days." Soreth made the comments at Windhover's Pharmaceutical Strategic Alliances Conference in New York. Soreth's comments are consistent with BioCentury's September 22nd report that CDER director Janet Woodcock stated that the guidance would be issued "promptly."

It is clear that FDA has been steadily working toward a biosimilars draft guidance. After a long period of radio silence, in August the New England Journal of Medicine published an article titled "Developing the Nation's Biosimilar's Program" co-authored by FDA employees, including CDER director Janet Woodcock. We reported on that article here. Most commentators believe that FDA's upcoming guidance will hew closely to the principles set out in August's NEJM article.

In particular, FDA will likely allow itself a large amount of flexibility in determining the requirements for the approval of a biosimilar application, including the types of clinical and/or analytical studies necessary. Agency flexibility is particularly critical here because (1) biological products vary significantly in terms of complexity and difficulty in characterization and (2) analytical techniques will likely evolve over time. In addition, it would not be surprising for FDA to adopt principles from recent EMA draft guidelines. Finally, given the lack of attention paid to interchangeability in the NEJM article, it seems doubtful that FDA will focus much on such requirements in the upcoming guidance.

FDA and industry have also recently reached a "tentative" agreement on the user fee structure for biosimilar applications. Indeed, the proposed user fee structure reflects FDA's expectation that developing a biosimilar product will require more early-stage interaction with FDA. The tentative agreement appears to be similar to the original FDA proposal, which included product development and application fees for pending products as well as product and establishment fees for marketed products. Also, the tentative agreement requires at least $20 million in "non-user fee funds" (read federal funding).

by Kyle Deighan

On September 19, FDA issued a Compliance Policy Guide ("CPG") intending to crack down on countless drug products being marketed in the United States without FDA approval. The CPG."Marketed Unapproved Drugs-Compliance Policy Guide, Sec. 440.100 Marketed New Drugs Without Approved NDAs or ANDAs", makes clear that unapproved drugs introduced on the market after September 19, 2011 are "subject to immediate enforcement action at any time, without prior notice and without regard to the enforcement priorities." This comes as part of FDA's enforcement efforts under the Unapproved Drugs Initiative.

Unapproved Drugs-Compliance Policy Guide, Sec. 440.100 Marketed New Drugs Without Approved NDAs or ANDAs

FDA estimates that as many as several thousand drug products lack approval and are thus being marketed illegally. These products are on the market for various reasons, but in all cases manufacturers have failed to provide FDA with required safety and efficacy data. For these unapproved drugs, FDA stated that it will take steps to encourage the submission of required information from the manufacturers or remove the products from the market.

by Brian Malkin

On September 27, FDA published in the Federal Register a Notice about the availability of a revised guidance, User Fee Waivers, Reductions, and Refunds for Drugs and Biological Products. The Guidance updates an interim guidance issued in July 16, 1993. The Notice explains that the revised guidance was proposed on March 14, 2011 but received no comments by the end of its comment period on June 13, 2011.

The Guidance describes: (1) the types of waivers, refunds, and reductions available under the user fee provisions of the Federal Food, Drug, and Cosmetic Act ("FD&C Act") and (2) procedures for requesting waivers, refunds, or reductions and reconsiderations and appeals of FDA decisions of such requests. FDA's revised guidance also clarifies related issues such as user fee exemptions for orphan drugs.

by Erin Lawrence

On September 19, 2011, Plaintiffs James Sherley and Theresa Deisher, filed a notice of appeal in their lawsuit Sherley v. Sebelius. The appeal asks that the Court of Appeals for the District of Columbia reverse the District Judge Royce Lamberth's July 27th decision that the government can continue to finance embryonic stem cell research. (See our previous blog here).

Judge Lamberth dismissed the Plaintiffs' lawsuit in July citing the Court of Appeals April holding that government-backed research on embryonic stem cells is likely lawful under the Dickey-Wicker Amendment. The appeal now seeks an opposite decision from the same Court of Appeals. The appeal requests that the Court of Appeals block the U.S. Health and Human Services Department and the National Institute of Health from spending federal funds on research involving human embryonic stem cells.

The scientist hired a Christian law firm, Jubilee Campaign to file the appeal. The Jubilee Campaign is spondering the "Law of Life Project" which is dedicated to "defending the right to life and dignity of the human being from biological conception. . . ."

The next step will be for Court of Appeals to set a schedule for submission of legal briefs and oral arguments. Although Plaintiffs' success in the appeal may be a far shot--especially given that the Court of Appeals has already decided that it is highly likely that government funding of embryonic stem cell research is legal--a victory for Plaintiffs' would put the stem cell battle on a path to the U.S. Supreme Court.

by Fitz Beckwith Collings

The U.S. District Court for the middle district of Florida dealt FDA a setback in U.S. v. Franck's Lab, ruling that the agency did not possess the statutory authority to regulate the traditional compounding practices of veterinary pharmacies.

Franck's Lab is a large, Florida-based compounding pharmacy. In 2009, Franck's was responsible for the deaths of 21 Venezuelan national polo team ponies. The deaths were traced to a mathematical error made by one of Franck's prescribing veterinarians during the compounding process. The resulting solution of Biodyl proved too potent, and the Florida Board of Pharmacy imposed fines and reprimanded Franck's. After this incident, FDA expressed concern that Franck's compounded a number of the drugs at its facility outside the context of a valid veterinarian-client-patient relationship. The scope and scale of Franck's production, combined with the alleged lack of a veterinarian relationship, led FDA to conclude that Franck's was operating as a drug manufacturer.

Under Florida state law, pharmacists are permitted to compound a medication when a veterinarian prescribes it for an individual patient. This process enables the veterinarian to tailor the medication to the animal's needs, e.g., by accounting for allergies to ingredients in commercially-available medications. Franck's routinely prepared quantities of compounded medications from bulk substances in the absence of a prior prescription by a veterinarian, with the expressed purpose of maintaining a sufficient supply for new customers. FDA ultimately sought to enjoin Franck's from compounding any quantity of veterinary pharmaceuticals from bulk substances indefinitely - a first for the agency - unless Franck's obtained FDA approval as a drug manufacturer. The central issue in the case was whether the Food, Drug and Cosmetic Act (as originally enacted in 1938) conferred to FDA the authority to enjoin Franck's from engaging in traditional veterinary compounding.

by Howard E. Rosenberg, Ph.D.

On September 14, the Senate Health, Education, Labor and Pensions ("HELP") Committee, chaired by Senator Tom Harkin (D-IA), held a hearing to discuss the issues raised by the recent the Government Accountability Office ("GAO") report, which stated that up to 80% of the chemicals and ingredients of prescription drugs are made outside the United States and that globalization has placed increasing demands on FDA in ensuring the safety and effectiveness of drugs marketed in the United States. While inspections of foreign drug manufacturers are an important element of FDA's oversight of the supply chain, it has been shown in previous GAO reports that FDA conducts relatively few such inspections. Given the difficulties that FDA has faced in inspecting and obtaining information on foreign drug manufacturers, and recognizing that more inspections alone are not sufficient to meet the challenges posed by globalization, the report recognized that the agency had begun to implement other initiatives to improve its oversight of the drug supply chain.

This aspect was addressed by Deborah Autor, Deputy Commissioner for Global Regulatory Operations and Policy, . The Deputy Commissioner described several potential problem areas such as: 1) the increasingly complex path that medical products travel, from raw source materials to finished products for consumers, where at every stage in this process opportunities arise for the product to be contaminated, diverted, counterfeited, or otherwise adulterated and 2) Cargo thefts of prescription drugs, where in 2009 alone, an estimated 46 drug cargo thefts occurred, valued at a total of $184 million. Some of these drugs ended up being used by consumers after being stored at incorrect temperatures and consequently having lost potency.

by Kyle Deighan

On September 16, FDA argued that its required graphic warnings on cigarette packages next year should not be blocked by a preliminary injunction because the tobacco companies' free speech rights would be outweighed by the public interest in disclosing the dangers of smoking.

In June, FDA mandated that labels showing graphic warnings about the risks associated with smoking appear on packs of cigarettes. The labels show images such as a sewn-up corpse, a man smoking through a hole in his throat, and a picture of a black diseased lung. The pictures are accompanied by warning messages regarding smoking, such as "Cigarettes are addictive" and "Smoking can kill you." Cigarette-manufacturers are required to print the labels on the top-half of cigarette packs, both front and back. Additionally, the warnings must occupy at least 20% of each cigarette advertisement. According to an FDA timeline, cigarette manufacturers are not allowed to distribute cigarettes in the U.S. after October 22, 2012 without the required warnings.

Tobacco companies, including R.J. Reynolds Tobacco Co. and Lorillard Tobacco Co., filed suit against FDA in August in the U.S. District Court for the District of Columbia. The tobacco companies argued that the labels violate their free speech rights, force them to engage in anti-smoking advocacy for the government, and will cost them millions of dollars. They also argued for a preliminary injunction to stop the labeling requirement while the free speech suit is decided. A representative of the companies stated: "The notion that the government can require those who manufacture a lawful product to emblazon half of its package with pictures and words admittedly drafted to persuade the public not to purchase that product cannot withstand constitutional scrutiny."

by Scot Pittman

A recently released draft, five-year plan from the FDA includes procedures aimed at increasing the Agency's involvement in the area of orphan diseases. Rare, or orphan, diseases are those that affect less than 200,000 people in the United States; but with more than 7,000 known rare diseases, they are anything but rare and affect a significant number of people in the U.S. (30 million) and worldwide (250 million). Many of these diseases, however, lack meaningful treatment options for those afflicted.

FDA's draft, five-year plan includes meaningful steps to address the lack of treatment options for orphan diseases. Starting next year, FDA will complete a staffing and implementation plan for the Rare Disease Program of the Center for Drug Evaluation and Research ("CDER"). This will include adding five staff members and a liaison in the Rare Disease Program for the Center for Biologics Evaluation and Research ("CBER").

The draft plan outlines a continual program of guidance and policy dissemination that will aid FDA reviewers in staying informed about the latest in development of drug and biologic treatments for orphan diseases. The Rare Disease Program staff will also increase its outreach to the industry through public meetings seeking input on complex issues involved in the approval of drugs for these rare diseases.

by Kyle Deighan

On September 12, Jon Leibowitz, Chairman of the U.S. Federal Trade Commission ("FTC") and staunch opponent of "pay-for-delay" settlements, once again urged Congress to restrict these types of agreements, arguing it would lower federal deficits.

Pay-for-delay settlements are agreements between innovator pharmaceutical companies and generic manufacturers in which the brand pays the generic to stay off the market or delay entry for a period of time. The FTC has long opposed these agreements as anti-competitive, arguing they tend to increase drug prices and, therefore, overall health care costs. (See some of our previous blogs on this here and here and here.) Generic drugs generally sell at a fraction of the price of their brand counterparts. When a brand and generic engage in pay-for-delay settlements, consumers (and their insurance companies or the federal government) do not get the benefit of the lower cost generic drugs until much later and are forced to continue paying for the higher priced brand product.

Monday, in a letter to the Joint Select Committee on Deficit Reduction (the so-called "Deficit Supercommittee"), Leibowitz argued that restricting pay-for-delay settlements would also lower prescription drug bills for federal health programs such as Medicare and Medicaid. He estimated that over ten years, restricting the agreements would save the government $8.8 billion dollars. Leibowitz urged the Committee to include the restrictions in recommendations it will provide to Congress on reducing the deficit.

by Howard E. Rosenberg, Ph.D.

Novartis's patent application for a novel crystal form of the cancer drug imatinib mesylate was rejected in India by the Chennai patent office back in 2006, citing that Indian patent law does not allow patent exclusivity for derivatives or marginally innovated forms of known drugs unless it is proved that it enhances the treatment value substantially. The issue concerns the interpretation of Section 3(d) of the Indian patent law, a clause peculiar to India and also potentially at odds with the Agreement on Trade Related Aspects of Intellectual Property Rights ("TRIPS").

Section 3 (d) of the Indian patent law lists out one such non eligible patentable subject matter:

d) the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such process results in a new product or employs at least one new reactant.

For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.

In essence, section 3(d) aims to prevent the phenomenon commonly referred to as "evergreening" by providing that only those pharmaceutical derivatives that demonstrate significantly enhanced "efficacy" are patentable. (See, for example, The 'Efficacy' of Indian Patent Law: Ironing out the Creases in Section 3(d) by Shamnad Basheer & T. Prashant Reddy)

by Fitz Beckwith Collings

The Center for Inquiry ("CFI") and its affiliate, the Committee for Skeptical Inquiry ("CSI") - want to know why FDA has not yet regulated the labeling and sale of homeopathic drugs. On August 26, the organizations jointly filed three citizen petitions requesting that FDA "require all commercially available drugs to be proven effective and be adequately labeled for their intended uses."

HomeopathicCP

While homeopathic remedies have been on the market for some time, their use has become more widespread in recent years. Sales in the U.S. are approaching $1 billion, and CFI believes that this money would be better spent on remedies that have been proven as safe and effective as allopathic drugs. With flu season arriving, CFI's petitions specifically target homeopathic drug manufacturer Boiron and its flu-treatment drug, Oscillo--the "#1 Pharmacist Recommended Brand" despite the Centers for Disease Control and Prevention's ("CDC's") insistence that there is no scientific evidence that any homeopathic remedies have any benefit against influenza.

In its statement of grounds, CFI alleges that homeopathic drugs are no more effective than placebos. CFI asserts that the principles underlying homeopathy, which correlate increased dilution with increased effectiveness, result in over-the-counter ("OTC") homeopathic drugs that are actually devoid of active ingredients. In a typical "24X" homeopathic preparation, for example, the "active" ingredient is diluted 1:10 24 consecutive times and the resulting drug contains (on average) not one molecule of the "active" ingredient. Boiron's Oscillo product, by comparison, is a "200C" preparation (200 consecutive 1:100 dilutions), which CFI points out would contain only one molecule of the "active" ingredient in a volume more than 30 billion times the size of Earth.

by Andrew S. Wasson

Facebook changed its advertising guidelines recently to allow advertising for legal dietary supplements. The new advertising guidelines also permit online pharmacies to advertise on Facebook in some circumstances. The changes come on the heels of Facebook's recent policy change which prevented pharmaceutical companies from blocking comments on some of their Facebook pages. Taken together, the changes demonstrate the ongoing development of rules to govern the role of the pharmaceutical industry in social media.

Facebook's new rules set forth specific content guidelines for advertising. The guidelines do not focus on pharmaceuticals. Rather, they touch on a wide variety of areas, ranging from alcohol and drugs to dating, gambling and lotteries. In this dubious company, Facebook also delineates the content guidelines for "Pharmaceuticals and Supplements." In particular, the guidelines cover advertising in the context of: (1) prescription pharmaceuticals, (2) online pharmacies, and (3) dietary and herbal supplements.

Facebook's stance on the advertising of prescription pharmaceuticals is unequivocal: it is not allowed. At least, advertising in the direct sense. As we have seen recently, after initially shunning social media, pharmaceutical companies started to utilize applications like Facebook for more oblique advertising in the form of community pages. The drug company-sponsored Facebook pages remain permissible even though a number of manufacturers shut down their pages after Facebook no longer allowed them to block comments.

by Howard Rosenberg

The MHRA announced yesterday in a press release that the first ever children's medicine to hold a Paediatric Use Marketing Authorization (PUMA) had been granted by the European Commission.

For many years it has been recognized that medicines are generally developed and designed for adults with their use in children coming as an after thought. In an effort to get around this problem incentives have been developed in many countries for new medicines to be tested for acceptability in children either at the time of submission for regulatory approval or within certain time scales. The incentives generally increased the new product's patent life and/or added a data exclusivity period to slow down generic entry. However, for old medicines with no intellectual property cover there was a need to find some way to encourage the research and development of formulations acceptable to children and to incentivize companies to make these products available.

The MHRA has been pushing for an increase in the availability of specific children's only medicines for several years, particularly as in general many adult medicines are offered to children only as cut-down doses.

by Andrew Nason

On September 1, 2011, the U.S. Food and Drug Administration ("FDA") released its draft commitment letter for reauthorization of the Prescription Drug User Fee Act for fiscal years 2013 through 2017 ("PDUFA V"). The letter comes after nearly a year of negotiations between FDA and representatives from the pharmaceutical industry, and it centers on a new review model for drug applications. The new model will take effect for New Molecular Entity New Drug Applications ("NME NDAs") and original Biologics License Applications ("BLAs") on October 1, 2012.

FDA hopes the program will help improve the efficiency and effectiveness of the first cycle review process and decrease the number of review cycles necessary for approval. At its core, the new model provides for more communication between FDA and the applicant both before and during the review period. The model encourages applicants to discuss the planned content of the application at a pre-submission meeting, and it also entitles sponsors to mid- and late-cycle meetings with agency staff during the review. FDA will extend the expected review time to at least 12 months for standard applications by delaying the start of the review clock until after a 60-day filing period, but the increase in transparency should give companies a glimpse into FDA's thoughts and concerns during the review period.

by Andrew S. Wasson

FDA recently released a short draft guidance titled "Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation." A tablet score is a debossed line which runs across a tablet surface to facilitate splitting the tablet into smaller portions. FDA reports that doctors and pharmaceutical companies have increasingly recommended tablet splitting because it allows patients to better adjust doses and to also save money. In the draft guidance, FDA developed criteria to evaluate scored tablets with regard to: (1) chemistry, manufacturing, and controls ("CMC") review, (2) nomenclature consistency, and (3) product labeling information.

• FDA provided the following guidelines and criteria for the review and approval of scored tablet applications:
• The dosage amount after splitting should not be less than the approved minimum effective dose.
• The scored dosage form should be safe to handle.
• Modified release products where scoring would compromise the release mechanism are not allowed (i.e. osmotic pump or film-coated dosage forms).
• The split tablet should still meet stability requirements.
• The split tablet should meet the same finished-product testing requirements as the whole tablet.
• The indicated patient population should be able to split the tablet correctly.
• "Scoring configuration of generic drug products should be the same as the RLD."
• Level 2 and Level 3 product changes require new study data on tablet splitability during the postapproval period.

The Agency's comment that generic drug products "should be the same" as the RLD is particularly interesting. The draft guidance continues, "[W]here the scoring configuration is protected by patent, contact the Office of Generic Drugs for guidance." It is unclear whether this statement means that OGD will excuse the scoring requirement when the scoring pattern is covered by a patent, or whether FDA is contemplating a brokered license similar to the scheme enunciated in the REMS context.

by Brian Malkin

On August 19, the Natural Resources Defense Council, Inc. ("NRDC") sued FDA for declaratory and injunctive relief for FDA to grant NRDC's citizen petition to remove the chemical bisphenol A ("BPA") from food packaging and other products where it comes in contact with food. NRDC alleges that BPA may be found in a wide variety of the liners of metal food cans and hard plastic containers such as baby bottles.

NRDC is a nonprofit environmental and public health advocacy organization headquartered in New York, New York with more than 400,000 members. NRDC engages in research, advocacy, and litigation to improve the regulation of harmful substances in food, drugs, and consumer products.

NRDC's original citizen petition was filed in October 2008 yet remains unanswered by more than 1000 days. According to NRDC, FDA should have responded to this type of petition within 90 days and has a maximum time of 180 days to respond. NRDC asserts that FDA's failure to respond to NRDC's petition prolongs its members from unwanted exposure to BPA in food packaging. FDA's failure to respond to the petition, moreover, has denied NRDC from seeking judicial review, if necessary, NRDC further alleges.