Drug Industry Daily - June 13, 2011 Issue

Vol. 10 No. 115

U.S. Supreme Court Decides to Leave Patent-Challenge Standard Alone

Brand drugmakers can breathe a sigh of relief as the U.S. Supreme Court has ruled to uphold a long-used standard to judge patent validity.

In the High Court’s decision, released Thursday, patent challengers must present “clear and convincing evidence” that a patent is invalid.

In the case Microsoft v. i4i, Microsoft sought to lower the standard, arguing that challengers should only have to present a “preponderance of evidence,” the standard with other civil cases.

Following the current standard, a lower court held that Microsoft’s 2003 and 2007 versions of Word infringed i4i’s patent relating to custom XML. Microsoft argued that prior art rendered the patent invalid because the feature was included in a program i4i sold more than a year before it applied for the patent.

However, the Supreme Court Thursday ruled in favor of i4i, the equivalent of the brand drugmaker in this case.

Even though the case involved two computer software companies, the decision carries huge weight with the pharmaceutical industry.

A decision favoring Microsoft likely would have altered the delicate balance established between brand drugmakers and the patents that protect their products versus generic-drug makers’ ability to invalidate those patents.

Victory for Brand Drugmakers

“This is certainly a huge victory for brand-name drug companies,” Aaron Barkoff, a biochemist, patent attorney and partner with McAndrews, Held & Malloy, told DID.

When Congress passed the Patent Act of 1952, it stated in section 282 of the law that a patent should be presumed valid, but lawmakers failed to specify what standard of proof courts should use in judging patents.

“Indeed, had Congress intended to drop the heightened standard of proof where the evidence before the jury varied from that before the U.S. Patent and Trademark Office (PTO), it presumably would have said so expressly,” Justice Sonia Sotomayor wrote for the court in an 8-0 decision.

PhRMA filed an amicus brief siding with i4i, noting that patents protect innovators’ work, helping them recoup money from their investments.

“In PhRMA’s view, a ruling lowering that standard of proof would dramatically diminish incentives for innovation,” the brief states. “This chilling effect would disproportionately affect PhRMA’s members, who rely on the incentives provided by strong patent protection when they choose to make extraordinary investments in research and development.”

Brand drugmakers Bayer and Genentech and the Biotechnology Industry Organization also filed briefs in support of i4i.

Siding with Microsoft, Synerx Pharma wrote in an amicus brief that maintaining a clear and convincing evidence standard “makes some patents essentially unchallengeable in practice.”

Apotex and Teva Pharmaceutical also supported a ruling favoring Microsoft in briefs.

Because of Thursday’s decision, district courts that hear patent cases — some of which don’t evenly apply validity standards, Barkoff said — may be more consistent in their decisions.

“To the extent that there was any inconsistency, I think that will go away, and the courts will uniformly apply this clear and convincing standard,” said Barkoff, author of the Orange Book Blog.

Also, the court wrote that evidence material to the challenger’s case that wasn’t presented to the PTO should be given more weight in cases. Therefore, a challenger may have an easier time meeting the higher clear and convincing standard.

View the court’s opinion here www.supremecourt.gov/opinions/10pdf/10-290.pdf. — David Pittman


BMS Warning Resolved, Path to Nulojix Approval Clear

In a recent closeout letter, the FDA told Bristol-Myers Squibb (BMS) that the corrective actions BMS has taken at its Manati, Puerto Rico, facility “sufficiently addressed” concerns raised in an August 2010 warning letter, paving the way for approval of BMS’ kidney transplant drug Nulojix.

BMS received a warning letter from the FDA in August 2010 after an inspection of its Manati facility found repeat good manufacturing practice (GMP) violations, including that BMS employees repeatedly failed to comply with company aseptic procedures (DID, Sept. 15, 2010).

After issuing the warning letter, the FDA informed BMS that it would not approve the company’s application for Nulojix (belatacept) until the Manati facility’s manufacturing issues were resolved (DID, Oct. 28, 2010).

The resolution of the Manati warning lifts an overhang for BMS, Leerink Swann analyst Seamus Fernandez notes. Global sales of Nulojix — which has a user fee action goal date of June 15 — could grow to $600 million by 2017, Fernandez says.

BMS “remains committed to ensuring the actions it has taken at the Manati site are maintained and that the site is in compliance with both company and regulatory requirements,” the company says.

To resolve the warning, BMS conducted an assessment of its facility, procedures, processes and systems, and took corrective actions to address the FDA’s observations, BMS spokesman Ken Dominski told DID.

Nulojix has had a tough path to approval. In addition to the Manati warning letter, in a complete response letter last year the FDA requested 36-month data from ongoing Nulojix Phase III trials to better analyze the treatment’s safety and efficacy (DID, May 4, 2010).

Nulojix’s benefits include improved blood pressure and renal function, and reduced rates of diabetes mellitus following transplant. Risks associated with the treatment include higher rates and grades of acute rejection, post-transplant lymphoproliferative disorder and progressive multifocal leukoencephalopathy.

The Manati warning resolution also clears the way for the approval of BMS’ rheumatoid arthritis treatment Orencia (abatacept), which has a user fee date of August 4. Orencia sales could grow to $1.7 billion by 2017, according to Fernandez.

Last year a House committee expressed concern over FDA oversight of Puerto Rico facilities. Reps. Edolphus Towns (D-N.Y.) and Darrell Issa (R-Calif.) sent the agency a letter that asked if the FDA’s Puerto Rico district office was “having difficulty exercising oversight on the numerous pharmaceutical manufacturing facilities on the island,” (DID, Nov. 10, 2010). — Kevin O’Rourke


FDA, Industry Collaborate to Prevent Drug Shortages

In response to an increased number of drug shortages for medically necessary products, the FDA is asking manufacturers to report changes in production that might impact their ability to meet market demand.

While drug companies are responsible for ensuring the quality and safety of their products, the FDA works with them if they experience problems with quality or sourcing of supplies to mitigate a shortage, the agency says.

Companies are required to notify the FDA six months in advance if they plan to discontinue the manufacture of a drug for which they are the sole source.

The agency also urges companies to acknowledge any issues that could lead to a shortage and to retain multiple sources for materials, such as active pharmaceutical ingredients (APIs), excipients, their precursor chemicals and other needed supplies as a backup if something goes wrong with a usual source.

The FDA says it is willing to discuss contingency plans for additional manufacturing sites, production lines and suppliers. It will also meet with new companies aiming to make drugs susceptible to shortages.

Shortages often occur when a company halts production to fix a manufacturing issue, the FDA says.

According to CDER’s Drug Shortage Program, there were 178 shortages in 2010, triple the 61 shortages in 2005. This year’s shortages are trending higher for sterile injectables and other medically necessary products, the FDA says. Such drugs are used to treat or prevent a serious disease or medical condition, or are the only source of treatment for a disease.

Dozens of recent articles and broadcast segments in consumer media have focused on the impact to consumers of certain drug shortages, and members of Congress have acted to bring about change.

Last year Senator Amy Klobuchar (D-Minn.) sent a letter to FDA Commissioner Margaret Hamburg requesting the agency address the long-term challenges facing the nation’s drugs supply (DID, Dec. 9, 2010).

The FDA then discussed shortages at a Prescription Drug User Fee Act reauthorization meeting, urging drugmakers to notify the agency when a product is discontinued (DID, Jan. 18). In February, legislation was introduced in the Senate requiring manufacturers to make such notifications (DID, Feb. 10).

Klobuchar again has urged the FDA to take action against drug shortages (DID, Feb. 14). Following suit, Sen. Herb Kohl (D- Wis.) recently directed the FTC to consider the role pharmaceutical company mergers may play in causing drug shortages. He contends that consolidation of brand- and generic-drug makers may lead to shorter supplies of pharmaceuticals in high demand (DID, May 24).

The FDA’s message to drugmakers on how to avoid or mitigate shortages is available at www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm257746.htm. — Molly Cohen


FDA Updates Label for Merck, GSK Prostate Cancer Drugs

The FDA is updating the label for the 5-alpha reductase inhibitor (5-ARI) class of drugs to include information about the increased risk of a more serious form of prostate cancer linked to their use.

The label update is based on the agency’s review of two large trials evaluating daily use of two 5-ARIs, finasteride and dutasteride. Data from the trials showed 5-ARIs offered a decreased incidence of lower-risk forms of prostate cancer. However, both trials also showed an increased incidence of high-grade prostate cancer.

The new label reads “5 ARIs may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 ARIs to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established.”

The FDA is advising healthcare professionals to be aware that finasteride and dutasteride come with an increased risk of this serious form of prostate cancer and to perform appropriate evaluations to rule out other urological conditions with similar symptoms of benign prostatic hyperplasia (BPH) before initiating therapy with 5-ARIs.

Finasteride is marketed by Merck as Proscar (finasteride 5 mg) and Propecia (finasteride 1 mg). GlaxoSmithKline (GSK) markets dutasteride as Avodart and in combination with tamsulosin as Jalyn.

Proscar, Avodart and Jalyn are FDA-approved to improve symptoms of BPH. Proscar and Avodart are also approved to reduce the risk of urinary retention or surgery related to an enlarged prostate. Propecia is approved to treat male pattern hair loss.

The FDA based its review on the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which looked at daily use of dutasteride 0.5 mg versus placebo over four years. GSK believes there are several possible scientific explanations for the increased number of patients diagnosed with high-grade prostate cancer in the dutasteride group compared to placebo group during the trial, spokeswoman Bernadette King told DID.

These reasons include:

  • Reduced prostate volumes in men on dutasteride made it more likely to find high-grade tumor lesions;
  • Selective dutasteride effectiveness to reduce low-grade cancer growth and limited effect of dutasteride to prevent high-grade cancers; and
  • More men with prostate cancer detected on biopsy in the placebo group at two years were withdrawn from the study creating a bias resulting in fewer patients who might have developed high-grade tumors in years three and four.

GSK believes dutasteride for BPH in men with an enlarged prostate continues to have a favorable risk/benefit profile, King says, as the overall risk of high-grade prostate cancer is low.

The FDA also saw similar results from Merck’s Prostate Cancer Prevention Trial (PCPT), which evaluated daily use of finasteride 5 mg versus placebo for seven years.

“Merck stands behind the demonstrated safety and efficacy of Proscar and Propecia. Merck conducts routine and ongoing monitoring of post-marketing adverse events to help ensure patient safety for those taking Proscar or Propecia,” company spokesman Lee Davies told DID.

According to the FDA about 5 million male patients received a 5-ARI prescription between 2002 and 2009. — Molly Cohen


FDA: Nanotechnology Draft Guidance Important ‘First Step’

Outlining a “roadmap for discussion,” the FDA released Thursday a draft of its nanotechnology guidance, to help industry better determine whether an FDA-regulated product uses nanotechnology.

The draft guidance, Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology, “outlines the agency’s view on whether regulated products contain nanomaterials or involve the application of nanotechnology,” the FDA says.

Nanotechnology is an “emerging technology with a broad range of potential applications,” and the draft guidance represents “the first step toward providing regulatory clarity on the FDA’s approach to nanotechnology,” the FDA notes.

While the FDA has not yet set a strict definition of nanotechnology, the term is most commonly used to refer “to the engineering … of materials that have at least one dimension in the size range of approximately 1 to 100 nanometers,” according to the agency.

Because “materials at the nanoscale” have different biological, chemical and physical properties than their “conventionally-scaled counterparts,” nanotechnology and nanomaterials can be used in a variety of ways in FDA-regulated products. For example, the technology can be used to increase the bioavailability of a drug or to improve product packaging, the agency says.

The recently released draft guidance outlines questions — “points to consider” — the agency will ask when considering whether an FDA-regulated product contains nanomaterials or application of nanotechnology.

The FDA will ask whether a product has at least one dimension in the nanoscale range (approximately 1nm to 100 nm), or whether engineered materials or end products exhibit properties or phenomena attributable to their dimension(s).

Terms used in the “points to consider” are also defined in the draft guidance. For example, the phrase “engineered material or end product” is used to differentiate between products that have been engineered to contain nanotechnology/nanomaterials and those which might contain incidental amounts of nanomaterials due to natural occurrence.

Because there is a “critical need” to learn more about the potential impact of nanotechnology on FDA-regulated products, the draft guidance stresses the important role premarket review can play in better understanding the technology.

In cases of products that might be using nanotechnology but which are not subject to premarket reviews, the FDA nonetheless urges manufacturers to talk to the agency during the product development process.

In 2007, the FDA’s Nanotechnology Task Force released a report recommending the agency release a nanotechnology materials-related guidance (DID, July 26, 2007). Similarly, in 2008 British officials, citing an urgent need for testing and regulation of nanomaterials, called for further regulation of the technology (DID, Nov. 17, 2008).

“With this guidance, we are not announcing a regulatory definition of nanotechnology,” FDA Commissioner Margaret Hamburg said, adding that with the draft guidance, the FDA wants “to narrow the discussion to these points and work with industry to determine if this focus is an appropriate starting place.”

The Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology draft guidance, docket number FDA-2010-D-0530, is available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm. — Kevin O’Rourke

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Reporters: Virgil Dickson, Molly Cohen, David Pittman, Kevin O'Rourke, Sarah Karlin

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