DID - Oct. 5, 2007 Issue

Vol. 6 No. 196

FDA Aims to Approve Record Number of Generics in Fiscal 2008

The FDA approved or tentatively approved 682 generic drugs in fiscal 2007, more than ever before and 33 percent more than last year, the agency announced.

The agency also unveiled a new umbrella policy aimed at increasing the number and variety of generic drugs available. The Generic Initiative for Value and Efficiency (GIVE) program will help the agency modernize and streamline the generic drug approval process, the FDA said.

“To keep pace with the increasing number of generic drug applications, FDA will implement some changes to the generic drug approval process,” Gary Buehler, director of the FDA’s Office of Generic Drugs (OGD), said. “The GIVE plan outlines ways to maximize the use of our resources so that FDA can review and approve even more high-quality generic drugs during the upcoming fiscal year than it did in 2007.”

The agency said it plans to hire and train new generic drug reviewers and focus on enhanced use of electronic programs for handling drug submissions and internal documents. Buehler said OGD intends to use increased funding proposed in the fiscal 2008 FDA budget to hire the additional staff.

The FDA is also revising the first-come, first-served review order for certain generic drug applications. For example, applications for first generic products for which there are no patent or exclusivity protections on the reference-listed drug will be moved to the front of the line.

The current backlog of generic applications hovers around 1,300 applications, Buehler said, but he noted that more than half of the drugs are still protected by patents or exclusivity and can’t be approved yet. The FDA first announced this plan to alter the review order a year ago (DID, Oct. 19, 2006).

FDA officials said the GIVE plan goes hand-in-hand with the “Critical Path Opportunities for Generic Drugs” report, which the agency announced earlier this year, as a way to increase generic drug access (DID, May 3).

“While we all share the goal of increasing efficiency in the generic approval system, another initiative in name only simply will not get the job done,” Generic Pharmaceutical Association (GPhA) President and CEO Kathleen Jaeger said. “For years, the agency has tinkered around the edges with programs and initiatives designed to increase efficiency but have proven to yield little in the way of significant results.”

“There are serious legislative and regulatory issues that must be addressed to yield a true increase in the number of affordable generics brought to market,” she continued. And GPhA is willing to work with the FDA to address these issues, including the possibility of generic user fees. Other issues that need to be discussed include citizen petitions and other barriers to generic entry, according to GPhA. 

More information on the FDA’s plan is available at www.fda.gov/oc/initiatives/advance/generics.html. — Breda Lund


House Lawmakers Introduce Bill to Reverse CMS’ ESA Coverage Decision

Reps. Anna Eshoo (D-Calif.) and Mike Rogers (R-Mich.) introduced a bill to reverse the Centers for Medicare & Medicaid Services’ (CMS) national coverage decision that would limit reimbursements for anemia medications.

The bill, H.J. Res. 54, would provide for congressional disapproval of the CMS’ final coverage decision that would restrict reimbursement to low-dose levels of erythropoiesis-stimulating agents (ESAs) in cancer settings. If passed, it would make the rule “have no force or effect,” the bill says.

The final decision, issued in July, would limit initiation of ESA therapy to when a patient’s hemoglobin levels are less than 10 g/dL, limiting the ESA treatment duration to a maximum of eight weeks after a chemotherapy sessions, limiting the starting dose to the FDA-recommended starting dose and limiting dose escalation levels (DID, July 31).

The CMS proposed new limitations on its ESA reimbursement policies after the FDA issued a public health advisory on ESAs and required manufacturers to include a black box warning on the labels because of an increased risk of death and serious life-threatening side effects (DID, May 16).

The Senate recently passed a resolution by unanimous consent asking the CMS to reconsider its coverage determination (DID, Sept. 6). The final coverage decision concerns physicians and patients and could “severely compromise” the quality of cancer care in the U.S., the resolution says. It also calls for the CMS to consult with oncologists to determine appropriate revisions to the coverage decision.

Fifty-two senators and 235 members of the House of Representatives have written to the CMS expressing concern with the draft version of its national coverage decision, H.J. Res. 54 says. Leading national medical organizations have requested that CMS reconsider its restrictions.

The American Society of Clinical Oncology, the American Society of Hematology and U.S. Oncology recently claimed the CMS misinterpreted data on Amgen’s ESA Aranesp (darbepoetin alfa) (DID, Sept. 26). The groups also said the hemoglobin level restriction is inconsistent with the FDA-approved labeling and national guidelines.

H.J.Res. 54 was referred to the House Energy and Commerce Committee as well as the House Ways and Means Committee Sept. 27.

Due to sales losses over Aranesp, Amgen recently announced it would lay off 2,200 to 2,600 employees. The company also said it is indefinitely postponing its plans for a manufacturing facility in Ireland.

More information on H.J. Res. 54 can be seen at thomas.loc.gov/cgi-bin/bdquery/z?d110:h.j.res.00054:. — Emily Ethridge


FDA Tightening Potency Standards for Thyroid Drugs

The FDA is tightening specifications for thyroid drugs due to concerns that the drugs’ potency deteriorates before their expiration dates, the agency announced.

The agency is mandating that levothyroxine sodium products, used to treat underactive thyroid glands and other thyroid conditions, meet 95 percent to 105 percent potency specification until their expiration dates. The products are currently allowed a range of 90 percent to 110 percent, according to the FDA.

The 95 percent lower specification will ensure the drugs do not deteriorate by more than 5 percent of the labeled claim before their expiration date, the agency said. The 105 percent specification allows for analytical testing variability, the agency said.

“Tightening the potency specifications will ensure that the most vulnerable patients taking thyroid medication will receive the appropriate level of drug therapy needed for their condition,” FDA Deputy Commissioner, Chief Medical Officer and CDER Acting Director Janet Woodcock said.  

The FDA examined stability data received from manufacturers of all marketed and approved levothyroxine sodium products made between July 2003 and June 2005. The data showed a trend toward potency loss, with some products rapidly degrading during their shelf life.

Some strengths and package types decline more rapidly than others, so expiration dates can vary within product lines, according to the FDA. Although some products lost less than 5 percent of their potency within two years, others lost approximately 10 percent of their potency in nine months.

Limiting the amount the products can deteriorate during their shelf life will reduce variability in stability profiles, which could have consequences in achieving target thyroid levels, the FDA said.

Manufacturers have two years to comply with the new specifications, the FDA added. More information can be seen at www.fda.gov/cder/drug/infopage/levothyroxine/default.htm. — Emily Ethridge


CDER Getting $1.5 Million Makeover

The FDA said it is paying a private contractor $1.5 million over two years to assist in the transformation of CDER. The agency said the payment to the Oakland, Calif.-based Center for Professional Development (CPD) is part of its response to recommendations the Institute of Medicine (IOM) made in a report last December (DID, Sept. 25, 2006).

CDER’s makeover will “focus on steps to improve workplace leadership, empower staff and establish more effective business practices,” the FDA said. CPD will help develop practical strategies to strengthen CDER’s organizational effectiveness, including training, tools and processes.

“This transformative program will provide CDER with the tools and expertise necessary to create a sustainable environment of open and transparent communication, collaborative decisionmaking and improved morale and staff retention,” Acting CDER Director Janet Woodcock said. Woodcock is also the FDA’s deputy commissioner for scientific and medical programs and chief medical officer.

The IOM report pointed out problems with CDER’s workplace culture and recommended that external management consultants be brought in to develop a comprehensive strategy to address them. CDER’s entire work force of approximately 2,300 “will be included in the workplace transformation effort,” the agency said. — Martin Gidron


Genzyme Cited for Thymoglobulin Manufacturing Operations

Genzyme used components and intermediates for the production of bulk Thymoglobulin lots that exceeded prespecified bioburden and pathogenic microorganism limits, according to a Sept. 19 FDA warning letter.

Thymoglobulin (anti-thymocyte globulin [rabbit]) is a polyclonal antibody that suppresses certain types of immune cells responsible for acute organ rejection in transplant patients. Genzyme Polyclonals manufacturers the product in Lyon, France.

Although finished product derived from the lots in question met all specifications, the FDA said if the firm does not correct the problem then the risk of future product failures would increase substantially.

“Of particular concern is that you continued to use components and intermediates that did not meet your internal in-process limits, and you did not fully investigate these deviations and implement appropriate corrective and preventive actions,” the FDA told Genzyme in the letter, which was posted on the agency’s website earlier this week.

Genzyme also failed to control the purified water system used to manufacture bulk lots of Thymoglobulin and did not investigate testing failures and adverse events appropriately, the FDA said.

The relationship between the deaths and adverse event reports, both associated with the same bulk Thymoglobulin lot, should have triggered a thorough investigation into all areas of the production process, the FDA said.

Genzyme was cited for not studying the effectiveness of disinfectants against fungi and spore-forming microorganisms as well, a repeat Form 483 observation. The agency said spore-forming microorganisms have been routinely associated with the firm’s Thymoglobulin manufacturing process, accounting for 17 percent, 14 percent and 7 percent of total isolates in 2004, 2005 and 2007, respectively.

When Genzyme responded to the FDA’s Form 483 observations, issued after the June 6–19 inspection, the company said it planned to complete an additional study to evaluate the effectiveness of its disinfectants by the first quarter of 2008. However, the FDA said the completion date was excessive.

Genzyme did not respond to a request for comment by press time. The warning letter can be accessed at www.fda.gov/foi/warning_letters/s6520c.pdf. — Christopher Hollis


FDA Approves Ranbaxy’s Generic Biaxin

Ranbaxy Laboratories has received final FDA approval to manufacture and market generic Biaxin for oral suspension, making Ranbaxy the first generic company to receive approval for this product, the company announced.

Abbott Laboratories’ Biaxin (clarithromycin) for oral suspension, 125- and 250-mg/mL, is an antibiotic indicated for treating tonsillitis, community-acquired pneumonia, uncomplicated skin and skin structure infections, and disseminated mycobacterial infections, Ranbaxy said. The drug had annual sales totaling $25.3 million during the 12-month period that ended in June, according to IMS Health data.

“This approval further expands our product portfolio of affordable generic alternatives and will be shipped immediately to all classes of trade,” Jim Meehan, vice president of sales and distribution for Ranbaxy Pharmaceuticals, said.

Ranbaxy also announced this week that it has increased its stake in Zenotech Laboratories to 45 percent.

“The increasing importance of biologics in the global pharmaceutical industry and the opening up of the generic biologics in the regulated markets, makes it opportune for Ranbaxy to enhance its presence in this area,” Malvinder Mohan Singh, CEO of Ranbaxy, said. “Having worked with Zenotech for almost two years, we believe that this investment and partnership provides a strong platform for us to leverage these opportunities”

Zenotech has received approvals in India for three biopharmaceuticals, and the company has seven more biopharmaceutical products in the pipeline, Ranbaxy said. The company’s R&D facilities are in New Jersey, while its manufacturing facilities are in India. — Breda Lund


GSK Asks WHO for Cervarix Prequalification

Following the European Commission’s approval of GlaxoSmithKline’s (GSK) cervical cancer vaccine Cervarix last month, the company submitted a file to the World Health Organization (WHO) to have the product prequalified for distribution in developing nations, the company announced yesterday.

The WHO prequalification program is intended to provide developing nations access to medicines that have been approved by recognized national health authorities. United Nations agencies and mass-vaccination programs can provide the products to poor countries once they are prequalified.

Cervarix (human papillomavirus vaccine [HPV], AS04 adjuvant-adsorbed) was approved in Europe for the prevention of high-grade cervical intraepithelial neoplasia causally related to HPV types 16 and 18.

The product has been launched and is priced in the UK the same as Merck’s Gardasil (quadrivalent HPV types 6, 11, 16, 18 recombinant vaccine). Sanofi-aventis’ vaccine division, sanofi pasteur, markets Gardasil in Europe.

Gardasil is approved to prevent more HPV virus types than Cervarix, specifically HPV types 6 and 11, responsible for 90 percent of genital warts, and types 16 and 18. GSK said its vaccine is focused strictly on preventing cancer and that HPV strains 16 and 18 are responsible for 71 percent of cervical cancers in Europe.

Cervarix has a proprietary adjuvant system, AS04. The adjuvant induces a stronger immune response than conventional aluminum hydroxide adjuvant systems, GSK said. Gardasil uses an aluminum-containing adjuvant system (amorphous aluminum hydroxyphosphate sulfate).

To help differentiate Cervarix from Gardasil, GSK is conducting a head-to-head clinical trial testing the two vaccines against each other. Results could be available by mid-2008 and the trial is studying the vaccines’ effects on immune responses for virus types 16 and 18.

According to separate Phase III clinical trial data for Cervarix, the product provides some protection against other HPV strains. Protection against six-month persistent infection from virus types 31 and 45 was 36 percent and 60 percent, respectively. In addition, protection against 12-month persistent infection caused by a combination of 12 other cancer-causing virus types was 27 percent, GSK said.

A biologic license application for Cervarix is currently pending at the FDA with an estimated late-January 2008 action date. — Christopher Hollis

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Reporters: Martin Gidron, Emily Ethridge, April Astor, Breda Lund, Christopher Hollis

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