DID - Jan. 14, 2009 Issue

Vol. 8 No. 8

CBER Meets Fast-Track Designation Deadlines Most of the Time

CBER, which received more than 200 fast-track designation requests over the past 10 years, made decisions on the applications within the statutory 60-day deadline 98 percent of the time.

CBER acted within two months on 202 of the 207 requests it received between March 1, 1998, and Dec. 31, 2008, according to a statement posted on the FDA’s website Monday. Only five decisions on requests were delayed until after the deadline, with one request pending.

Within the deadline, 128 requests for fast-track status were granted, 72 were denied and two are pending, the agency says.

A recent report by Tufts University’s Center for the Study of Drug Development found that fast-track designation brings a drug to market approximately four months sooner than those that undergo standard reviews (DID, Sept. 4, 2008). Fast-track designation also gives companies the opportunity to have more interactions with the FDA. — Christopher Hollis


FDA Deals Setback to Zegerid OTC Switch Application

Schering-Plough received a complete response letter for its application to market an OTC version of the heartburn treatment Zegerid.

The NDA for OTC Zegerid (omeprazole/sodium bicarbonate) was submitted in March 2008. Schering-Plough licensed the OTC rights to the drug from Santarus (DID, March 12, 2008).

Schering-Plough would not comment on the details of the complete response letter but said it “will continue to work closely with the FDA on potential approval of OTC Zegerid.”

“We do not comment on ongoing discussion with the FDA nor speculate on timing,” Schering-Plough told DID in a statement Tuesday.

Santarus would not comment on the details of the complete response letter either, but it indicates in a statement that the FDA had more than one question about the application.

“Santarus is in regular communication with Schering-Plough, who intends to continue to work closely with the FDA on a confidential basis to expeditiously address these questions and secure approval,” Santarus says.

The OTC switch application is for the 20-mg strength omeprazole. Although Santarus does not publish sales for Zegerid, it is a relatively small product line. According to the company’s 10-Q SEC filing in November, Santarus had $19.4 million in product sales during the third quarter of 2008. — Christopher Hollis


CDISC Standard Used to Improve Adverse Event Reporting

A collaborative study based on a Clinical Data Interchange Standards Consortium (CDISC) form will search for ways to improve postmarketing adverse event reporting.

Clinical Research Information Exchange (CRIX) International is leading the collaboration, which relies on CDISC’s Retrieve Form for Data Capture standard. Pfizer and Partners HealthCare are among the participants, and the project will be evaluated every three months throughout the year.

In the study, Adverse Drug Event Spontaneous Triggered Electronic Reporting (ASTER), drug adverse events will be entered into the electronic Longitudinal Medical Record system at Partners HealthCare members Brigham and Women’s Hospital and Massachusetts General Hospital. The adverse events will be recognized automatically and turned into reports that CRIX will forward within minutes to the FDA and drugmakers.

Physicians currently use what CRIX calls a spontaneous reporting system (SRS) to notify the FDA and drugmakers about drug adverse events.

“Analyzing data on adverse events is only effective if the data is accurate and complete, which is not always the case with the current SRS,” James Bland, executive director of CRIX International, said. “By making the reporting system easier and broadening the pool of reporters, we will create a database that will vastly improve the system.”

From Pfizer’s standpoint, “the goal is to advance the quality of data relating to benefits and risks of medicines, thereby giving physicians and patients better treatment options,” Michael Ibara, Pfizer’s head of pharmacovigilance information management, said.

CDISC’s effort on SRS is an extension of work by three other healthcare industry organizations — Integrating the Healthcare Enterprise, Health Level Seven and the Healthcare Information and Management Systems Society. — Martin Gidron


FDA Hasn’t Reached Verdict on Singulair Side Effects

More than 10 months after the FDA began studying whether Merck’s allergy and asthma drug Singulair had mood and behavioral side effects, the agency reports that no conclusion has been reached.

“FDA is continuing to review clinical trial data to assess other neuropsychiatric events, (mood and behavioral adverse events) related to drugs that act through the leukotriene pathway,” the agency says in a MedWatch report issued Tuesday.

The blockbuster Singulair (montelukast sodium) is a leukotriene receptor antagonist. The FDA also is investigating similar drugs, including AstraZeneca’s Accolate (zafirlukast) and Critical Therapeutics’ Zyflo (zileuton) and Zyflo CR.

The report was a follow-up to an Early Communication issued last year that notified healthcare professionals that the FDA was investigating a possible connection between Singulair and changes in mood involving suicidal thoughts (DID, March 28, 2008).

Merck responded in a statement Tuesday: “After a thorough review of the data from the controlled clinical trials of Singulair, and a careful assessment of post-marketing adverse events, Merck believes that the data support the continued use of Singulair in appropriate patients with asthma and allergic rhinitis.”

Merck said last year that the availability of OTC Zyrtec and the FDA Early Communication prompted it to reduce its 2008 sales forecast for the product by $200 million to as much as $4.6 billion (DID, July 23, 2008). The company later reduced its sales estimate for the drug to $4.3 million to $4.5 million.— Christopher Hollis


Warning Letter Says Researcher Overdosed Cancer Patients

A clinical investigator in a cancer trial gave two patients too much of an experimental drug because he based the dosage on the weight recorded on their driver’s licenses, according to an FDA warning letter.

The letter cited Nicola Spirtos of the Women’s Cancer Center of Nevada, accusing him of basing a patient’s dosage on her driver’s license weight of 190 pounds despite her drop to 127.6 pounds over five separate visits to the center. The FDA posted the Jan. 3 warning on its website Tuesday.

Spirtos did not report another patient’s hospitalization with chest pain for more than four months. The serious adverse event (SAE) should have been reported to the sponsor of the Phase II study within one working day, according to the letter, which was based on an FDA inspection conducted in November 2007. The trial subinvestigator was aware of the incident. The patient later received a left heart catheterization, bilateral selective coronary angiogram and angioplasty.

Another patient became severely neutropenic but continued to receive the standard dose of the investigational drug instead of a reduced dose as the trial protocol specified for patients who develop a low white-blood-cell count. The patient’s blood tests were not done on time, the warning letter says.

Other protocol violations cited in the letter include cases in which patients received investigational drugs in the incorrect order or not on schedule and did not get required lab procedures at the specified times.

Documentation failures cited in the letter include:

  • Inaccurate case histories;
  • Failure to sign and date source documents;
  • Lack of proof that study medications were stored at the temperature specified in the protocol;
  • Lack of proof that the site submitted an SAE report to the institutional review board for a subject who was hospitalized; and
  • Unexplained use of correction fluid and write-over corrections in multiple places throughout the source documents, which the FDA says made it impossible to verify the information in the records.

Spirtos told the FDA he had replaced his research staff and data coordinators in response to the agency findings, adding that he believed the FDA inspector “would have found an ever-decreasing number of deviations as [the] site responded to previously noted deficiencies and made changes to the data management team.”

 The FDA says Spirtos’ response was inadequate.

“As the clinical investigator, it was your responsibility to ensure that the study was conducted in accordance with the investigational plan and that adequate and accurate case histories were maintained as specified in applicable FDA regulations,” the warning letter states. “In addition, we note that your sole corrective action appears to be the termination and replacement of your staff with no information provided as to corrective actions your site will take to ensure that these violations will not take place in any ongoing or future studies.”

Spirtos did not respond to a request for comment by press time. The warning letter can be viewed at www.fda.gov/foi/warning_letters/s7077c.htm. — Martin Gidron


Neurobiological Technologies Dropping Viprinex, Reducing Staff

Neurobiological Technologies is reducing its workforce by 75 percent after it canceled development of its stroke drug Viprinex because it failed to show a clinical benefit in Phase III testing.

“It was determined that there was no group of patients in which Viprinex [ancrod] improved outcome, and therefore further development is not warranted,” Warren Wasiewski, chief medical officer for the company, says in a written statement Tuesday.

The Viprinex Phase III program for the treatment of acute ischemic stroke was halted last month after an analysis by an independent data safety monitoring board concluded that the product was not likely to show benefit in patients receiving the drug six hours after having a stroke.

“Following the receipt of these results, we have taken steps to reduce costs to preserve the company’s remaining cash and to reduce personnel to the level necessary to preserve the company’s other assets,” Abraham Cohen, Neurobiological’ chairman, says.
The company is firing the majority of its employees this week, paring down staff to the minimum necessary to carry out operations and complete contractual obligations, Neurobiological says. — Christopher Hollis


BMS, ZymoGenetics to Co-Develop Hepatitis C Therapy

Bristol-Myers Squibb (BMS) and ZymoGenetics will collaborate on the program for PEG-interferon lambda, a novel Type 3 interferon in Phase Ib development for the treatment of hepatitis C.

The companies have agreed to co-develop PEG-interferon lambda in the U.S. and EU and share development costs. ZymoGenetics anticipates conducting a significant portion of the continuing Phase I and certain Phase II development activities, the companies say in a statement.

ZymoGenetics said in a conference call that the companies had not finalized the Phase II program but should have a better sense of the product’s development path in the latter part of the quarter.

Last November, ZymoGenetics reported interim results from the ongoing Phase Ib trial. PEG-interferon lambda showed a meaningful reduction in the amount of hepatitis C virus and was well tolerated, according to a company statement.

Under the terms of the agreement, BMS will make an upfront cash payment of $85 million to ZymoGenetics for the development and commercialization rights to the drug as well as an additional license fee of $20 million, according to the statement.

ZymoGenetics could receive additional payments of up to $430 million based on pre-defined development and regulatory milestones for PEG-Interferon lambda in hepatitis C, as well as up to $287 million in development and regulatory milestones for other potential indications, which could include hepatitis B, according to the ZymoGenetics conference call.

ZymoGenetics will have the option to co-promote the product in the U.S. and share profits on product sales. Outside the U.S., BMS will have responsibility for commercialization, and ZymoGenetics will receive royalties on product sales.

“The profile of PEG-Interferon lambda offers the possibility of improvements in the safety and effectiveness of combination treatment for Hepatitis C and makes it an ideal fit with our emerging portfolio of small molecule anti-virals,” Francis Cuss, BMS’ senior vice president of discovery and exploratory clinical research, says in the statement. 

“We believe Bristol-Myers Squibb is the ideal partner for ZymoGenetics and that we share the vision that PEG-Interferon lambda could become an important part of treating patients with Hepatitis C,” ZymoGenetics CEO Douglas Williams adds.

The agreement is subject to antitrust clearance by the FTC and Justice Department. — Elizabeth Jones


Customer Service: Carmen Park
(888) 838-5578 • +1 (703) 538-7600
Editorial: David Grant
(703) 538-7600
Ad Sales: Andrew McSherry
(703) 538-7643
Content Sales: Alka Desai
(703) 538-7669

300 N. Washington St., Suite 200 • Falls Church, VA 22046-3431
Phone: (888) 838-5578 • +1 (703) 538-7600 • Fax: +1 (703) 538-7676

Reporters: Martin Gidron, Christopher Hollis, Elizabeth Jones

President: Cynthia Carter; Publisher: Matt Salt; Editorial Director: David Grant; Executive Editor: Theresa Barry

Copyright © 2009 by Washington Business Information Inc. All rights reserved. Drug Industry Daily (ISSN 1541-6607), an executive briefing on the regulation of pharmaceuticals, is published daily, 250 issues, for $1,495. Photocopying or reproducing in any form, including electronic or facsimile transmission, scanning or electronic storage is a violation of federal copyright law and is strictly prohibited without the publisher’s express written permission. Subscribers registered with the Copyright Clearance Center (CCC) may reproduce articles for internal use only. For more information, contact CCC at www.copyright.com or call (978) 750-8400. For site licenses for multiple users or to purchase multiple copies, contact Content Sales Manager Alka Desai at (703) 538-7669.