DID - Aug. 19, 2009 Issue

Vol. 8 No. 161

FDA: Patients in J&J Trial May Have Been at Risk

Nine patients in a clinical trial of the antibiotic ceftobiprole, which Johnson & Johnson (J&J) is developing for complicated skin and skin structure infections, may have been at risk of worsening infection or death because an investigator delayed giving them the study drug, an FDA warning letter says.

The investigator took as long as 11 days to administer the treatment, which the protocol said was supposed to be given the day patients were randomized into the trial, potentially placing them at increased risk for worsening of primary infection, dissemination of infection, sepsis and death, according to the letter dated Aug. 10 and recently posted on the FDA’s website.

The agency cites J&J’s Pharmaceutical Research & Development (PRD) for not taking action against the investigator, who is not named in the warning letter. The name of ceftobiprole also is redacted out of the warning letter, but J&J spokesman Ernie Knewitz disclosed it to DID.

The FDA warning letter also cites J&J PRD for hiring an investigator at a different site than the one with the study administration delays despite the study monitor’s warning that the researcher had compliance problems.

The monitor had noted that the investigator in question displayed a “lack of compliance in completing regulatory documents, including IRB [institutional review board] approvals, lack of diligence in study start-up procedures and inadequate patient population,” the warning letter says.

The study monitor also recommended that this site not be used because it didn’t use Spanish-language informed consent forms.

The company told the FDA that the contract research organization conducting the study in which the problematic investigator was hired had overruled the study monitor, but the agency rejects that explanation, saying that J&J PRD was responsible for hiring investigators.

The letter details several other problems with the ceftobiprole study and a separate trial of a different drug, the name of which is redacted from the version of the warning letter posted online Aug. 18.

For example, J&J PRD’s study monitors did not detect the fact that ineligible patients were enrolled in the ceftobiprole study.

Other problems noted in the warning letter that the study monitors either failed to notice or did not address adequately include:

  • Faulty drug accountability records;
  • Faulty study blinding procedures at one site;
  • Reversal of the drug infusion order for the fourth and fifth daily infusion at one site; and
  • Missing IV stability worksheets for all 39 subjects enrolled at one site, and inadequate corrective actions by study monitors.

“J&J PRD has received a warning letter from the FDA regarding the responses submitted to questions initially raised by the agency involving the development of ceftobiprole.  We will continue to work with the agency to address their concerns,” spokesman Ernie Knewitz told DID.

The warning letter can be viewed at www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm177398.htm. — Martin Berman-Gorvine


Protalix Wins Protocol Approval During Cerezyme Drug Shortage

The FDA has approved the treatment protocol for Protalix BioTherapeutics to test prGCD, its experimental medicine for Gaucher’s disease, and the company plans to file an NDA by the end of the year.

Genzyme recently announced a shortage of the only approved treatment for Gaucher’s disease, Cerezyme (imiglucerase), after a temporary production halt due to viral contamination at the company’s Allston, Mass., plant (DID, June 17). As a result, the FDA asked Shire and Protalix in July to submit treatment protocols for their experimental Gaucher’s disease medicines (DID, July 7).

Genzyme says in an announcement this week that the shortage is more severe than anticipated (DID, Aug. 17). It plans to release new material in November or December and expects the supply of Cerezyme and its Fabry disease treatment Fabrazyme (agalsidase beta) to be back to normal by the end of the year.

Protalix’s Phase III study of prGCD should be completed in September, and the company expects to announce results in October, the drugmaker says in a statement this week.

Shire already has begun a rolling NDA submission for its Gaucher’s treatment, velaglucerase alfa, and plans to complete the submission by the end of September, spokeswoman Jessica Cotrone told DID. The submission was initiated July 30, after the treatment received fast-track designation (DID, July 17). The FDA accepted Shire’s treatment protocol in early August, Cotrone said.

She added Shire has conducted three Phase III studies for the drug — the first achieved all primary endpoints and results from the other two will be presented at scientific meetings before the end of the year.

Protalix did not respond to a request for comment by press time. — April Hollis


Bayer Takes J&J Unit to Court Over Simponi  Drug

Bayer HealthCare is suing Centocor, a unit of Johnson & Johnson (J&J), for infringing a patent by selling its Simponi rheumatoid arthritis (RA) treatment — in the latest in a series of such suits.

Simponi is an anti-tumor necrosis factor (TNF)-alpha therapy. Centocor is accused of willfully infringing Bayer’s ’407 patent on human monoclonal antibodies that bind to TNF-alpha, which was issued to Bayer in 1997, according to court documents. A judgment of willful infringement would allow Bayer to collect treble damages.

In May, Abbott Biotechnology brought a suit against Centocor alleging that the sale of Simponi infringed the ’394 patent covering the tumor necrosis factor inhibitor Humira (adalimumab), which also is used to treat RA.

Centocor received FDA approval to market Simponi April 24 for three indications — RA, psoriatic arthritis and ankylosing spondylitis (DID, April 27). The biologic is an important part of J&J’s strategy to replace drug sales lost to generic competitors (DID, April 15).

Bayer HealthCare LLC v. Centocor Ortho Biotech Inc., was filed Aug. 14 in the U.S. District Court for the District of Massachusetts.— Elizabeth Jones


GSK, Brazil Collaborate to Manufacture Synflorix Vaccine

GlaxoSmithKline (GSK) will provide Brazil’s Ministry of Health with the technology to begin producing its Synflorix vaccine for pediatric pneumococcal disease.

GSK will produce the vaccine for the ministry’s Oswaldo Cruz Foundation (Fiocruz), until the technology transfer is complete, GSK says in a statement. Synflorix, which was approved by Brazilian regulatory authorities in June, will be incorporated into the country’s immunization program, GSK says.

The partners also will establish an R&D program at Fiocruz to develop a vaccine for dengue fever, following a series of collaborations on vaccines for polio, influenza, measles, mumps, rubella and rotavirus.

Synflorix, a 10-valent pneumococcal conjugate vaccine, has the potential to protect against more than 80 percent of the cases of invasive pneumococcal disease in Brazilian children younger than 5, GSK says.

GSK wasn’t available to provide details on the technical assistance it is providing by press time. — David Belian


Drugmaker Input Leads FDA to Revise Hotline Advertising Study

The FDA will expand a study of television drug advertising to determine the effectiveness of listing a consumer hotline for reporting adverse events, based on drug industry comments.

The FDA Amendments Act (FDAAA) calls for the agency to determine whether consumers understand and remember messages about the toll-free hotline in direct-to-consumer TV ads. The agency now plans to show mock TV ads to 6,000 participants, compared with the 1,600 it originally planned to enlist, according to a notice in the Aug. 18 Federal Register.

Merck and Sanofi-Aventis recommended a larger sample size than was originally proposed, in a comment period on the proposed study that ended Jan. 26. PhRMA advised a longer test time than the 15 minutes planned by the agency.

In addition, the Risk Communication Advisory Committee recommended at a May 2008 meeting that the FDA look at viewers who have a direct or indirect contact with the condition discussed in the ad.

Participants now are expected to spend 20 minutes viewing ads, and the agency has budgeted funding for two pre-tests to refine the study procedure before the official study. The Federal Register notice also includes details on how the results will be analyzed.

Participants will watch four mock television ads: two 15-second non-drug-related ads; a 30-second drug ad that includes the toll-free statement; and the test ad, a 60-second ad for a fictitious blood pressure medication. The prominence, duration and placement of the toll-free statement will vary.

Study participants will include people with high blood pressure as well as a general population sample. The agency believes understanding and retention of the hotline information will be stronger in the diagnosed sample.

The FDA notes the proposed study questionnaire is available upon request and says the mock advertisement will be available upon request after the study is completed. — April Hollis

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