Ceftobiprole, a new antibiotic from Basilea Pharmaceutica to treat the tougher bugs like MSRA-resistant bacteria, has been rejected by USFDA.
US Food and Drug Administration issued to the sponsor, Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (Johnson & Johnson PRD), a Complete Response Letter on ceftobiprole saying that the agency cannot approve the application in its present form, Baselia said in a press release.
Ceftobiprole is an anti-MRSA broad-spectrum cephalosporin antibiotic.
US FDA recommended that two new and well-controlled studies to be conducted to evaluate the safety and efficacy of ceftobiprole for the treatment of skin and skin structure infections (cSSSI).
Data from Studies BAP00154 and BAP00414 cannot be relied upon because inspections and audits of approximately one-third of the clinical trial sites for these studies found the data from a large proportion of these sites to be unreliable or unverifiable, raising concerns regarding the overall data integrity for both studies, US FDA pointed out.
In addition, US FDA’s Division of Scientific Investigations (DSI) determined that Johnson & Johnson PRD failed to adequately monitor the clinical investigators’ conduct of these studies, as outlined in its Warning Letter issued earlier this year to Johnson & Johnson PRD.
Given the number of clinical sites from which data are considered unreliable and/or unverifiable (10 of 49 clinical investigator sites audited by FDA or the third party auditor) and the types of monitoring inadequacies, including those that affect key safety and/or primary efficacy findings identified in the third party auditor reports, a favorable conclusion regarding data reliability at remaining clinical investigator sites cannot be reached, US FDA stated.
US FDA also requested further information related to the justification of the non-inferiority margin for two patient subsets with abscess following primary incision and drainage or diabetic foot infections.
In August 2009, US FDA issued to Johnson & Johnson PRD a Warning Letter on its role as a sponsor of clinical trials.
US FDA noted that under the terms of the agreement between Basilea and Cilag GmbH International, a Johnson & Johnson company, all rights and responsibilities for ceftobiprole clinical trials were transferred to Johnson & Johnson PRD and it concluded that Johnson & Johnson PRD did not adhere to the applicable statutory requirements or FDA regulations governing the conduct of clinical investigations.
US FDA found numerous objectionable conditions during its investigation into Johnson & Johnson PRD’s role as a sponsor of the two phase III trials of ceftobiprole for the treatment of cSSSI.
Basilea anticipates an arbitration decision prior to the end of 2010.
In February 2005, Cilag GmbH International, a Johnson & Johnson company, was granted an exclusive worldwide license to ceftobiprole. The NDA for ceftobiprole for the treatment of cSSSI was submitted to the FDA by Johnson & Johnson PRD in May 2007.
The FDA issued an Approvable Letter in March 2008. Thereafter, the Agency conducted additional inspections of the investigator sites and an inspection of the sponsor Johnson & Johnson PRD and issued a Form FDA 483 informing the company about the Agency’s observations on Johnson & Johnson PRD’s failure to ensure proper monitoring of the studies as well as deficiencies in study conduct.
In November 2008, US FDA indicated in its Complete Response Letter to Johnson & Johnson PRD the existence of data integrity issues and that further resolution of specific deficiencies of study conduct was necessary.
Following a review of Johnson & Johnson PRD’s response to the Form FDA 483, US FDA issued a Warning Letter to Johnson & Johnson PRD in August 2009.
In August 2009, US FDA accepted for review the Complete Response submission by Johnson & Johnson PRD to the ceftobiprole NDA for cSSSI. The Complete Response submission addressed the FDA Complete Response Letter issued in November 2008.
Basilea expects an opinion by the EU Committee for Medicinal Products for Human Use (CHMP) in Q1 2010.
Due to the deficiencies identified by the FDA in Johnson & Johnson PRD’s conduct of the clinical investigations and Basilea’s claimed breaches of the License Agreement, the company submitted a Request for Arbitration under the License Agreement for ceftobiprole in February 2009.
Basilea’s claims under arbitration include that Johnson & Johnson PRD breached the License Agreement by, among other things, causing the delay in the approval of ceftobiprole in the U.S. and EU. Basilea’s initial significant damage claims, including milestone payments and additional damages, in the arbitration will increase as a result of this further delay.
Ceftobiprole is currently being reviewed in EU regulatory agencies for the treatment of complicated skin and soft tissue infections (cSSTI).
Ceftobiprole is marketed in Canada as Zeftera for the treatment of cSSSI, including non-limb threatening diabetic foot infections without concomitant osteomyelitis and in Switzerland (Zevtera) for the treatment of cSSTI including diabetic foot infections without concomitant osteomyelitis.
Ceftobiprole is also approved in Russia, Azerbaijan, Ukraine and Hong Kong.
Basilea Pharmaceutica Ltd, whichi is headquartered in Basel, Switzerland, focuses on new antibacterial, antifungal and oncology agents to fight drug resistance and on the development of dermatology drugs.
Basilea owns a diversified portfolio including two commercialized drugs (Toctino, Zeftera/ Zevtera) and one investigational drug (isavuconazole) in phase III clinical development. Toctino (alitretinoin) is marketed in Denmark, France, Germany and the United Kingdom and is approved in Austria, Belgium, Canada, Finland, Luxemburg, the Netherlands, Spain and Switzerland. Toctino has been recommended for approval in 16 European countries.
A phase III clinical trial on alitretinoin for the treatment of severe chronic hand eczema is ongoing in the US.