The US Food and Drug Administration (FDA) has sent a warning letter to Johnson & Johnson (J&J) accusing the company of lax oversight in its role as sponsor of two clinical studies with ceftobiprole (Zeftera/Zevtera), the anti-MRSA antibiotic developed by the company in partnership with Switzerland’s Basilea Pharmaceutica.

The warning further complicates an already fractious relationship between J&J and Basilea, which has filed a damages claim against the US company over delays to the approval of ceftobiprole in the US and Europe. These delays relate to potential deficiencies at trial sites used by J&J in its late-stage development of the drug.

According to the FDA, an investigation of Johnson & Johnson Pharmaceutical Research & Development’s role as sponsor of the ceftobiprole studies revealed “objectionable conditions” that were not adequately addressed in the company’s responses to a Form FDA 483 inspection report sent out in June 2008 and to later requests for information.

The Office of Compliance in the agency’s Center for Drug Evaluation and Research concluded that J&J “did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations” in the ceftobiprole trials.

Last November, the FDA put back a decision on the New Drug Application (NDA) for ceftobiprole until it had resolved “issues of data integrity” raised in a complete response letter for the drug, which was filed for US approval for the treatment of complicated skin and skin structure infections, including diabetic foot infections.

The letter cited J&J’s “failure to ensure proper monitoring of the studies” submitted with the NDA. It requested information on the company’s clinical quality assurance programmes and a new audit plan addressing “deficiencies in contract research organisation monitoring”.

Subsequently, the European Medicines Agency’s Committee for Medicinal Products for Human Use told J&J that full approval of ceftobiprole in the EU (for the treatment of complicated skin and soft tissue infections) would have to be stalled pending Good Clinical Practice inspections of trial sites run by Janssen-Cilag in the late development programme.

The FDA’s warning letter did not identify ceftobiprole by name but J&J has confirmed that the agency’s concerns relate to the antibiotic. The company said it continued to work with the FDA on the problem and that only “a handful” of trial sites were involved.

The warning letter emphasised four areas of alleged deficiency in J&J’s management of the ceftobiprole trials:

- Failure to ensure proper monitoring of the clinical investigations, which resulted in “deficiencies in record-keeping with respect to case histories and drug accountability by clinical investigators participating in the above-referenced studies”.
- Failure to ensure that an investigation was conducted in accordance with the general investigational plan and protocols, as specified in the Investigational New Drug (IND) application for ceftobiprole (e.g., study monitors failed to ensure that the planned trial blinding procedures were followed correctly at one site).
- Failure to secure investigator compliance with the investigator plan and applicable FDA regulations (e.g., all patients should have begun dosing on the same day as randomisation; this did not happen at one site).
- Failure to ensure that only investigators qualified by training and experience were selected as appropriate experts for the trials – for example, one doctor was chosen despite a pre-study monitoring visit documenting that the investigator was “not recommended” due to lack of compliance in completing regulatory documents, lack of diligence in study start-up procedures, and an inadequate patient population.

J&J was given 15 working days from receipt of the warning letter to notify the Office of Compliance in writing “of the actions you have taken or will be taking to prevent similar violations in the future”. Failure to explain adequately and promptly the violations detailed in the letter “may result in regulatory action without further notice”, the Office added.

Announcing its interim results on 14 August, Basilea noted that clinical site inspections for ceftobiprole had now been completed both in the US and Europe. “Subject to acceptability of the resubmission, a decision by the FDA on the complete response [letter to J&J] could occur in the first half of 2010,” it stated. “The EMEA Committee for Medicinal Products for Human Use could potentially issue a recommendation to the EU Commission by the end of 2009.”