Biotech Values

[rhaab]

Phenoxodiol newsletter may answer some questions.

http://www.marshalledwardsinc.com/pdf/MSHL%20Newsletter.pdf

OVATURE has 470 patients in two arms. The SPA includes agreed endpoints for accelerated approval based on PFS following an interim analysis (said separately to occur when all patients recruited and 97 events recorded - estimated to take 12-18 months) and that the company has conducted a pilot study to test the efficacy of oral PXD in the OVATURE setting. Also, from a recent conference: "It is well known that within 6 months of resistance it is very unlikely that any women will respond - if at all, only a few percentage. In our Phase III protocol we will only be selecting women who have failed on previous therapy within 6 months before entry into the PXD/Carboplatin regimen."

A 15 month odyssey

The Phase 3 OVATURE study has undergone considerable progress towards initiation over the past 15 months. MSHL has worked closely with the FDA on the OVATURE Study. The company retains the services of the Health Care division of one of the largest law firms in the US to advise on regulatory matters, including helping to guide the regulatory strategy and to coordinate the liaison with the FDA.

Mindful of the fact that a number of pivotal drug studies by other companies over the past 2 years have received criticism by the FDA for their inadequate design, MSHL has sought to design this pivotal study in a way that is compatible with the latest FDA guidelines. This is always challenging because of the inevitable shift in official thinking over time as different clinical studies conclude and yield data that varies from the unexpected to the contentious. There are few absolutes in the oncology field, each set of data being considered on its own merits, and often the cause of considerable debate between the sponsor and the agency.

The design of this pivotal study has been an exhaustive process that commenced with the appointment of a Steering Committee (comprising sponsor representatives and respected oncologists), which then consulted with senior oncologists from the UK and US who had agreed to participate in OVATURE and to be Principal Investigators for their hospitals. Overseeing the whole design process and liaising with the FDA, is the company’s Washington-based legal and regulatory representatives.

Pursuant to a meeting with the FDA in late 2004, a study design was selected that was finally ratified by a meeting of 20 international oncologists in Florida in April 2005. That design was duly submitted to the FDA for its approval under the IND (Investigational New Drug) scheme in May 2005, a default scheme where a trial can start unless blocked by the FDA for reasons such as safety concerns. That submission coincided with the completion by another major pharmaceutical company of a large study of an anti-cancer drug for use in late-stage lung cancer patients. The FDA had earlier granted Accelerated Approval status on the basis of an apparent delay in tumour progression but a continuation of the study failed in the FDA’s view to provide ultimately any overall survival benefit. The rescinding by the FDA of regulatory approval for that drug in that particular indication is the subject of ongoing discussion.

A major consequence of this experience was to cause the FDA to review its policy concerning Accelerated Approval, an entirely unanticipated outcome, but one which obliged MSHL to undertake a major re-design of the OVATURE study. A new design subsequently was discussed with the FDA, using a design that involved a novel approach by which reversal of chemoresistance could be tested. However, MSHL considered it prudent to test this novel, highly stringent approach in a pilot study using a small group of patients with late-stage ovarian cancer. Sufficient data subsequently was generated by that pilot study to allow the re-designed protocol to be lodged with the FDA in November 2005.

That protocol has now been agreed between MSHL and the FDA and will provide the basis for two determinations by the FDA – the first being consideration for Accelerated Approval following the interim analysis, and the second being consideration for New Drug Approval status following the final analysis. Based on this agreement OVATURE will now proceed, with patient enrolment commencing in Q306.

In the meantime MSHL, along with the Contract Research Organisation retained for project management, has used the available time to establish the trial infrastructure and to select and appoint hospital sites within the US, Europe, UK and Australia.

The ability to manufacture the considerable quantity of drug product required for a Phase 3 clinical trial also has been developed in this interim period.