Cancer Prevention Drugs Require Protocol Assessment Before Phase III – FDA

All oncologic risk reduction drugs should have a special protocol assessment (SPA) before entering Phase III trials, FDA advises staff in a recently issued "Manual of Policies and Procedures" guidance.

Oncologic drug sponsors "should be encouraged to submit an SPA for Phase III prevention studies, even when the trial is used to open a new IND," the MaPP states.

The MaPP, entitled "Clinical Review of Drugs to Reduce the Risk of Cancer," outlines the review policies for cancer prevention agents to be followed by FDA's Office of Oncologic Drug Products.

Established as part of the recent reorganization of the Center for Drug Evaluation & Research's Office of New Drugs, OODP officially began operations this past summer under the leadership of Director Richard Pazdur (¹ (Also see "FDA Oncology Drug Reviews Headed By Justice Under Revised Structure" - Pink Sheet, 27 Jun, 2005.), p. 11).

Prior to the establishment of OODP, FDA transferred regulatory oversight for most non-biologic cancer prevention applications from various CDER review divisions to the Division of Oncology Drug Products, which now is a component of the new cancer office.

Two approved products - Pfizer's Celebrex (celecoxib) and Axcan's Photofrin (porfimer) - and 69 investigational new drugs have been transferred to the division.

Noting that the standard 30-day review "may not permit sufficient time to evaluate a complex Phase III prevention study submitted as a new IND," the MaPP instructs OODP reviewers to "encourage sponsors to schedule pre-IND application/end-of-Phase II meetings before submitting the IND."

If the safety review of a Phase III study submitted as part of an IND requires consultation with a specific subject matter review division (SSMRD) or other office or center, sponsors should be informed that such discussions will necessitate the "full 45-day review clock of an SPA," the MaPP states.

Existing INDs that include cancer risk reduction studies and studies for other indications will be split administratively into separate INDs, FDA states.

Sponsors with a new molecular entity for cancer risk reduction should submit the protocol to OODP as a new IND. A supplement for a new cancer risk reduction indication for a previously approved drug will be submitted to OODP rather than the SSMRD that reviewed the original application.

Jurisdiction for dual co-primary endpoints contained within a single protocol - one for cancer prevention and the other for a non-cancer risk reduction indication - will be determined by the relevant division directors. In cases of disagreement, adjudication will be handled by the office directors.

OODP will sign off on the first cancer prevention indication for an NDA, BLA or supplement, with the exception of nonmelanoma skin cancer risk reduction, which will be handled by the Division of Dermatologic & Dental Drug Products.

Sign-offs for subsequent cancer prevention indications "will follow standard CDER practices," the document says.

OODP "will consult the appropriate SSMRD for all cancer prevention NDAs, BLAs, efficacy supplements, Phase III studies, pivotal chemoprevention trials and SPAs, as appropriate," the MaPP states.

For other submissions, such as labeling supplements with clinical data, the SSMRD and other offices and centers will be consulted "as needed."

If a relevant SSMRD outside OODP does not exist, such as for a breast cancer application, "consultation with an SSMRD or another office or center may be warranted on the basis of expertise in related efficacy or safety issues."

For example, the Division of Reproductive & Urologic Drug Products could be consulted for "risk reduction strategies using oral contraceptives regardless of cancer site," the MaPP states. Consultations should be focused on specific questions and not a global evaluation of the submission, the document notes.

With the publication of the MaPP, drugs being developed for cancer prevention claims that are now in Phase II will have to meet the new requirements.