Beginning August 11, 2008, the U.S. Food and Drug Administration (FDA) will change the way it communicates with sponsors of pending new drug applications (NDAs). Under newly adopted regulations, FDA will issue a “complete response” letter instead of an “approvable” or “not approvable” letter when the agency has completed its initial review of an NDA and determined that the application is not ready for approval.1 The new policy applies to all letters issued on or after August 11, 2008, regardless of when an NDA was submitted to FDA.

This change is intended to avoid any implication regarding the ultimate approvability of a drug.2 According to FDA, “in the past, some drug manufacturers expressed concern that a not approvable letter sent an unintended message that a marketing application would never be approved, which could adversely affect a company’s ability to raise capital.”3 A complete response letter is “a more consistent and neutral mechanism to convey” that FDA “cannot approve an application in its present form.”4

Without an implication as to whether a drug eventually may be approved, a sponsor that receives a complete response letter and has public reporting obligations may need to disclose more information than before about the content of the letter. This disclosure may be necessary in order to provide investors with a balanced perspective on the likelihood of a drug eventually being approved. Under prior regulations, the implications of an application being “approvable” may have led to the conclusion that less disclosure was appropriate.

The new regulations also give FDA broader discretion to defer action on amendments to pending original applications and efficacy supplements.5 Presently, “major” amendments submitted more than three months before the end of the initial review cycle and “minor” amendments submitted at any time during the cycle generally are resolved within the initial review cycle.6 Beginning August 11, 2008, FDA may choose to defer its review of all amendments to the next review cycle. The agency declined to specify any criteria by which it will determine whether to defer an amendment, stating that it did not believe it could codify all the circumstances under which it “might” do so.7

The breadth of the agency’s discretion in this area and the resulting uncertainty for sponsors are reinforced by a new “MaPP” (a component of the Center for Drug Evaluation and Research’s (CDER) Manual of Policies and Procedures) regarding “communication to applicants of planned review timelines,” issued by FDA just a few weeks before the regulations.8 Among other things, the new MaPP suggests that the responsible CDER review division has significant discretion in revising review timelines and issuing new goal dates after the submission of major amendments to applications. The new MaPP also indicates that, in certain situations, the review divisions may determine that original review timelines will no longer apply and that no new timelines will be provided.

The new regulations also codify concepts that previously had existed informally under user fee policy and guidance documents, thus giving these concepts the force of law. For example, the regulations include definitions of “Class I” and “Class II” resubmissions of an application following receipt of a complete response letter.9

There is no change in FDA policy regarding non-disclosure of complete response letters. In the preamble to the final rule, the agency reiterates that “before approval, [even] the existence of an application is confidential commercial information” and will not be publicly disclosed by FDA.10

Taken together, the new regulations and MaPP may well reduce the predictability of the FDA review process. The immediate impact will be felt both in planning for the outcome of an ongoing review, and in communicating the status of a pending application to shareholders and other outside constituents.