A new guidance document issued by the US Food and Drug Administration's (FDA) drug and biologics review divisions explains how the agency handles Prior Approval Supplements (PAS) under its generic drug user fee amendments (GDUFA) program.

Background

A PAS is an application which seeks to make changes to an already-approved application, such as an Abbreviated New Drug Application (ANDA), which is used by FDA to approve generic drugs.

Unlike other change notification processes, such as FDA's Changes Being Effected (CBE) process, FDA must explicitly approve a PAS before a company can implement the changes contained within it. It is most often used when a company is implementing major changes to a drug's manufacturing process, but can also be used for:

• addition or revision of standard operating procedures if the change is less restrictive than it was before
• manufacturing additional products using the same equipment
• requesting an exemption to federal regulations
• requesting approval for a comparability protocol
• requesting an exemption for which there is no published guidance
• changing manufacturing facilities, the manufacturing process, the manufacturing equipment, or the contractor
• changing the legal name of an applicant
• making changes to the label of a drug to reflect new safety information

A New PAS Guidance

FDA's PAS process is well-established, and hasn't substantially changed since 2004, when FDA released its guidance document, Changes to an Approved NDA or ANDA.

But for ANDA holders, understanding how the PAS process works with FDA's generic drug user fee program can be slightly tricky.

Like full generic drug applications, PASs are subject to performance and review goals under GDUFA, which are intended to make sure FDA reviews applications quickly. In return, industry helps fund FDA through the submission of fees. The PAS submissions aren't cheap, with each one costing $31,930—half the cost of a full ANDA submission.

The question on most PAS applicants’ minds: When can I expect to obtain approval from FDA for a PAS?

To better clarify the process of how PAS applications are treated under the GDUFA program, FDA is now out with a new draft guidance document, ANDA Submissions — Prior Approval Supplements Under GDUFA.

The Basics

Under GDUFA—a part of the Food and Drug Administration Safety and Innovation Act (FDASIA)—FDA committed to incremental improvements in its review of PAS applications. In general, PASs will be reviewed within six months of the date of submission if the application does not require a facility inspection, and 10 months if it does. FDA's current goal is to meet these standards in 60% of cases in 2015, 75% of cases in 2016, and 90% of cases in 2017.

A PAS is defined as having been "submitted" to FDA on the date the agency receives the application through its electronic submission systems. Therefore, the day an application is submitted counts as the first day of the review period.

However, that review period assumes that an application was both received and accepted by FDA, which is not always the case. In some cases FDA "refuses to file" (RTF) an application because of deficiencies. The most common of these deficiencies is a failure to pay fees associated with the PAS, such as the $31,930 fee, but also includes failing to pay fees associated with the manufacturing facility where the drug is made.

Timelines and Amendments

One of the trickiest parts of the PAS submission process is determining whether or not an application requires FDA to come inspect the manufacturing facility. The agency concedes that "it is not always immediately evident upon submission whether a PAS requires an inspection," meaning a PAS could be on hold for an extra four months in some cases.

FDA indicates in its guidance document that companies should assume any PAS that requires "an assessment of the need for an inspection" will require an on-site inspection and therefore take up to 10 months under normal circumstances.

Amendments to the PAS will cause the GDUFA goal date to change, FDA notes in its guidance. Those amendments fall under three categories: Tier 1, 2 and 3. Tier 1 amendments are reserved for the first solicited major amendments and the first five minor amendments to an application. Tier 2 amendments are those unsolicited by FDA. Tier 3 amendments are those which are solicited, but occur after the limits set by the Tier 1 standard.

Under GDUFA, FDA says it will try to review all Tier 1 and 2 amendments between 3 and 12 months after the time of submission. Tier 3 amendments are not subject to GDUFA goal date metrics.

A comment period on the guidance is open for 60 days.

ANDA Submissions — Prior Approval Supplements Under GDUFA (FR)