Will Your Generic Drug Application Get Rejected by FDA? New Guidance Documents Explain

The US Food and Drug Administration (FDA) has released two new guidance documents intended to clarify for generic drug makers the criteria by which the agency determines which applications it will "refuse to receive" due to deficiencies in an Abbreviated New Drug Application (ANDA) filing.

Background

The submission of an ANDA, as with most applications submitted to FDA, involves two stages: the submission of the application to FDA, and FDA agreeing to file the application with its review team.

Each stage has its own set of submission criteria, which are meant to weed out deficient applications which would otherwise cause an application not to obtain approval. For example, if FDA notices that an application is missing an entire section, the agency might refuse to accept it. Similarly, if a section is complete but is missing key information, FDA might similarly refuse to accept an application.

"A refuse-to-receive decision indicates that FDA determined that an ANDA is not sufficiently complete to permit a substantive review," FDA has explained. FDA has already established similar criteria for new drugs, such as in its October 2013 Manual of Policies and Procedures, Good Review Practice: Refuse to File.

Now FDA is releasing similar documents for generic drug manufacturers.

New Guidance: Impurities and Refused Applications

In a new draft guidance, ANDA Submissions – Refuse to Receive for Lack of Proper Justification of Impurity Limits, FDA explains that ANDA submissions are often rejected at the early stage for one of three reasons:

1. failing to provide adequate justification for proposed limits in drug substances and drug products for specified identified impurities that are above qualification thresholds
2. failing to provide adequate justification for proposed limits for specified unidentified impurities that are above identification thresholds
3. proposing limits for unspecified impurities (e.g., any unknown impurity) that are above identification thresholds

As FDA goes on to explain in the guidance, it considers information regarding the purity of a drug substance to be essential to the ANDA review process. If companies are unable to demonstrate the purity of their drug—or at least that present impurities are justifiable—FDA will refuse to receive a drug.

FDA said companies should be able to show one of four things in their submissions:

1. The observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug product,
2. The impurity is a significant metabolite of the drug substance.
3. The observed impurity levels and proposed impurity limits are adequately justified by the scientific literature.
4. The observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies.

New Guidance: General Refuse to Receive Consideration

The agency's second guidance, ANDA Submissions –Refuse-to-Receive Standards, is a deep dive into the same process, but from a more general perspective.

As with the earlier draft guidance on the same subject, the document contains a laundry list of regulatory do's and don'ts. Do, for example, make sure your active pharmaceutical ingredient is justified according to the ICH Q11 guidance. Don't submit an application with missing information about API sterility.

The list is apparently needed. FDA said it refused to receive nearly 10% of all ANDAs last year because of deficiencies, and as many as 18% in 2010.

But beyond those details, FDA also makes some changes to the guidance to better reflect the difference between "major" and "minor" deficiencies.  "Generally, a major deficiency is one that in FDA’s judgment cannot be easily remedied," FDA explained. Minor deficiencies, in contrast, can be easily remedied, and FDA will grant the ANDA applicant "a prescribed time period" in which to provide additional information. However, if there are 10 or more minor deficiencies in an application (or just one major deficiency), FDA will refuse to receive the application.

Sponsors should also be aware of FDA's requirement that they be current on their user fee obligations. Failure to pay fees under the Generic Drug User Fee Act (GDUFA) will cause an application to be rejected, FDA's guidance explains.

ANDA Submissions – Refuse to Receive for Lack of Proper Justification of Impurity Limits (FR)

ANDA Submissions –Refuse-to-Receive Standards (FR)