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USFDA’s Refuse to Receive (RTR) standards for
ANDA and PAS Filings
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When an applicant submits an ANDA to agency, OGD (Office Generic Drugs)
first conducts a review to
determine whether the application is sufficiently complete to permit a
substantive review. OGD refers to this period as the filing review. The filing review takes approximately 60 days from
the ANDA’s receipt date to complete it. If the submitted application is not
complete or any deficiencies are identified, then "refuse to file
letter" is issued by the OGD/CDER to the applicant. In case the
application has found complete without any deficiencies then it's accepted
& application is then sent to the internal review team for the
identification of Bio-Equivalence, Chemistry/Microbiology, Plant inspection
& Labeling review issues. Once the
ANDA submission is complete and acceptable without any further queries, the
applicant finally receives FDA approval letter.
Refuse To Receive (RTR)
RTRs, which apply both to ANDAs and to certain prior approval supplements (PASs) to ANDAs
(required when making a major manufacturing or other change to a previously
approved ANDA), indicate that FDA does not consider the submitted information
to be substantially complete. When an ANDA is submitted to the FDA, the agency
evaluates each application to ensure that it is complete and contains all the
required information as per the section 505 (j) (2) (A) of the Federal Food,
Drug and Cosmetic Act (FD&C Act) and doesn’t contain any deficiency as
described in 21 CFR 314.101 (a) and (e).
In applicants prospective issuance of an RTR determination will add financial burden,
delayed market-entry, and loss of market share. During OGD review, an
application can be refused to receive, based on:
- Inadequate
stability data
- Incomplete
response to screening deficiency
- Inadequate
dissolution data
- Qualitatively
(Q1) and quantitatively (Q2) dissimilarity from the innovator drug
- Response
to screening deficiency delayed beyond the prescribed time limit.
RTR Scenarios: Major And Minor Deficiencies
When an ANDA is submitted for review, the FDA will determine if
the application is complete from a high-level view. The FDA will check for any
missing details, highlight deficiencies (both major and minor), and mark if any
corrections are necessary. To ensure an application is correctly completed and
filed, it is important to understand the differences between major and minor
deficiencies.
- A major
deficiency is one the FDA considers “significant in nature, such
as some found in 21 CFR 314.101(d) and 314.101(e). If a major deficiency
is identified, FDA will RTR the ANDA.
- A minor
deficiency is one that the agency considers less critical in
nature and can be remedied easily. If the ANDA contains fewer than 10
minor deficiencies, the FDA will notify the applicant via phone, fax, or
email and give them seven calendar days to correct these deficiencies or
amend the ANDA. If an ANDA applicant receives an IR (information request)
from FDA listing minor deficiencies identified during the filing review, and if the
requested information is not submitted and received within seven calendar days, FDA will RTR
the ANDA. Responses to IRs should completely address all outstanding
issues identified in the IR.
The below
flow chart shows the FDA’s process for reviewing ANDAs and issuing RTRs,
depending on the number and type of deficiencies found.
Deficiencies In ANDAs
This section provides example deficiencies, organized by module
of the Common Technical Document (CTD), that could lead to an RTR.
Module 1
Minor Deficiencies:
- Incomplete
Form FDA 356h, such as
- Field
11: Full chemical name not provided
- Field
20: Patent certification is inconsistent with the patent certification
provided in Module 1.3.5.2
- Field
28: Establishment information does not match with the facilities
information provided in Modules 3.2.S and 3.2.P
- Field
29: Typo in drug master file (DMF) number or failure to list all the DMFs
referenced in module
- Basis
for submission 21 CFR §314.94(a)(3)
- Failing
to provide the appropriate basis of submission — designated reference
listed drug (RLD) and reference standard (RS; if applicable) currently
listed in the Orange Book
- If
an ANDA suitability petition is required, failure to provide the docket
number or FDA’s correspondence approving the petition
- Labeling
(Module 1.14)
- eCTD:
Legibility of draft and RLD container labels
- Failing
to provide the proposed container and carton labels for each strength and
each packaging configuration (container size)
- Failing
to provide the RLD container and carton label for each strength
Major Deficiencies:
- Unsigned
Form FDA 356h
- Failure
to submit Form FDA 356h
Module 2
Minor Deficiencies:
- Provide
separate PDF and Word documents
- Missing
summary data tables in module 2.7
- Failure
to provide the certificate of analysis for each strength of the RLD
- Failure
to provide the exact location of the long-term storage stability (LTSS)
study reports and data (Table 10), along with working hyperlinks to
respective information
Major Deficiencies:
- Inadequate
dissolution studies, lacking:
- Minimum
of 12 units
- Use
of FDA-recommended test media
- ½
tablet dissolution for modified-release products with functional score
marks
- General
deficiencies of in-vitro dissolution (Table 5)
- Not
conducted on 12 units
- Not
conducted on all strengths (test vs. RLD)
- Not
conducted in all test media
Module 3
Minor Deficiencies:
- Lack
of legibility in documents/data
- Failure
to translate non-English content into the English language
- Failure
to follow the ANDA checklist
- Missing
batch reconciliation and label reconciliation information
- Executed
batch reconciliation tables don’t include theoretical, actual, and
packaged yield
- Yield
is not expressed in dosage or product units (e.g., number of tablets and
bottles, number of vials, etc.)
- Potential
impurities not listed in tabular format as per FDA recommendation
Major Deficiencies:
- Failure
to demonstrate Q1/Q2 sameness for sterile drug products, ophthalmic,
and otic solutions to the RLD
- Lack
of justification for unknown/unspecified impurities
- Not
providing method validation/verification reports
- Inconsistent
functional scoring configuration with RLD
- Lack
of compliance with inactive ingredient database (IID) limits for
excipients for solid orals/parenterals/opthalmics/otics/topical drug
products
- Lack
of justification (supporting data and information) for impurities
(specified identified or specified unidentified) where proposed acceptance
criteria (AC) percentage exceeds qualification threshold (QT) or
identification threshold (IT), respectively
- Proposed
AC percentage exceeds QT or IT percentage, as applicable
- Failure
to provide stability data on two discrete API lots for each strength of
drug product, and on a minimum of three drug product batches of each
strength
- Failure
to provide six months (180 days) of stability data with a minimum three
time points
- Accelerated
and long-term stability studies
- Intermediate
studies for all three batches of the specific strength if accelerated
stability study shows significant change or failure of any attribute
- Failure
to submit worst-case scenario and non-worst-case stability data related to
container orientation
- Lack
of verification for all stability start and pull dates
Impacts of FDAs RTR decision on submitted ANDA’s
When the FDA issues an RTR, agency returns 75 percent of ANDA
fee already paid by applicant. Following are the major implications of RTR,
- Loss
of 25 percent of the ANDA fee
- Loss
of original submission date (Change in goal date)
- Loss
of market exclusivity period (180 days) in the case of NCE-1 submissions
- Delay
in product launch and loss of market share
If the applicant submits required information and material to
correct the deficiencies, the FDA is all open to consider (if found
substantially complete) the new and corrected version of ANDA. Upon such new
submission, however, the applicant needs to pay the total ANDA submission fee,
accordingly. The date of the revised submission will be considered as the new
application date.
The applicant can request the FDA for a reconsideration, if the
applicant disagrees with the major deficiencies identified and notified by the
agency. Then the ANDA applicant can provide the relevant supporting information
and material to the FDA and request for reconsideration. If the FDA does not
agree even after submission of the supporting information, the applicant can
request for a teleconference with the Agency for further evaluations. If the
reconsideration issue remains unsolved, the applicant should refer to 21 CFR
314.103 and guidance for industry Formal Dispute Resolution.
