The Food and Drug Administration (FDA), as part of its Drug Competition Action Plan, published a draft guidance detailing good practices for the submission of ANDAs on January 3, 2018. The guidance highlights common, recurring deficiencies that may lead to a delay in the approval of an ANDA and makes recommendations to applicants on how to avoid such deficiencies. A typical ANDA requires an average of four review cycles before approval. The delay happens when ANDAs are submitted without all the information that the FDA needs to determine whether the ANDA meets FDA standards for approval, which leads to additional review cycles.

ANDA Approval Process

The draft guidance specifically addresses deficiencies commonly arising with respect to four components of ANDA submissions: (i) patents and exclusivities, (ii) labeling, (iii) product quality, and (iv) bioequivalence. Highlighted below are some of the important takeaways from the draft guidance.

Patents and Exclusivities

The draft guidance highlighted that applicants often do not submit required information concerning the timely dispatch of a Paragraph IV notice letter, filing of a legal action by a patent owner, or failure by a patent owner to file any such legal action within the specified time frame. Also, when a new patent is listed for an Reference Listed Drug (“RLD”), applicants mistakenly file “serial submissions” of amendments to their paragraph IV certifications before FDA regulations allow such amendment or, alternatively, fail to provide the requisite certification for a newly listed patent altogether. The draft guidance reiterated requirements regarding the following aspects related to their ANDA:

  1. Documentation and notification of a legal action filing
  2. Resolution or appeal of a legal action
  3. Notice of paragraph IV certification
  4. New or revised information in the Orange book
  5. Amendments to an unapproved ANDA
  6. Notification of commercial marketing

Labeling

The draft guidance highlighted that applicants have improperly submitted draft container labels that do not accurately portray the formatting factors used with the final printed labels. Also, that the applicants have submitted container labels with insufficient color differentiation for the different strengths of a drug product. For parenteral drug products, the guidance mentioned that the applicants have mistakenly proposed package types that differ from the type approved for the RLD. The draft guidance reiterated requirements regarding the following aspects related to their ANDA:

  1. Draft container labels and carton labeling
  2. Color differentiation for container labels and carton labeling
  3. Labeling format
  4. Parenteral drug products

Product Quality Deficiencies

The draft guidance addressed common issues associated with in vitro dissolution (biopharmaceutics) and manufacturing facilities, among many other subtopics. For in vitro dissolution testing, applicants commonly omit solubility data for the full physiologic pH range, a detailed description of the proposed dissolution test for evaluation of the product (including developmental parameters used in selecting the proposed method), data demonstrating the dissolution method’s discriminating ability, and complete dissolution data and information for all strengths of the test and reference products. For manufacturing facilities, the draft guidance mentioned that applicants have frequently neglected to provide complete information in their Form FDA 356h and in the correct modules within their applications.

  1. Drug substance, including API starting material, manufacturing process and impurities
  2. Drug product, including establishing critical quality attributes
  3. In vitro dissolution (biopharmaceutics)
  4. Facilities
  5. Commercial manufacturing process
  6. Microbiology considerations

Bioequivalence

The draft guidance suggested that applicants include in their bioanalytical study reports complete dilution integrity data (as well as stock stability and recovery data), analytical raw data from all study runs, serially selected chromatograms (representing 20% of study subjects), and bioanalytical standard operating procedures. For differences in formulations and inactive ingredients, the draft guidance mentioned that applicants have sometimes failed to provide necessary justifications and documentation addressing these differences. If and when a different inactive ingredient or amount of an inactive ingredient was used in a placebo test formulation for bioequivalence testing, the applicant must explain why this change did not affect their showing of bioequivalence of the proposed drug product to the RLD. The draft guidance reiterated requirements regarding the following aspects related to their ANDA:

  1. Bioanalytical study data
  2. Clinical summary
  3. Deviations from product-specific guidances
  4. Information on bioequivalence and safety related to in vivo bioequivalence studies
  5. Differences in formulations and inactive ingredients
  6. Waiver requests under 12 CFR 314.99(b)