The FDA published two related guidance for generic drugs in January:  the 11-page MAPP 5241.3 titled ‘Good Abbreviated New Drug Application Assessment Practices‘ and a 30-page heavily footnoted draft guidance titled ‘Good ANDA Submission Practices.’  Both contribute to the ‘Drug Competition Action Plan’ that is developed to increase drug competition with the production and approval of high-quality generic drugs.

Late last year we published articles that looked at several new guidance in the generic drug area, HERE and HERE. Let’s begin with the lengthy guidance first because it addresses actions that can be taken by generic firms. Then we will follow up with a look at the MAPP that describes how the FDA will assess, rather than review, these submissions.

DRAFT GUIDANCE, Good ANDA Submission Practices:

This guidance is intended to assist sponsors in the preparation of ANDAs. The guidance identifies common deficiencies (and how to avoid them), includes granularity in requirements, and makes significant use of footnotes. The overall intent is to reduce the number of review cycles conducted before generic drugs are approved. The guidance covers six broad areas, of which we will cover four in detail — namely sections III through VI.

  • Section I Introduction (page 1)
  • Section II Background (pages 1 – 3)
  • Section III, Patent and Exclusivity Deficiencies (pages 3 – 9)
  • Section IV, Labeling Deficiencies (pages 9 – 12)
  • Section V, Product Quality Deficiencies (pages 12 – 26)
  • Section VI, Bioequivalence Deficiencies (pages 27 – 30)

Patent and Exclusivity Deficiencies

I’m going light on this section because of the legal details which I’m not anywhere near an expert with. Patents protect the innovator drug for a specified term of exclusivity after which generic versions of the ‘reference listed drug’ may enter the market. This section of the guidance provides significant detail on the filing requirements, notifications that the sponsor must make, and how legal actions may be resolved or appealed.

Labeling Deficiencies

Generic drug labels must generally be the same as that for the reference listed drug with few exceptions that may include expiry dating and formulation. The FDA reviews label format, including “formatting factors such as the font size, style, and color of the required text; the labeling’s identification of different product strengths; and other methods used to ensure that the required information is presented with adequate prominence.” 

The guidance identifies deficiencies that occur when sponsors submit draft containers or carton labeling that do not meet the formatting requirements for the commercial product. Failure to provide adequate labeling can result in delays as the FDA works to confirm the adequacy of the proposed labeling. Firms are responsible for seeing that approval granted to draft labeling adequately reflects the final commercial labeling. If labeling used on a commercial product differs from the approved labeling, it may be deemed ‘misbranded.’

When labels use color, it should be applied to ensure differentiation from other “…pending and approved products in their product line.” The FDA identifies that sometimes applicants have submitted container and carton labeling that does not adequately differentiate between multiple strengths and other drug products.  Further, this guidance identifies the software that should be used to submit electronic copies of draft labeling.

The FDA identifies some deficiencies they have encountered in this area, including but not limited to:

  • Failure to convey safety information critical for the prevention of life-threatening situations for drug products with integrated ferrules and cap overseals;
  • Including ‘extraneous’ information on ferrules and cap overseals for some drug products such as display of lot numbers, logos, or product names.
  • Black colored overseals may be used only for potassium chloride injectable products.
  • Failure to ensure that the drug product strength is correctly expressed on container labels so that the health care professional administering the drug can correctly calculate the dosage.

Product Quality Deficiencies

This section is the largest of the guidance and is subdivided to address APIs, drug products, biopharmaceutics, facilities, commercial manufacturing processes, and microbiological considerations. Within this section, and as footnotes, the FDA references other guidance that is relevant to the various topics. It also specifies the location within the CTD formatted submission where the sponsor should present various information.

  • For APIs, this guidance includes advice on API starting materials, API manufacturing processes, impurities and their removal/reduction during the manufacturing process, specifications for isolated intermediates, and tests for critical quality attributes.
  • For Drug Products, this guidance addresses the importance of identifying critical quality attributes, identification, control, qualification of impurities, justification of inactive ingredients and their safety, and validation of analytical methods.
  • For In Vitro Dissolution (Biopharmaceutics), this guidanceaddresses the need to develop and validate dissolution methods, provide complete method development information in the submission, provide dissolution acceptance criteria from representative bio-batches, address specifics for immediate release solid oral dosage forms, and modified release solid oral dosage forms.
  • For Facilities, applicants have often not provided full and accurate information identifying all manufacturing, testing, and warehouse sites. For combination products, this includes the site(s) of manufactures of ‘non-lead’ constituent components. The sponsor should confirm that all sites are ready for inspection at the time of the ANDA submissions and should communicate exceptions on the Form FDA 356h. And, finally, applicants must ‘certify’ that contract sites are cGMP compliant. The FDA has deemed ANDAs not approved because the FDA found that the contract manufacturer was not GMP compliant. These expectations speak to the importance of selection, qualification, and oversight necessary when firms employ contract manufacturers.
  • For Commercial Manufacturing Processes, the FDA says they have found that “…applicants often provide inconsistent, inaccurate, or incomplete information in these modules, leading to refusals to approve.” Applicants should be ready for commercial-scale manufacturing with an appropriate control strategy identified. Open-ended in process parameters such as NMT 100 L/Min, should not be used. Finally, applicants should provide a tabulation of conditions for hold times of intermediates and bulk drug products used in commercial manufacturing.
  • Microbiological Considerations, include those for both in-process bioburden limits and validation of endotoxin test methods. The FDA states that “applicants have not always accounted for the additional dilution that resulted from sample pooling in maximum valid dilution (MVD) calculations, which has again led to FDA’s refusal to approve the ANDAs.”

Bioequivalence Deficiencies

  • The FDA expects complete bioanalytical study reports. The guidance states that this includes “analytical raw data from study runs…of all subjects.” It will be interesting to see if this means electronic data if that is how the data are collected.  Health authorities (including the FDA) state that paper printouts of electronic data do not qualify as “raw data.”
  • Sponsors should provide clinical data from BE studies in template tables that the FDA developed and made available. The FDA has identified deficiencies where Applicants, however, have submitted summary tables that are neither filled out completely nor prepared properly. For example, applicants have failed to list, in formulation tables, all of the strengths of the products for which they are seeking approval. Applicants have also submitted summary tables to FDA in a scanned document rather than in a text-based PDF file and Microsoft Word document. These actions have led to FDA’s refusal to approve the ANDAs.”
  • Applicants that do not meet the requirements in the product-specific guidance should justify their approach and provide data in support of the justification. When a sponsor employs alternative statistical approaches, they should provide both justification and data.
  • ANDA submissions should include all BE and safety data associated with the BE studies. The FDA states that “applicants have not always included in their original ANDAs the information that is necessary 982 for FDA to fully evaluate the BE of the test product in a timely manner, resulting in FDA’s 983 refusal to approve the ANDAs.” This section of the guidance identifies specific information that the sponsor should provide.
  • For the ANDA in support of an injectable product, the applicant should justify any difference in formulation and inactive ingredients from the Reference Listed Drug.

MAPP 5241.3, Good Abbreviated New Drug Application Assessment Practices

Now that we’ve covered the new guidance, let’s look at how the FDA will ‘review’ these applications when they are received. MAPP 5241.3, ‘Good Abbreviated New Drug Application Assessment Practices’ became effective January 3, 2018.  The MAPP is intended to increase the efficiency of ANDA review and decrease the number of review cycles needed for ANDA approval.  Based on GDUFA I from 2012, the FDA implemented performance goals for the review of ANDAs.

Review practices have evolved and frequently differ among the various offices at the FDA conducting submission reviews. It’s been a common refrain from BLA, NDA, and ANDA sponsors that often the FDA requests nice-to-have data that may not have direct relevance to the safety and efficacy of the product under review. This MAPP states that the Office of Generic Drugs and Office of Product Quality “will use the term assessment in place of review. Assessment means the process of both evaluating and analyzing submitted data and information to determine whether the application meets the requirements for approval and documenting that determination.” This MAPP implements 3 changes to the FDA’s practices in this area, and because of their importance, we provide them below:

  • Establishes that assessment teams should, when available, use templates and assessment tools provided by the sub-disciplines that focus the primary assessment of quality, bioequivalence, or labeling data or information on the critical attributes of the application. These critical attributes templates and assessment tools will help guide assessors to convey:
    • Their determination of whether the application meets the requirements for approval and
    • Their message to applicants, when applicable, explaining the deficiency, why a major or minor amendment is necessary to respond to that deficiency (e.g., by referencing guidance documents), and what missing or additional information is needed to support an approval decision
  • Clarifies the roles and responsibilities of primary assessors, secondary assessors, and division directors (who, under this MAPP, will no longer perform the role of a typical tertiary reviewer). This clarification will reduce duplicative and unnecessary work, which will increase FDA’s efficiency and effectiveness.
  • Establishes that OGD and OPQ will clearly communicate to applicants what deficiencies must be corrected for their ANDAs to be approved. This communication will enable applicants to develop high-quality re-submissions and to reduce the number of subsequent cycles to approval.”

Key MAPP Takeaways

Starting on page 5 of the MAPP, the FDA describes the process for assessment of ANDA submissions along with how the ‘primary assessor’ is to accomplish the process and determine whether the ANDA meets the regulatory requirements for approval.  It states “Information that is scientifically or academically interesting but is not needed to make a regulatory decision is not relevant. In other words, primary assessors should focus on issues in their specific discipline that are need to know and not nice to know.” The responsibility of a ‘secondary assessor’ is to “assess the assessment, not conduct the assessment.” Finally, the Division Director is to ensure consistency across teams’ assessments and not redo the work of the primary or secondary assessor except in special circumstances.

I think these are likely the most important few sentences in the document. It will be interesting to see if the FDA extends this expectation to original BLAs and NDAs which I’m sure industry would welcome.

As stated above, this process, along with the previous draft guidance is intended to increase the number of generic drugs by speeding their review process and ensuring they meet necessary quality requirements. The MAPP describes an assessment process that will focus on whether the application meets the ‘requirements for regulatory approval.’

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