FDA's new Guidances on the Approval of Generic Drugs

Over the last six weeks, the FDA published a number of guidances regulating various issues in regards to the new Generic Drug User Fee Act (GDUFA II), which came into force on August 18, 2017. In the following, the content and background of these guidances are summarized (release date in brackets).

Guidance for Industry (Draft) ANDA Submissions - Amendments to Abbreviated New Drug Applications under GDUFA (October 02, 2017)

The document describes how and within which deadlines amendments for generic authorisation applications are processed. Three categories were defined: "major amendments", "minor amendments" and "unsolicited amendments". The goals in regards to the processing times of such amendments are defined in accordance with "Generic Drug User Fee Amendments Reauthorization (GDUFA II)".

Example: the agency's processing and reaction time for 90% of all applications for a "major" change is eight months after receipt, provided that no preapproval inspections are necessary. In cases where such inspections are necessary, the period amounts to ten months. In case of Prior Approval Supplements (PAS), the FDA processes 90% of all applications in six months (no preapproval inspections necessary) or in ten months time (preapproval inspections necessary).

Guidance for Industry (Draft) ANDA Submissions - Refuse-to-Receive Standards: Questions and Answers (October 02, 2017)

Authorisation applications for generics in which essential information is missing will be denied by the FDA. As a reason for their refusal, the FDA states that the communication with the applicant - the request for missing information and the thus growing number of review cycles - absorbs too much resource capacity and therefore opposes the GDUFA II requirements for a higher efficiency in application processing and shorter approval procedures. In a question-answer-format, the guidance describes the minimum standards the applicant has to meet in order for their documents to be processed and offers indications on how the procedure will be in case of general deficiencies, deficiencies in Drug Master Files, the description of product quality, details on bioequivalence and the presentation of clinical data. This guideline complements the Guidance for Industry "ANDA Submissions - Refuse-to-Receive Standards (Revision 2)" published in December of 2016.

Guidance for Industry (Draft) Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA (October 02, 2017)

This guideline describes how an applicant has to proceed if they want to initiate and conduct a meeting on product development, a pre-submission meeting or a mid-review-cycle-meeting with the FDA. Especially with complex products involved, it usually takes several such meeting before the review cycles may be concluded. The guidance defines complex products based on the FDA's GDUFA II commitments as follows:

• Products containing active substances such as peptides, polymers, complex substance compounds and complex excipients such as liposomes, colloids or complex dosage forms (transdermal, inhaled) or drugs for dermatological or ophthalmological use;
• Combination products such as auto-injectors or inhalers;
• Novel products with high innovation potential and further research needs.

Guidance for Industry (Draft) ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin (October 02, 2017)

This guideline covers synthetic peptides with a chain length of 40 and less amino acids. Compounds with a higher chain length are classified as proteins. The applicant has to prove to the agency that the synthetic peptide is identical ("sameness") and bioequivalent with the biotechnologically (via rDNA) manufactured substance in the already approved reference listed drug. Application conditions, dosage form, strength and labelling must comply with this product. The guidance offers detailed requirements on what data the FDA expects about the quality of a synthetic peptide substance. The impurity profile of the substance is crucial for the successful processing of such an application; the impurities concentration must not be higher than in the original product.

Guidance for Industry (Draft) ANDAs: Pre-Submission of Facility Information Related to Prioritized Generic Drug Applications (Pre-Submission Facility Correspondence) (October 03, 2017)

In this document, the FDA lays down their expectations towards applicants regarding the information about the production site. Content of the site description as well as deadlines for the submission are defined. Furthermore, the procedure of processing an ANDA is explained. If the application data is complete and accurate, it is determined whether the requirements for prioritised processing are met. The categories for this are defined in paragraph 505(j)(11)(A) of the Food, Drug and Cosmetic Act and in the Office of Generic Drug's operating instruction 542.3 "Prioritization of the Review of Original ANDAs, Amendments, and Supplements (MAPP 5240. 3 Rev. 4)". The site description should cover the units in which the production, packaging and quality control of the generic takes place as well as the areas in which bioequivalence and clinical studies and performed.

Guidance for Industry (Revision 1) ANDA Submissions - Prior Approval Supplements Under GDUFA (October 04, 2017)

In this guideline, the applicants find information on how amendments are processed by the agency under the GDUFA program. The FDA's agreed goals as determined in GDUFA I and GDUFA II define the number of applications to be processed in certain periods of time. The guidance describes how these metric goals influence the processing time, differentiating between standard and priority applications and major and moderate changes. Another relevant criterion for the length of processing periods is the classification of changes in regards to their influence on product quality, meaning whether or not a pre-approval inspection is necessary. A decision tree in the annex of the guideline offers a good overview of different scenarios. This document is a revision of the original version published in October 2016.

Guidance for Industry (Draft) Determining Whether to Submit an ANDA or a 505(b)(2) Application (October 11, 2017)

There are various procedures for submitting an application for a generic based on the different paragraphs in the Food, Drug & Cosmetic Act (FD&C Act). There is an application as per paragraph 505(j), known as ANDA (Abbreviated New Drug Application), and an application as per paragraph 505(b)(2). For the latter, the applicant has to submit elaborate data on safety and efficacy. They may only rely on reference drug data collected by the FDA if it refers to characteristics which are identical to the submitted generic (e.g. active substance, dosage form, strength, indication, etc.). For an ANDA based on 505(j), far less detailed data is needed; a requirement for a successful approval procedure in both cases however is the proof of bioequivalence with the reference medicinal product. Another application process, in which a petition for permission to submit an ANDA is addressed to the FDA, is used if the generic's characteristics differ from the reference product. This guidance offers applicants a guideline on which procedure to choose in which case.

Guidance for Industry (Draft) Post-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA (October 13, 2017)

Usually, the FDA's Office of Generic Drugs sends out a post-complete response letter (CRL) at the end of each review cycle, in which further information is requested due to incomplete data. In order to swiftly clarify any inconsistencies, the applicant may ask for a post-CRL meeting. This guideline offers recommendations for the application, preparation and execution of such a meeting (face-to-face as well as teleconference) and important deadlines as per GDUFA II.