FDA Publishes New Product-Specific Guidances to Facilitate Generic Drug Development

The FDA has published a new batch of product-specific guidances (PSGs). PSGs provide recommendations for developing generic drugs and generating evidence to support abbreviated new drug application (ANDA) approvals. FDA publishes PSGs to help facilitate generic drug development, streamline ANDA assessment, and support greater access to safe, effective, and high-quality treatments. Improving access to generic medicines supports the agency’s mission to advance public health, as outlined in our Drug Competition Action Plan.

Today’s batch of 60 PSGs (29 new and 31 revised) contains:

• 38 PSGs for products with no approved ANDAs (including 22 complex products)
• 31 PSGs for complex products (12 new and 19 revised PSGs)
• PSGs for products used for treatment of pulmonary hypertension, ovarian cancer, urothelial cancer, vaginal atrophy, and other conditions
• Additional noteworthy PSGs are described below, including PSGs that were supported by GDUFA-funded research. These PSGs reference products used for the treatment of schizophrenia, atopic dermatitis, and other conditions.

When finalized, the PSGs in today’s batch posting will describe the agency’s current thinking and recommendations on how to develop generic drug products that are therapeutically equivalent to the specific reference listed drugs. FDA considers all comments to the public docket before finalizing PSGs.

Newly Updated – Upcoming PSGs

The FDA also updated the “Upcoming Product-Specific Guidances for Generic Drug Product Development” web page, which includes new and revised PSGs under development and includes the planned revision categories and brief descriptions of the revisions. As stated in the GDUFA III Commitment Letter, eligible applicants may request a PSG teleconference to obtain FDA’s feedback on the potential impact of a new or revised PSG on its development program and a subsequent PSG meeting following feedback received at the PSG teleconference. See the guidance for industry Product-Specific Guidance Meetings Between FDA and ANDA Applicants Under GDUFA for more information. The web page also provides information about the agency’s plans for issuing new or revised PSGs in the coming year for all generic drug products (complex and non-complex), along with anticipated publication dates, consistent with FDA’s GDUFA III commitments.

Noteworthy PSGs in Today’s Batch:

• New PSG for Treatment of Schizophrenia in Adults
  •  Aripiprazole Lauroxil (Reference Listed Drug (RLD): ARISTADA INITIO KIT, NDA 209830)
    • Aripiprazole lauroxil is an atypical antipsychotic indicated for the treatment of schizophrenia in adults. This is the first PSG to recommend an in vitro bioequivalence (BE) study for a suspension antipsychotic injectable product. The in vitro BE approach was supported by an improved understanding of the formulation characteristics and drug release mechanisms of aripiprazole lauroxil and similar drug substance suspension products, gained through GDUFA-supported research and considering the totality of the evidence.

• Revised PSG for Treatment of Iron Deficiency Anemia

  • Ferumoxytol (RLD: FERAHEME, NDA 022180)

    • Ferumoxytol is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients who have an intolerance to oral iron or have had an unsatisfactory response to oral iron or have chronic kidney disease. The revised PSG adds an alternative in vivo BE study approach. Applicants can measure the concentrations of total iron and transferrin-bound iron and establish BE based on (1) the maximum value of the difference in concentration between total iron and transferrin-bound iron over all time points measured; and (2) the difference in AUC between total iron and transferrin-bound iron.

• New PSG for Treatment of Pulmonary Hypertension

  • Treprostinil (RLD: TYVASO DPI, NDA 214324)

    • Treprostinil is a prostacyclin mimetic indicated for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease to improve exercise ability. This is the first PSG for this indication that includes both in vitro and in vivo BE studies. Notably, this PSG does not include a comparative clinical endpoint (CCEP) BE study. Instead, the recommended studies include both alternative in vitro BE and in vivo charcoal block pharmacokinetic BE studies in lieu of a CCEP BE study. The PSG also includes recommendations for test formulations containing no difference in inactive ingredients with the reference standard, along with device similarity and an optional computational modeling study.

• Revised PSG for Treatment of Atopic Dermatitis

  • Tacrolimus (RLD: PROTOPIC, NDA: 050777)

    • Tacrolimus ointment is indicated for short-term and intermittent long-term therapy in the treatment of patients with moderate to severe atopic dermatitis in whom the use of other therapies is deemed inadvisable because of potential risks, or in the treatment of patients who are not adequately responsive to or are intolerant of alternative, conventional therapies. The PSG is being revised to incorporate a waiver approach wherein pivotal in vitro permeation test (IVPT) or CCEP BE studies may not be necessary for the second strength once BE has been established based on relevant recommendations within the PSG for one strength. The inclusion of the waiver approach is supported by multi-year GDUFA-funded research.

• New PSG for Treatment of Urothelial Cancer

  • Mitomycin (RLD: JELMYTO, NDA 211728)

    • Mitomycin is an alkylating drug indicated for the treatment of adult patients with low-grade upper tract urothelial cancer (LG-UTUC). This is a new PSG developed for a pyelocalyceal powder for solution. This is the first and only product approved for this route of administration. In addition to the unique route of administration, the drug product also has a unique dosage form, as the reconstituted drug product has reverse thermal properties. After instillation into the pyelocalyceal cavity in the kidney, the liquid forms a semisolid gel that dissolves from normal kidney urine flow, releasing the active ingredient. As an in vivo BE approach presents ethical and logistical challenges for this locally acting drug product, an in vitro, characterization-based BE approach is recommended to demonstrate BE for mitomycin pyelocalyceal powder.

• New PSG for treatment of Vaginal Atrophy

  • Conjugated Estrogens (RLD: PREMARIN, NDA: 020216)

    • Conjugated Estrogens vaginal cream is a mixture of estrogens indicated for the treatment of atrophic vaginitis and kraurosis vulvae and moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. This is a new PSG for a vaginal product that contains a complex active pharmaceutical ingredient (API) in a complex dosage form. Despite the marketing of the RLD for more than four decades, there are no approved generics for this product. This PSG includes recommendations related to establishing pharmaceutical equivalence (i.e., API sameness) and two options for establishing BE: a characterization-based BE approach and a combination of a CCEP and PK BE studies. The PSG recommendations were developed following multiyear GDUFA-funded internal research at FDA and coordinated efforts across multiple offices across the agency.

• Revised PSG for Treatment of Ovarian Cancer

  • Olaparib Tablets (RLD: LYNPARZA, NDA: 208558)

    • Olaparib is a poly (ADP-ribose) polymerase inhibitor indicated for maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, and deleterious or suspected deleterious germline breast cancer [BRCA] gene-mutated advanced ovarian cancer in its initial labeling in 2017. The PSG was revised to incorporate new indications approved in the labeling in September 2023. The current PSG recommends conducting one BE study at steady state in patients, rather than in healthy subjects, due to safety concerns. Given that olaparib tablet is classified as a drug product with a high-risk of bioinequivalence due to food effect due to its formulation design as amorphous solid dispersion, the updated PSG specifies that the test product has the same product design as the RLD, including the same type of polymer and the quantity of the polymer does not differ by more than 10% (weight/weight) based on the total excipients from the RLD for the amorphous solid dispersion. This is the first PSG to incorporate formulation and manufacturing process recommendations to mitigate the risks associated with a high-risk drug product, while maintaining the recommendation for one BE study at steady state in patients.

• New and Revised PSGs Based on Approved Suitability Petitions

  • Allopurinol Oral Suspension (RLD: ZYLOPRIM Tablet, NDA 016084)

  • Clonazepam Oral Suspension (RLD: KLONOPIN Tablet, NDA 017533)

  • Memantine Hydrochloride Orally Disintegrating Tablet (RLD: NAMENDA Tablet, NDA 021487) Three new PSGs were published based on approved suitability petitions for a new dosage form of the respective RLDs. The PSGs are the first of their kind, providing BE options depending on the availability of the designated reference standard. These PSGs will streamline generic drug development efforts for developing for ANDAs with an approved suitability petition to expand overall and enhance access to these medications.

  • Enzalutamide (RLD: XTANDI, NDA 213674) This PSG was revised to include two higher strengths approved under a suitability petition. Various BE options were provided based on the development program and availability of the designated reference standards.

• New and Revised PSGs for Coagulation Disorders Phytonadione (RLD: AQUAMEPHYTON; NDA 012223, MEPHYTON; NDA 010104, Vitamin K1; ANDA 087954, 087955, and 083722)

  • Phytonadione is indicated for coagulation disorders due to faulty formation of factors II, VII, IX and X when caused by vitamin K deficiency or interference with vitamin K activity. FDA revised PSGs for phytonadione injection injectable (NDA 012223) and phytonadione oral tablet (NDA 010104) and published new PSGs on phytonadione injection injectable (ANDA 083772 and ANDA 087954, and 087955). The PSGs on phytonadione injection injectable products include an in vitro bioequivalence approach which reflects the improved understanding of the dosage form of phytonadione injection injectable products obtained via FDA’s internal lab research. These PSGs clarify the active ingredient standards for phytonadione submitted in an ANDA and an alternative bioequivalence approach to promote generic development.

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