FY 14 GDUFA Regulatory Research Priorities

In the Generic Drug User Fee Amendments (GDUFA) of 2012, FDA committed to prepare a yearly list of regulatory science priorities based on input from industry and other stakeholders.

For Fiscal Year (FY) 2014, FDA’s regulatory science priorities for generic drugs will be

  • Post-market Evaluation of Generic Drugs
  • Equivalence of Complex Products
  • Equivalence of Locally Acting Products
  • Therapeutic Equivalence Evaluation and Standards
  • Computational and Analytical Tools

Because of the market penetration of generic drugs (84% of prescriptions in 2012) it is important that the generic drug program have a range of tools to monitor that these products are being successfully substituted and have the same safety and efficacy profile as their reference listed drug (RLD).  Post-market Evaluation of Generic Drugs includes research into surveillance/monitoring methods for generic drugs, and understanding of patient perceptions of generic drug quality and effectiveness. It also includes evaluation/verification of therapeutic equivalence via brand to generic switching studies in patients. These investigations provide additional data in therapeutic areas where there is concern expressed about substitutability of generic drugs. Based on public comments and issues within FDA, FY 14 priorities are anti-epileptic drugs, immunosuppressant drugs, bupropion, ADHD drugs and cardiovascular drugs.

The amount of OGD review and policy development time spent on complex products is increasing and future generic products will need to demonstrate equivalence to increasingly complex RLDs. Equivalence of Complex Products includes research to make generic versions available in all product categories and for all available RLDs, including products that have unique characteristics. These scientific investigations will support guidance and policy development needed to clarify the Abbreviated New Drug Application (ANDA) pathway for complex products. This priority will impact drug-device combinations, transdermal systems, implants and parenteral microspheres, liposomes and iron colloids, as well as products that contain complex mixtures and peptides.

The lack of efficient bioequivalence methods for locally acting drugs has limited the availability of generic drugs in this category. Equivalence of Locally Acting Products includes research into new bioequivalence (BE) methods and pathways for local acting drugs. Product categories in priority order are inhalation, topical dermatological, nasal, GI acting, ophthalmic and otic products. This priority includes re-evaluation of some statistical methodologies for topical product adhesion and irritation, and investigation of alternatives to clinical endpoint bioequivalence studies.

Therapeutic Equivalence Evaluation and Standards research supports the evolution of equivalence and product quality standards to focus on ensuring therapeutic equivalence across all dosage forms and routes of delivery.  Areas of research include identifying the pathway for generic versions of abuse-deterrent formulations, risk-based equivalence standards for narrow therapeutic index (NTI) drugs, methods for BE study analysis such as pAUC, product quality standards (Quality by Design or QbD) for generic drugs, patient use factors such as tablet size, and advancing IVIVC/predictive dissolution for solid oral dosage forms.

Computational and Analytical Tools impact all four other priority areas and are essential to developing a modern ANDA review process that fully utilizes available computational and analytical tools. Modeling and simulation tools that will be investigated include PBPK/absorption models, PD models/clinical trial simulation, and quantitative risk modeling. To enable these tools for research and review will require investment in data warehouse infrastructure. Priorities for advanced analytical methods include characterization of peptides and other complex mixtures and particle size and surface chemistry. At the interface between methods and modeling are the statistical methods for evaluation of in vitro equivalence.

Public Input

This list was prepared based on internal CDER discussions, comments received at a June 21, 2013, public meeting and comments submitted to a public docket. At the public meeting1, topics raised included: opening the pathway for generic inhalation and ophthalmic products, generic substitution of anti-epileptic drugs and immunosuppressant drugs, product quality standards and characterization methods, and the need for social science and patient perception research to understand concerns about generic substitution. Generic industry comments included: that GDUFA research should develop ANDA pathways for complex or novel products, refine current technical issues and address emerging scientific issues. The industry requested QbD examples on other dosage forms, harmonization in statistical methods for nasal equivalence, refinement of BE approaches for mesalamine to account for variability and clarification of policy on synthetic peptide ANDAs referencing recombinant RLDs. Finally, they asked for reports on completed products to be quickly made public.

Written comments to the docket echoed the meeting comments with the most frequently mentioned topics being:

  • QbD use cases for complex products (3 comments).
  • Development of advanced in vitro dissolution methods, incorporating physiological factors and release models for complex products (2 comments).
  • General and individual BE guidance for complex dosage forms (3 comments).
  • BE standard for NTI drugs (2 comments).
  • Post marketing surveillance (2 comments).
  • Anti-epileptic drugs (3 comments).

Other factors included in the prioritization process were: tracked safety issues (TSI) opened by OGD, scientific issues raised in citizen petitions, and topics of meeting requests and controlled correspondence submitted to OGD.

FY13 Results and Project Continuation in the FY14 priorities

FDA and industry agreed in the September 2011 GDUFA commitment letter to 13 FY13 research topics:

  1. BE of local-acting ,orally-inhaled drug products
  2. BE of local-acting, topical dermatological drug products
  3. BE of local-acting, gastro-intestinal drug products
  4. Quality by design of generic drug products
  5. Modeling and simulation
  6. Pharmacokinetic studies and evaluation of anti-epileptic drugs 
  7. Excipient effects on permeability and absorption of BCS Class 3 Drugs
  8. Product- and patient-related factors affecting switchability of drug-device combination products
  9. Postmarketing surveillance of generic drug usage patterns and adverse events
  10. Evaluation of drug product physical attributes on patient acceptability
  11. Postmarking assessment of generic drugs and their brand-name counterparts
  12. Physicochemical characterization of complex drug substances
  13. Develop a risk-based understanding of changes in API manufacturing and controls

The FY13 topics map to the FY14 priorities as follows:

  • Post-market Evaluation of Generic Drugs
    • Topics: 6,9,10,11
  • Equivalence of Complex Products
    • Topics:  8,12
  • Equivalence of Locally Acting Products
    • Topics:  1,2,3
  • Therapeutic Equivalence Evaluation and Standards
    • Topics: 4,7,10,13
  • Computational and Analytical Tools
    • Topics:  5,12

In FY13, FDA’s Office of Generic Drugs (OGD) awarded $17 million in external contracts and grants to initiate new research in the FY13 program areas. Four million was allocated to support internal research through equipment for FDA labs and support for research fellows at FDA.

Key accomplishments from OGD since the FY13 list was published include: draft guidance recommending new bioequivalence methods for products without generic competition such as Albuterol Sulfate Metered Dose Inhaler, Fluticasone Propionate, Salmeterol Xinafoate Dry Power Inhaler, Acyclovir Topical Ointment and Cyclosporine Ophthalmic Emulsion.



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