FDA Guidances: Least Burdensome Principles, Refusal to File, Nanomaterials – Drug and Device Digest


Capture.JPGThe Least Burdensome Provisions: Concept and Principles

Definition:  “Least burdensome” is the minimum amount of information necessary to adequately address a regulatory question or issue through the most efficient manner at the right time

  • Applies to devices throughout the total product lifecycle (premarket and postmarket)

Guiding Principles

  • FDA:  intends to request minimum necessary information
    • streamline processes and policies, timeliness, interactive and tailored approaches, just-in-time data collection, data from other countries
  • Industry: submissions that are least burdensome for FDA review
    • well-organized, clear, and concise information

Applications of Least Burdensome Principles

  • The minimum information necessary
    (1) Less burdensome sources of clinical data: Leveraging existing data, Real-World Evidence
    (2) Use of nonclinical data: Bench performance testing, computer modeling and simulation 
    (3) Acceptance of alternative approaches: Resolution of scientific issues, alternative labeling, 
  • The most efficient means
    (1) Reducing burden of traditional clinical studies: Historical control groups, non-comparative studies, subject as own control, adaptive design, sample collection alternatives
    (2) Use of benefit-risk assessments in marketing submissions
    (3) Streamlining processes and reducing administrative burden: Bundled submissions, MDDT, MDR burden reduction
    (4) Smart regulation: 510(k) exemption
    (5) Global harmonization:  Voluntary consensus standards, IMDRF, MDSAP
  • The right time: Balancing premarket and postmarket information needs
  • Compliance Policies that Support the Goals of the Least Burdensome Concept


Capture.JPGRefuse to File: NDA and BLA Submissions to CDER

FDA will file an NDA/BLA within 60 days of receipt or inform the applicant of the Refusal to File (RTF)

  • Filing an application means that FDA has made threshold determination that application is sufficiently complete to permit a substantive review
  • To efficiently and effectively review applications, it is critical to have applications that are not deficient and are complete
  • FDA exercises RTF authority for incomplete applications to optimize the use of both the applicant’s and the FDA’s resources

Filing Review and Assessment

Filing issues grouped into two categories:

  • Potentially easily correctable deficiencies: Corrected before filling
  • Complex significant deficiencies that cannot be corrected before filing:  Materially lacking or inadequately organized applications, inadequate information, single study when more than one trial needed, lack of abuse potential studies for CNS drugs,  content not submitted electronically

FDA Decision-Making and Notification to the Applicant

  • FDA internal filing meeting with Division director making final filing decision
  • If  application cannot be filed, communicate RTF action to by day 60



Drug Products, Including Biological Products, that Contain Nanomaterials


Guidance on the development of human drug products, including biological products, in which a nanomaterial  is present in the finished dosage form

  • nanomaterials serve a variety of functions, for example as active ingredients,  carriers loaded with an active ingredient, or inactive ingredients
  • material or end product engineered to have at least one external dimension, or an internal or surface structure, in the nanoscale range (approximately 1 nm to 100 nm)
  • material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to one micrometer (1,000 nm)


  • Adequacy of characterization, complexity of material structure and function
  • Mechanism of impact of physicochemical properties on biological effects, release
  • In Vitro-In vivo correlation
  • Physical and chemical stability, maturity, impact of manufacturing changes
  • Physical state upon administration, route of administration
  • Predictability of dissolution, bioavailability, distribution, biodegradation, accumulation


  • Description of the Nanomaterial(s) in the Drug Product
  • Nanomaterial Quality Attributes and Structural Characterization
  • Nanomaterial Physicochemical Characterization Methods
  • Dissolution/In Vitro Drug Release Methods for Quality Testing
  • Manufacturing Process and In-Process Controls
  • Excipients
  • Stability
  • Postmarket CMC Changes


  • General Applicability of Existing Guidance
  • Absorption, Distribution, Metabolism, and Excretion Considerations..
  • Routes of Administration: Topical, Subcutaneous, Inhalation, Intravenous, Oral
  • Testing of Representative Nanomaterial
  • Bridging Toxicology


  • Submission type: 505(b)(2), 505(j) (ANDA), 351(k) (Biosimilar)
  • Bioanalytical Methods
  • In Vitro Tests With Human Biomaterials
  • Immunogenicity




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