FDA Guidances: Least Burdensome Principles, Refusal to File, Nanomaterials


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




Market Authorizations: Boston Scientific Spinal Cord Stimulation System, ADMELOG, IXIFI, NUCALA, LUXTURNA

Diagram of the device, indicating External Trial Stimulator (ETS), Clinical Programmer (CP), Remote Control, Charger, Implantable Pulse Generator (IPG), Percutaneous Leads, and Surgical Paddle Leads.

Boston Scientific Spinal Cord Stimulation System

Boston Scientific 

Aid in the management of chronic intractable pain of the trunk and/or limbs including unilateral or bilateral pain associated with the following: failed back surgery syndrome, Complex Regional Pain Syndrome (CRPS) Types I and II, intractable low back pain and leg pain. Associated conditions and etiologies may be

  • radicular pain syndrome
  • radiculopathies resulting in pain secondary to failed back syndrome, herniated disc
  • epidural fibrosis
  • degenerative disc disease
  • arachnoiditis
  • multiple back surgeries



  • Implanted spinal cord stimulation system that was previously indicated as an aid in the management of chronic intractable pain of the trunk and/or limbs
  • Two main components include:
    • stimulator device (signal generator) implanted under the skin that sends electrical signals to the spinal cord through an insulated lead wire
    • hand-held remote control that allows the patient to control the implanted stimulator device in order to achieve the best pain control


  • Based on published clinical studies (22 publications, 633 implanted patients) relevant to Spinal Cord Stimulation System features and indications
  • Improvement in pain ranged from 29.2%-100% for CRPS patients, and 37-77% for those with back and leg pain due to surgery associated conditions and etiologies across the studies
  • Most common adverse event: Need for an additional intervention (surgical revisions to correct lead migration, IPG discomfort, battery depletion, infection, fractured leads)
  • Other reported adverse events: Pain, unpleasant sensation, infection, inadequate stimulation, discomfort


  • ICD-10-CM (diagnosis) Coding Guide for Spinal Cord Stimulation
  • Documentation for medical necessity
  • Payer Medical Policy for Spinal Cord Stimulation



ADMELOG (insulin lispro injection), subcutaneous or intravenous use


INDICATION: Improve glycemic control in adults and pediatric patients 3 years and older with type 1 diabetes mellitus and adults with type 2 diabetes mellitus


  • > 30 million diabetics in US
  • Increases risk of serious health complications, including heart disease, blindness, and nerve and kidney damage
  • Improvement in blood sugar control through insulin treatment
  • First short-acting insulin approved as a “follow-on” product


  • Relied on FDA’s finding finding of safety and effectiveness for Humalog (insulin lispro injection, Eli Lilly) to support approval
  • Demonstration that relianmalog safety and effectiveness was scientifically justified
  • Provided Admelog-specific data to establish the drug’s safety and efficacy for its approved uses


  • Clinical trials, adult and pediatric patients , Type I and II diabetes
  • Mean reduction in HbA1c that was non-inferior to that achieved with Comparator


  • Most common adverse reactions: Hypoglycemia, itching, and rash
  • May cause low blood sugar (hypoglycemia), which can be life-threatening
  • Severe, life-threatening, generalized allergic reactions, including anaphylaxis, may occur


  • Increase competition in the market for prescription drugs
  • Lower-cost alternative


CaptureIXIFI (infliximab-qbtx) injection


INDICATIONS: Crohn’s Disease, Pediatric Crohn’s Disease, Ulcerative Colitis, Rheumatoid Arthritis in combination with methotrexate, Psoriatic Arthritis, Plaque Psoriasis,  Psoriatic Arthritis and Plaque Psoriasis

ADDRESSING UNMET NEED: Third FDA-approved biosimilar to U.S.-licensed Remicade (infliximab)


  • Biosimilarity based on a showing that it is highly similar to Remicade
    • No clinically meaningful differences in safety and effectiveness
    • Only minor differences in clinically inactive components 
  • Required pediatric assessments and postmarketing commitments

MECHANISM OF ACTION: Tumor necrosis factor (TNF) blocker


Image result for nucala logoNUCALA (mepolizumab) injection


INDICATION:  Treatment of adult patients with eosinophilic granulomatosis with
polyangiitis (EGPA)


  • Approximately 0.11 to 2.66 new cases per 1 million people are diagnosed each year with EGPPA, with an overall prevalence of 10.7 to 14 per 1,000,000 adults
  • First approved treatment for challenging, rare disease that can provide significant improvement in symptoms


  • Priority Review and Orphan Drug designations
  • Previously approved in 2015 to treat patients age 12 years and older with specific subgroup of asthma


  • Randomized, placebo-controlled, multicenter, 52-week trial, n=136, NUCALA vs placebo  while continuing their stable daily oral corticosteroids (OCS) therapy
  • Co-primary Endpoints: Total accrued duration of remission defined as Birmingham Vasculitis Activity Score (BVAS) = 0 (no active vasculitis) and proportion of subjects in remission
  •  Significantly greater accrued time in remission with NUCALA; significantly higher proportion of patients achieved remission at both week 36 and week 48
  • Significantly more patients achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period


  • Most common adverse reaction: Headache, injection site reaction, back pain, and fatigue

REIMBURSEMENT: GSK Patient assistance program


CaptureLUXTURNA (voretigene neparvovec-rzyl)  intraocular suspension for
subretinal injection 

Spark Therapeutics

INDICATION: Adeno-associated virus vector-based gene therapy indicated for treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Patients must have viable retinal cells as determined by the treating physician(s).


  • Biallelic RPE65 mutation-associated retinal dystrophy affects approximately 1,000 to 2,000 patients in U.S.
  • Patients now have a chance for improved vision
  • First directly administered gene therapy targeting a disease caused by mutations in a specific gene
  • Reinforces potential of breakthrough approach in treating a wide-range of challenging diseases


  • Priority Review and Breakthrough Therapy designations, Orphan Drug designation
  • Granted Rare Pediatric Disease Priority Review Voucher
  • Post-marketing observational study to evaluate long-term safety


  • Designed to deliver normal copy of gene encoding RPE65 to cells of the retina
  • RPE65 produced in the retinal pigment epithelial (RPE) cells and converts all-trans-retinol to 11-cis-retinol during visual cycle critical in phototransduction
  • Mutations in the RPE65 gene blocks visual cycle resulting in impairment of vision


  • Open-label, two-center, randomized trial in pediatric and adult patients with biallelic RPE65 mutation-associated retinal dystrophy, n= 31 enrolled
  • Endpoint:  Multi-luminance mobility testing (MLMT) score change from Baseline to Year 1,  MLMT score change of two or greater considered clinically meaningful benefit in functional vision
  • Median MLMT score of 2 or greater with LUXTURNA vs 0 in control


  • Most common adverse reactions: Eye redness (conjunctival hyperemia), cataract, increased intraocular pressure and retinal tear


  • Could cost $1 million or more per patient
  • Will require assessment of coverage and reimbursement models


Image credits: Boston Scientific, Sanofi, GSK, Pfizer, Spark


FDA News and Views: 2018 Policy Goals, Gene Therapy, Homeopathic product Enforcements, Subjective Cognitive Decline infographic (CDC)

FDA BRIEF: Week of Dec 18, 2017

Dr. Scott GottliebLooking ahead: Some of FDA’s major policy goals for 2018

By: Scott Gottlieb, M.D., Commissioner

Modernize approach to work and improve efficiency, while fulfilling mandate to protect and promote public health and uphold gold standard for regulatory decision-making

  • Serve public health by advancing innovations that improve patient care, enhance choice and provide competition
  • Take action against serious threats to public health
  • Empower patients, consumers, healthcare providers with accurate and up-to-date information
  • Recognize need for new, more flexible regulatory approaches

Key priorities

  • Addressing the Nicotine Addiction Crisis
  • Advancing Drug Safety
  • Promoting Food Safety
  • Empowering Consumers
    • Providing Better Information on Drugs
    • Broadening Access to Nonprescription Drugs
  • Modernizing Standards
    • Harmonizing Global Standards
    • Modernizing Mammography Standards
    • Embracing Electronic Submissions
    • Removing Outdated Rules


Gene Therapy

What Is Gene Therapy? How Does It Work?

Gene therapy can used to modify cells inside or outside the body

  • Inside: Inject vector carrying the gene directly into the part of the body that has defective cells
  • Outside: Modify cells outside of body; blood, bone marrow, or another tissue taken from patient, and specific types of cells separated out. Vector containing desired gene is re-introduced into cells, multiplied and injected back into the patient
  • FDA is committed to helping speed up development by prompt review of groundbreaking treatments that have the potential to save lives


CaptureNew, Risk-based Enforcement Priorities to Protect Consumers from Potentially Harmful, Unproven Homeopathic Drugs

Homeopathy, an alternative medical practice first systematized in the late 1700s with two principles:

  • Substance that causes symptoms can be used in diluted form to treat symptoms and illnesses (“like-cures-like”)
  • The more diluted the substance, the more potent it is (“law of infinitesimals”)

Risk-based approach for drug products labeled as homeopathic and marketed without required FDA approval; enforcement and regulatory actions for products

  • With reported safety concerns
  • With ingredients associated with potentially significant safety concerns
  • For routes of administration other than oral and topical
  • Intended to be used for the prevention or treatment of serious and/or life
    threatening diseases and conditions
  • For vulnerable populations
  • Deemed adulterated under section 501 of the FD&C Act





Image credits: FDA, CDC

List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic


List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic

  • To improve transparency and encourage the development and submission of  ANDAs in markets with limited competition
  • Part I of the list identifies those drug products for which FDA could immediately accept an ANDA without prior discussion
  • Part II identifies drug products for which ANDA development or approval may raise potential legal, regulatory, or scientific issues that should be addressed with the Agency prior to considering submission of an ANDA


Image credit: FDA

FDA News and Views: Antimicrobial Resistance Tool, US Early Feasibility Studies, Clinical and Patient Decision Software Policies, 510(k) Modernization, Toxicology Roadmap, 3D printed Drugs, Type I Diabetes Devices

FDA BRIEF: Weeks of Dec 4 and Dec 11, 2017


New Tool for Sharing Information that Allows Doctors to Better Manage Antibiotic Use; Improve Patient Care

Antimicrobial resistance one of  most pressing public health challenges

  • Policy efforts to encourage new drug development, limit use in livestock
  • New steps for appropriate use in patient care; part of Cures Act

New Tool – Antimicrobial Susceptibility Test (AST) results to select appropriate antibacterial/antifungal drug for treatment

  • Tests rely on criteria — susceptibility test interpretive criteria or “breakpoints” — to help determine whether specific bacteria/fungi susceptible to antibacterial/ antifungal drugs
  • Bacteria and fungi change over time decreasing susceptibility to some drugs
  • Breakpoints updated accordingly – FDA-recognized breakpoints
  • Drug manufacturers will have to update labeling to reference FDA web page containing breakpoint information


Medical Device imageBringing Early Feasibility Studies for Medical Devices Back to the United States

Early Feasibility Studies Program (EFS) provides route for innovators, sponsors, FDA review teams, and clinicians to work together

  • Facilitate early clinical evaluation of medical devices in US
  • Limited clinical study in early development, typically before final device design
  • Evaluate device design concept with respect to initial safety and functionality
  • The EFS Program includes enhanced opportunities for collaboration, increased regulatory flexibility, and consideration of benefit-risk principles, while maintaining appropriate patient protection measures

IDEs submitted for EFS has more than doubled

  • Most studies receive timely FDA approval
  • Support device innovation and enhance early patient access to new technologies

Sponsor resources:  MDIC EFS working groups,  Early Feasibility Studies Webpage


FDA advances new digital health policiesAdvancing New Digital Health Policies to Encourage Innovation, Bring Efficiency and Modernization to Regulation

Three new, significant policy documents to advance development and proper oversight of innovative digital health tools

  • To support consumers and health care providers increasingly embracing digital health technologies to inform everyday decisions
  • Consumers makes more efficient decisions, improve lifestyles, health choices, and often experience better outcomes
  • Regulatory approach must foster, not inhibit, innovation; enhance access
  • Strike the right balance between ensuring patient safety and promoting innovation

(1) Draft guidance: Clinical and Patient Decision Support Software – CDS and PDS

  • Types of CDS would no longer be defined as medical device
    • Allows provider to independently review basis for  recommendations
  • Will enforce oversight of software programs
    • Intended to process or analyze medical images, Signals from in vitro diagnostic devices, Patterns acquired from a processor e.g. ECG
  • Not enforce oversight for lower-risk PDS
    • Should follow a similar regulatory structure as CDS
    • However, software that does not allow independent review of recommendation subject to FDA active oversight

(2) Draft guidance: Changes to Existing Medical Software Policies

  • Digital health provisions included in Section 3060 of Cures Act
  • FDA’s interpretation of types of software no longer considered medical devices
    • Low risk to patients, but provide great value to consumers
  • Update guidances on General Wellness and Mobile Medical Applications

(3) Final Guidance: Software as a Medical Device: Clinical Evaluation– SaMD

  • Harmonization with International Medical Device Regulators Forum (IMDRF)
  • Globally recognized principles in evaluating safety, effectiveness and performance


Capture.JPGFDA-Required Post-Marketing Studies of Approved Drugs Make a Big Difference for Public Health

Certain drug issues need additional evaluation after approval

  • to confirm clinical benefit when approved under accelerated approval provisions
  • further evaluation of potential safety issue
  • better characterize risk factors for known safety issue

FDA Amendments Act of 2007 (FDAAA) requires post-marketing requirements (PMRs) and post-marketing commitments (PMC) when new safety information

  • Committed to making sure industry fulfills  PMRs and PMCs
  • Public availability in a searchable database
  • Annual Federal Register (FR) report
  • Informs Congress on status and “backlog”



Advancing Policies to Promote Safe, Effective MedTech Innovation

Voluntary, alternative pathway for demonstrating substantial equivalence for 510(k) premarket notifications

  • More flexibility to use more modern criteria as reference standard
  • Permit comparisons to standards that more closely approximate the novel technology

Make review process more benefit-risk based

  • Adopt more modern tools for evaluating safety and benefits of new products
  • Embed patient-centric measures of risk and benefit

New Steps to Reform, Modernize 510(k) Review

  • Include FDA-recognized standards, FDA-developed guidance documents, or a combination of the two
  • For pre-specified categories of mature devices
  • Review framework to conform to international consensus standards


FDA's Toxicology Roadmap

Predictive Toxicology Roadmap to Enable Advances in Toxicity Testing

Toxicology testing plays a pivotal role in ensuring the safety of FDA-regulated products

  • Testing performed on people or animals to identify any potential risk from chemical, physical, or biological agents
  • Novel methods such as organs on a chip or mathematical modeling being developed for toxicity testing
  • Generating opportunities to improve ability to quickly and more accurately predict potential toxicities and reduce associated risks

FDA’s Predictive Toxicology Roadmap

  • Six-part framework for integrating predictive toxicology methods into safety and risk assessments
  • FDA research to identify data gaps and support intramural and extramural research
  • Development, validation and integration of promising technologies into product pipeline




 Promise and Potential of 3D Printed Pharmaceuticals

3D printing can change conventional methods  (large-scale processes, equipment, long production time) to offer personalized medicines

  • Allows for manufacture of solid drug products in various shapes, geometric designs, strengths and spatial distributions of the active and inactive ingredients
  • Release profile of active ingredients can be tailored to meet needs of specific patients
  • 3D printed Spritam®–FDA approved for epilepsy treatemnt; designed for large dose to disintegrate within seconds after a sip of water

Addressing 3D Printing Questions Through Research

  • FDA Office of Testing and Research conducting research on application of technology
  • Effects of material attributes, 3D geometric designs and 3D printing process parameters on dosage form performance
  • Mechanistic models for 3D printing processes to predict drug’s performance
  • Best ways to approach rapidly changing technology


Artificial Pancreas Diagram


Communication, Breaking Down Walls, and a Huge Step Forward for People with Type 1 Diabetes

Correct public assumptions about FDA’s overly cautious approach to diabetes treatment

  • Open a line of communication between FDA and the diabetes community
  • Artificial pancreas team worked to better understand daily struggles of living with type 1 diabetes
  • Productive relationships with key academic investigators and thought leaders on clinical trials
  • Approval of Medtronic’s Minimed 670G hybrid closed loop system
  • First FDA-approved,  first-in-the-world approved device to automatically monitor glucose; provide appropriate basal insulin doses
    • Came three years earlier than anticipated by company


Image credits: FDA

Patent Certifications and Suitability Petitions


Patent Certifications and Suitability Petitions

To continually improve its pre-ANDA interactions with applicants for generic drugs 

Paragraph IV Patent Certifications

  • Generic applicant provides “paragraph IV certification”  challenging brand product patent listed in FDA’s Orange Book
  • Must notify brand product sponsor/patent holder of ANDA submission and patent challenge
  • If approved, eligible for exclusive right to market generic drug for 180 days

Paragraph IV Certifications List

  • To assist generic drug applicants, FDA publishes list of drug products for which ANDA received containing Paragraph IV patent certification

Suitability Petitions

  • Generic application may petition FDA for ANDA for drug product different from Orange Book listing (e.g. route of administration, dosage form, strength, or active ingredient)


Image credit: FDA

CDRH FY 2018 Proposed Guidance Development & Retrospective Review

fda guidancesCDRH Fiscal Year 2018 (FY 2018) Proposed Guidance Development and Focused Retrospective Review of Final Guidance

Three lists:

  1. A-List:  fully intends to publish
  2.  B-List: intends to publish as resources permit
  3. Focused retrospective review: guidances issued in 2008, 1998, 1988, and 1978


Final Guidance Topics

  • Medical Device Accessories: Describing Accessories and Classification Pathway for New Accessory Types (revision)
  • Unique Device Identification: Policy Regarding Compliance Dates of Class I and Unclassified Devices
  • Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical Devices
  • Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases
  • Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics

Draft Guidance Topics

  • Export Certificates
  • Multifunctional Device Products: Policy and Considerations
  • The Least Burdensome Provisions: Concept and Principles
  • Humanitarian Devices Exemption (HDE) Program
  • 510(k) Third Party Review Program
  • Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program
  • Expansion of the Abbreviated 510(k) Program: Demonstrating Substantial Equivalence through Performance Criteria
  • The Application of Acceptable Uncertainty to Support Marketing Authorization Decisions for Medical Devices
  • Principles and Procedures for the Recognition and/or Withdrawal of Voluntary Consensus Standards
  • Validation of Automated Process Equipment Software



FDA Guidances: Additive Manufacturing, IDE and CMS coverage, Clinical and Patient Decision Support Software, Software as a Medical Device, Existing Software Policy Changes

CaptureTechnical Considerations for Additive Manufactured Medical Devices

Outline technical considerations with Additive Manufacturing (3D printing) and recommendations for testing and characterization

  • Builds object by sequentially building 2D layers, joining each to the layer below to rapidly produce alternative designs
  • Process Flow


Design and Manufacturing Process Considerations

  • Overall Device Design
  • Patient-Matched Device Design
  • Software Workflow
  • Material Control
  • Post-Processing
  • Process Validation and Acceptance
  • Quality Data

Device Testing Considerations

  • Device Description
  • Mechanical Testing
  • Dimensional Measurements
  • Material Characterization
  • Removing Manufacturing Material Residues and Sterilization
  • Biocompatibility


  • patient identifier, use, final design iteration or version used to produce the device


Capture.JPGFDA Categorization of Investigational Device Exemption (IDE) Devices to Assist the Centers for Medicare and Medicaid Services (CMS) with Coverage Decisions

Efficient CDRH categorization of investigational medical devices to support CMS’s Medicare coverage (reimbursement) determinations

  • Process and information to determine appropriate IDE category
  • Change of assigned category

FDA Interpretation of Medicare Coverage Categories A and B

  • Category A-Experimental: No PMA approval, 510(k) clearance, or De Novo,  being studied for new indication/new intended use; prior information  does not resolve initial safety/effectiveness questions
  • Category B- Nonexperimental/Investigational: No PMA approval, 510(k) clearance, or De Novo, being studied for a new indication/new intended use; prior information does resolve initial safety/effectiveness questions

Considerations When Changing from Category A to B – data to support

  • Peer-reviewed studies on similar device
  • Premarket or postmarket data from ex-US studies with similar device
  • Commercialization of similar device
  • Preliminary clinical data
  • Additional non-clinical data


CaptureClinical and Patient Decision Support Software

FDA’s regulatory oversight of:

(1) clinical decision support (CDS) software intended for healthcare professionals

(2) patient decision support (PDS) software intended for patients and caregivers who
are not healthcare professionals.

Scope of FDA oversight of CDS/PDS software:

  1. do not meet the definition of device as amended by the Cures Act
  2. may meet definition of device but will not require premarket clearance and premarket approval
  3. will require regulatory oversight

FDA Definitions:

CDS: Software functions that are considered as device:

  • intended to acquire, process, analyze a medical image/signal from in
    vitro diagnostic device or pattern or signal from signal acquisition system
  • intended for displaying, analyzing, or printing medical information
  • intended for supporting or providing recommendations to health care

Function excluded from the definition of device with additional criterion

  • intended for enabling health care professional to independently review basis for software recommendations and does not rely primarily on recommendation
    for clinical diagnosis or treatment decision

Examples of functions that are and are not considered as devices provided

PDS: Low risk devices and fall outside functionalities of regulatory oversight

  • enforcement discretion policy
  • software function should clearly explain:
    • purpose or intended use
    • intended user (e.g., patient, non-health care professional caregiver)
    • inputs used to generate recommendation
    • rationale or support for recommendation

Examples provided


CaptureCapture.JPGSoftware as a Medical Device (SAMD): Clinical Evaluation

Global regulatory framework and principles for SaMD

  • adopts internationally converged principles agreed upon by IMDRF
  • FDA adoption of principles

Clinical Evaluation of SaMD 

  • Valid Clinical Association
  • Analytical / Technical Validation
  • Clinical Validation of a SaMD


General Principles and Context of Clinical Evaluation Process 

  • Definition Statement and Category
  • Clinical Evaluation Processes

Clinical Evaluation Process Flow Chart 

  • Considerations for Generating and Assessing Evidence

Importance of Independent Review of Clinical Evaluation 

Continuous Learning Leveraging Real World Performance Data



Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act

Section 3060(a) of 21st Century Cures Act amended section 520 of (FD&C Act) removing certain software functions from definition of devic

  • affects FDA’s guidances related to medical device software.

Level 2 updates to be made to following guidance documents:

  • General Wellness: Policy for Low Risk Devices
  • Mobile Medical Applications
  • Off-The-Shelf Software Use in Medical Devices
  • Medical Device Data Systems, Medical Image Storage Devices, and Medical Image
    Communications Devices

Withdrawing following guidance document:

  • Submission of Premarket Notifications for Medical Image Management Devices

Interpretation of Cures Act and modifications to existing guidances:

  • Software Function Intended for Administrative Support of Health Care Facility
  • Software Function Intended for Maintaining or Encouraging Healthy Lifestyle
  • Software Function Intended to Serve as Electronic Patient Records
  • Software Function Intended for Transferring, Storing, Converting Formats, Displaying Data and Results.



Device Marketing Authorization: F1CDx Test (FDA approval + CMS coverage), RHA Dermal Fillers, TRIVISC

FDA BRIEF: Week of November 27, 2017

Capture.JPGFOUNDATIONONE CDx (F1CDx), in vitro diagnostic Test 

Foundation Medicine

Next generation sequencing (NGS)-based in vitro diagnostic (IVD) test that can detect genetic mutations in 324 genes and two genomic signatures in any solid tumor type


  • Run of one test to evaluate several appropriate disease management options
  • Avoids invasive process of extracting tumor samples multiple times
  • Help cancer patients and their health care professionals make more informed care decisions- eligibility for a single treatment or enrollment in a clinical trial


  • Sequencing DNA from patient’s tumor sample to determine the presence of gene mutations and alteration
  • Also detects certain molecular changes (microsatellite instability and tumor mutation burden)


  • Established through least burdensome means by comparing F1CDx to previously FDA-approved companion diagnostic tests
  • F1CDx ability to detect select mutation types (substitutions and short insertions and deletions) representative of the entire 324 gene panel is accurate approximately 94.6% of the time
  • Provides information on a number of different genetic mutations that may help in the clinical management of patients with cancer
  • Additionally, based on individual test results, can identify which patients with any of five tumor types may benefit from 15 different FDA-approved targeted treatment options
  • One test report to patients and health care professionals; avoiding duplicative biopsies


  • First device with the FDA’s Breakthrough Device designation
  • Coordinated, cross-agency approach; CDRH conducted clinical review with support from the FDA Oncology Center of Excellence

REIMBURSEMENT PATHWAY:  National Coverage Determination (NCD)

  • CMS provides coverage of NGS IVD tests to assist patients and their treating physicians in making informed cancer treatment decisions that improve health outcomes
  • Use of test as a diagnostic also help patients and their treating physicians determine candidacy for cancer clinical trials


  • FDA-CMS Parallel Review Program
  • Open to certain PMA applications for devices with new technologies and fall within the scope of a Part A or Part B Medicare-benefit category; have not been subject to NCD
  • CMS issued a proposed national coverage determination concurrent with FDA approval

Federal Register: Program for Parallel Review of Medical Devices

CaptureRHA® 2, RHA® 3, and RHA® 4 Dermal Fillers

Teoxane SA



  • RHA® 2 is indicated for injection into the mid-to-deep dermis for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF), in adults aged 22 years or older
  • RHA® 3 is indicated for injection into the mid-to-deep dermis for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF), in adults aged 22 years or older
  • RHA® 4 is indicated for injection into the deep dermis to superficial subcutaneous tissue for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF), in adults aged 22 years or older


  • Product Code : LMH (Implant, Dermal, For Aesthetic Use)


  • Viscoelastic, sterile, non-pyrogenic, clear, colorless, biodegradable gel devices
  • Produced with sodium Hyaluronic Acid (NaHA) using  Streptococcus equibacterial strain, crosslinked with 1,4-butanediol diglycidyl ether (BDDE)
  • Contain 0.3% lidocaine hydrochloride to reduce pain on injection
  • Exist in three formulations, from the least to the most cross-linked:  RHA® 2 (least cross-linked), RHA® 3,  RHA® 4 (most cross-linked)


  • 2 controlled, randomized, double-blinded, within subject (split-face), multicenter, prospective clinical studies; RHA vs non-treatment group, 15 months
  • Noninferioriority to respective control at 24 weeks after treatment, for the correction of NLF
  • Wrinkle Severity Rating Scale: Average improvement in the WSRS from preinjection was ≥ 1-grade
  • Improvement in Patient perspectives: Global Aesthetic Improvement (GAI),  FACE-Q, patient satisfaction survey


  • No reports of deaths, Treatment-Related Serious Adverse Events or Unexpected Adverse Device Effects in the study
  • All Treatment-Related Adverse Events were typically experienced following the injection of a dermal filler


CaptureTRIVISC (Sodium Hyaluronate ) injection


INDICATION:   Treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative non-pharmacologic therapy and simple analgesics (e.g., acetaminophen)



  • Product Code: MOZ


  • Sterile, viscoelastic, non-pyrogenic solution of purified, high molecular weight sodium hyaluronate, derived from a bacterial fermentation process
  • Sodium hyaluronate is a polysaccharide containing repeated disaccharide units of glucuronic acid and N-acetylglucosamine
  • TriVisc is supplied in a 3 mL glass syringe; sterile and non-pyrogenic


  • Adequate evidence of the sufficient similarity of TriVisc and VISCO-3™ with regard to chemical constituents, concentrations of constituents, solution characteristics, and molecular weight profiles of the sodium hyaluronate component
  • Application of FDAMA Section 216 to confirm evidence presented support reasonable assurance of its effectiveness of VICSO-3 is directly applicable towards
    establishing reasonable assurance of the effectiveness of TriVisc


Image Credits: Foundation Medicine, Teoxane, OrthogenRx 


FDA BRIEF: Week of Nov 27, 2017

FDA approved

OGIVRI (trastuzumab-dkst) injection



  • Adjuvant Breast Cancer: Adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature
  • Metastatic Breast Cancer: In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer, single-agent treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease
  • Metastatic Gastric Cancer: In combination with cisplatin and capecitabine or 5-fluorouracil, for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

ADDRESSING UNMET NEED:  First biosimilar to Herceptin (trastuzumab, Genentech, Inc.)


  • Approved as biosimilar, not as an interchangeable product
  • Approval was based on comparisons of extensive structural and functional product characterization, animal data, human pharmacokinetic and pharmacodynamic data, and clinical studies including clinical immunogenicity between Ogivri and U.S.-licensed Herceptin
  • Data demonstrate Ogivri is highly similar to U.S.-licensed Herceptin
  • No clinically meaningful differences between the products.


CaptureSUBLOCADE ( buprenorphine ) monthly subcutaneous injection


 Indivior Inc.

INDICATION: Treatment of moderate to severe opioid use disorder (OUD) in patients who have initiated treatment with a transmucosal buprenorphine‐containing product, followed by dose adjustment for a minimum of 7 days.
Should be used as part of a complete treatment plan that includes counseling and psychosocial support


  • Given scale of the opioid crisis, FDA expanding access to treatments that can help people pursue lives of sobriety
  • New treatment option for patients in recovery; benefit of once-monthly injection vs. other forms of buprenorphine
  • Reducing burden of taking medication daily as prescribed
  • Medication-assisted treatment (MAT); part of comprehensive recovery plan opioid use disorder


  • Buprenorphine currently approved to administer as a tablet, film or implant
  • Independent FDA advisory committee supported the approval
  •  Priority Review and Fast Track designations
  • Schedule III

MECHANISM OF ACTION & DESCRIPTION:  Partial agonist at the mu‐ opioid receptor and an antagonist at the kappa‐opioid receptor

  • Drug-device combination product that utilizes buprenorphine and the Atrigel Delivery System in a pre-filled syringe


  • A double‐blind efficacy and safety study and an opioid blockade study , n=848, subjects with moderate-to-severe OUD who began treatment with buprenorphine/naloxone sublingual film followed by  Sublocade by injection vs. placebo
  • MAT Response: Urine drug screening and self-reporting of illicit opioid use during six-month treatment period
  • More weeks without positive urine tests or self-reports of opioid use vs. placebo
  • Higher proportion of patients with no evidence of illicit opioid use throughout the treatment period vs. placebo


  • Boxed warning : Risks of intravenous self-administration; solid mass could cause occlusion, tissue damage or embolus
  • Prescribed and dispensed as part of a Risk Evaluation and Mitigation Strategy (REMS)


Image credits: Mylan, Indivior



FDA News and Views: Sentinel Initiative, Innovation and International Regulation, PEPFAR, 3D Printing

Week of Nov 27, 2017


CDER Conversation: The FDA’s Sentinel Initiative

The Sentinel Initiative is national electronic system that monitors safety of marketed drugs, vaccines, biologics and medical devices

  • Includes Active Risk Identification and Analysis (ARIA) system
  • 17 data partners such as insurance companies, HMOs, and hospitals
  • Access to 223 million members
  • Data derived from administrative claims databases that healthcare insurers use for reimbursement for diagnoses, procedures, and medications
  • Used as a resource for new product reviews

Sentinel System different from other systems 

  • Distributed data approach – data partners maintain physical and operational control over electronic data using Sentinel Common Data Model
  • Secure access to multiple data sources to achieve far larger sample sizes
  • Allow data aggregation while safeguarding patient privacy
  • Routine Querying Tools




FDA, International Regulators Look at Common Challenges, ‘Innovation’

 Global regulatory experts from 28 countries, including FDA, discussed ‘Innovation’ issues of mutual concern

  • regenerative medical products
  • international collaboration to fight antimicrobial resistance (AMR)
  • developing strategies to combat substandard or falsified medical products

FDA presentations

  • Use of real world evidence (RWE) in pre- and post-market activities
  • Align their approaches to the evaluation of antibiotics
  • Working with WHO in combating falsified/substandard medical products
  • Need for international cooperation and increased sharing of inspectional results, collaborating on pharmacovigilance needs, and advancing regulatory science



PEPFAR: FDA Approves 200th HIV/AIDS Therapy

FDA tentatively approved  the 200th antiretroviral drug application under the President’s Emergency Plan for AIDS Relief (PEPFAR)

  • PEPFAR launched in 2003 to address global HIV/AIDS epidemic by stimulating  development of new HIV therapies
  • FDA used guidance, outreach and expedited review process
  • FDA encouraged submission for single entity, fixed dose combination (FDC), and co-packaged versions of previously approved antiretroviral therapies

Advancements to facilitate treatment in areas of the world lacking advanced health care infrastructure, particularly in parts of Africa 

  • FDC even in circumstances with patent or exclusivity market protection for one or more of the components in the U.S
  • Due to the significant public health impact of these products, FDA prioritized review
  • Products purchased with U.S. funds under the President’s PEPFAR Fund



FDA ushering in new era of 3D printing of medical products

FDA has reviewed >100 3D printed devices currently on the market

  • Patient-matched devices tailored to fit patient’s anatomy – knee replacements, implants
  • Drug produced on 3D printer with more porous matrix
  • Envision 3D printed new skin cells for burn wounds

State-of-the-art 3D printing facilities on FDA campus

  • CDER scientists determine how 3D drug printing impacts manufacturing
  • CDRH scientists investigate the effect of design changes on device performnace
  • Understand policy framework to ensure quality and safety of 3D printed products

Providing comprehensive policy framework to manufacturers

  • CDER’s Emerging Technology Program
  • New guidance on technical aspects of 3D printing (additive manufacturing)
  • Review regulatory issues related to bioprinting of biological, cellular and tissue-based product


Image credits: FDA, PEPFAR