Device Authorizations: OSIRIX software for device development, EARLYBIRD bleed monitor, CLEARMATE ventilator, MITRACLIP for mitral regurgitation


OSIRIX CDE SOFTWARE MODULE (Medical Device Development Tool)

TBI Endpoints Initiative, Unv. of California, San Francisco

CONTEXT OF USE: Contusions, as assessed by an expert rater from MRI using OsiriX CDE Software Module MDDT, may be used for enrichment of clinical trials for therapeutic medical devices intended to improve outcomes at 3 months for patients aged between 18-65 years with acute non-penetrating head trauma and Glasgow Coma Scale (GCS) 13-15 who have undergone acute head CT (e.g., as part of standard clinical care) at a U.S. Level 1 trauma center


  • First biomarker test tool type
  • Tool for more efficient development of devices in traumatic brain injury (TBI) treatment


  • Software module that provides standardized way to mark boundaries and classify brain contusions (bruises) using Common Data Element (CDE) criteria
  • Information can be used to label abnormalities on MR images for enriching enrollment in clinical trials for therapeutic medical devices intended to improve outcomes of mild Traumatic Brain Injury (TBI) patients
  • Detection of a medical device effect (if present) is more likely than it would be in an unselected population
  • Can be used by medical device developers to identify and enroll patients into TBI studies.


  • Clinical study evaluate the association between contusions and diffuse axonal injury with 3-month Glasgow Outcome Scale  and Interrater reliability
  • Previous investigations and pilot studies on level of risk associated with MDDT use,  possible advantages/disadvantages

REGULATORY PATHWAY: Qualification through MDDT pathway

  • Program to qualify tools that medical device sponsors can use in the development and evaluation of medical devices
  • ‘Qualification’ means FDA has evaluated the tool and concurs with available supporting evidence that the tool produces scientifically and clinically meaningful measurements within the authorized context of use
  • Qualified tools serve as a resource that can be referenced by any medical device sponsor
  • When used consistent with the qualified Context of Use: Results support regulatory decision-making, eliminates sponsor burden to demonstrate validation, reduces workload of FDA staff e



EARLY BIRD Bleed Monitoring System

Saranas, Inc

INDICATION FOR USE: For the introduction of catheters, catheter balloons, and other diagnostic and interventional devices into the femoral artery or femoral vein while maintaining hemostasis during diagnostic and interventional endovascular procedures.
The Early Bird provides physicians with an early indication of a potential internal bleeding complication by initial detection and monitoring of extravascular fluid accumulation.

GENERIC TYPE OF DEVICE: Intravascular bleed monitor.

Probe, catheter, or catheter introducer that measures changes in bioimpedance and uses an algorithm to detect or monitor progression of potential internal bleeding complications.


  • Adverse tissue reaction: Biocompatibility evaluation
  • Infection: Sterilization validation, Pyrogenicity testing, Shelf-life testing, Labeling
  • Blood loss, bleeding, hematoma: Human factors testing, Labeling, Animal performance testing, Non-clinical performance testing
  • Embolization (micro or macro) with ischemia: Human factors testing, Labeling
    Animal performance testing, Non-clinical performance testing
  • Vascular trauma: Human factors testing, Labeling, Animal performance testing, Non-clinical performance testing
  • Electrical shock: Electrical safety testing
  • Device failure due to interference with other devices: Electromagnetic compatibility (EMC) testing, Electrical safety testing
  • Device failure due to software malfunction: Software verification, validation, hazard analysis

REGULATORY PATHWAY: De Novo classification

  • Regulation Number: 21 CFR 870.1345
  • Regulation Name: Intravascular bleed monitor
  • Regulatory Class: Class II
  • Product Code: QFJ



CLEARMATE ventilation device

Thornhill Research, Inc.

INDICATION FOR USE: To be used by emergency department medical professionals as an adjunctive treatment for patients suffering from carbon monoxide poisoning. The use of ClearMate enables accelerated elimination of carbon monoxide from the body by allowing isocapnic hyperventilation through simulated partial rebreathing


  • Carbon monoxide poisoning affects thousands of people each year
  • Hyperbaric treatment, necessary for severe poisoning, has low accessibility; only 60 US medical centers with hyperbaric units
  • New device provides access to lifesaving device


  • Gas mixer, valves, meters, breathing circuits, oxygen reservoir, mask and hoses
  • Speeds up elimination of carbon monoxide from body
  • Delivers both 100 % oxygen to patient, as well as a mixture of oxygen and carbon dioxide, to breathe faster
  • Increased breathing accelerates rate of elimination of carbon monoxide in body

GENERIC DEVICE TYPE: Isocapnic ventilation device

Prescription device used to administer a blend of carbon dioxide and oxygen gases to a patient to induce hyperventilation. This device may be labeled for use with breathing circuits made of reservoir bags (21 CFR 868.5320), oxygen cannulas (21 CFR 868.5340), masks (21 CFR 868.5550), valves (21 CFR 868.5870), resuscitation bags (21 CFR 868.5915), and/or tubing (21 CFR 868.5925).


  • Data from multiple clinical studies for efficacy and safety, n=100
  • Effective at eliminating carbon monoxide; combination of oxygen and carbon dioxide resulted in faster elimination of carbon monoxide but not faster than hyperbaric oxygen therapy
  • Patients did not experience any device-related complications


  • Hypocapnia (lacking CO2): Non-clinical performance testing, Labeling
  • Hypercapnia (excess CO2): Non-clinical performance testing, Labeling
  • Hypoxemia (lacking O2): Non-clinical performance testing, Labeling
  • High airway pressure (e.g., barotrauma): Non-clinical performance testing
  • Adverse tissue reaction: Biocompatibility evaluation

REGULATORY PATHWAY: De Novo classification

  • Regulation Number: 21 CFR 868.5480
  • Regulation Name: Isocapnic ventilation device
  • Regulatory Class: Class II
  • Product Code: QFB



 MITRACLIP NT Clip Delivery System and MITRACLIP NTR/XTR Clip Delivery System

Abbott Vascular

EXPANDED INDICATION:  To include secondary (or functional) mitral regurgitation (MR), when MR is caused by a dysfunctional left ventricle, not by degeneration of the mitral valve itself

ORIGINAL INDICATION (2013): For the percutaneous reduction of significant symptomatic mitral regurgitation (MR ≥ 3+) due to primary abnormality of the mitral apparatus [degenerative MR] in patients who have been determined to be at prohibitive risk for mitral valve surgery by a heart team, which includes a cardiac surgeon experienced in mitral valve surgery and a cardiologist experienced in mitral valve disease, and in whom existing comorbidities would not preclude the expected benefit from reduction of the mitral regurgitation.


  • 6.5 million American adults live with chronic heart failure
  • Small percentage also have moderate-to-severe or severe secondary mitral regurgitation, increasing risks and complicating heart failure treatment
  • This small percentage of patients could be candidates for the new indication


  • MitraClip device repairs MR without open-heart surgery and is delivered to the heart through a small incision in the leg
  • Clips portions of the leaflets, or flaps, of the mitral valve together to reduce the backflow of blood, restoring the heart’s ability to pump oxygenated blood more efficiently


  • Patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation, n=614,  transcatheter mitral-valve repair plus medical therapy (device group)  vs. medical therapy alone (control group)
  • Primary effectiveness end point: All hospitalizations for heart failure within 24 months of follow-up
    • 35.8% per patient-year in device group vs. 67.9% per patient-year in control group, P<0.001
  • Primary safety end point: Freedom from device-related complications at 12 months vs. performance goal of 88.0%
    • 96.6%  vs. 88% performance goal, P<0.001
    • Death from any cause: 29.1% in device group vs. 46.1% in control, P<0.001
  • Potential adverse events: Death, stroke, major bleeding, and atrial fibrillation


Image Credit: UCSF, Saranas, Thornhill, Abbott 

Drug Authorizations: SPRAVATO for treatment-resistant depression, CABLIVI for thrombotic thrombocytopenic purpura, EGATEN for fascioliasis


SPRAVATO™ (esketamine) nasal spray, CIII

 Janssen Pharmaceuticals, Inc.

INDICATION: In conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults
Limitations of Use: Not approved as an anesthetic agent


  •  Long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition
  • FDA review of safety and efficacy along with robust discussion with external advisory committee

MECHANISM OF ACTION: Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor; mechanism of antidepressant effect is unknown


  • Three short-term (four-week) clinical trials and one longer-term maintenance-of-effect trial; Spravato vs. placebo nasal spray – all patients on new oral antidepressant (AD) from time of randomization
  • Primary endpoint: Change in baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score
  • SPRAVATO plus AD demonstrated statistical superiority vs. placebo
  • Timecourse: SPRAVATO’s treatment difference observed at 24 hrs; both arms continued to improve to Day 28.
  • In the longer-term maintenance-of-effect trial: SPRAVATO + AD experienced a statistically significantly longer time to relapse of depressive symptoms vs, placebo


  • Boxed Warning: Risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug
  • REMS with Patient Enrollment Form and patient Medication Guide; self-administration of nasal spray under supervision of health care provider in certified doctor’s office or clinic; spray cannot be taken home
  • Most common side effects: Disassociation, dizziness, nausea, sedation, vertigo, decreased feeling or sensitivity (hypoesthesia), anxiety, lethargy, increased blood pressure, vomiting and feeling drunk.


  • The FDA approved ketamine (Ketalar) in 1970. This is the first FDA approval of esketamine for any use
  • Fast Track and Breakthrough Therapy designations
  • Postmarketing requirements: Long-term effects esketamine on cognitive function and urinary symptoms, further characterize potential risk of increasing thyroid stimulating hormone levels



 CABLIVI (caplacizumab-yhdp) 

Ablynx N.V.  and Genzyme (Sanofi)

INDICATION: Treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy

ADDRESSING UNMET NEED: Treatment option for a Rare disease

MECHANISM OF ACTION: Targets A1-domain of von Willebrand factor (vWF) and inhibits the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption

  • Clinical study, n=145 patients with aTTP stratified per Glasgow Coma Scale score, CABLIVI vs placebo,  median treatment duration of 35 days
  • Endpoint: Time to platelet count response (platelet count ≥150,000/µL followed by cessation of daily plasma exchange within 5 days
  • Time to platelet count response shorter with CABLIVI vs. placebo, lower number of  TTP-related deaths (0 vs. 3) and TTP recurrence (3 vs. 28)
  • Recurrence of TTP in overall study period lower with CABLIVI vs placebo (28/73 patients [38%]; p<0.001)
  • Most common adverse reactions:  Epistaxis, headache, and gingival bleeding.


  • Priority review and orphan product designation
  • Postapproval commitments on manufacturing and testing

EGATEN™ (triclabendazole) tablets, for oral use


INDICATION:  Treatment of fascioliasis in patients 6 years of age and older.
  • WHO estimates ~ 2.4 million infected people infected in > 70 countries worldwide
  • Treatment option for global markets

MECHANISM OF ACTION: Anthelmintic against Fasciola species


  • Open label, randomized trial, in Vietnam, n=100 children, EGATEN vs. artesunate, 3 months treatment
  • No clinical symptoms in  92% EGATEN vs in 76% placebo, p = 0.035
  • Six nonrandomized, open label studies in Cuba, Bolivia, Peru, Chile, Iran, n=245 adult and pediatric patients with stool-confirmed fascioliasis
  • Cure defined as absence of Fasciola eggs in stool based on Kato-Katz method. Day 60
  • Dose response seen in all studies


  • Most common adverse reactions: Abdominal pain, hyperhidrosis, nausea, decreased appetite, headache, urticaria, diarrhea, vomiting, musculoskeletal chest pain, pruritus


  • Fast Track and Orphan Drug designations
  • Tropical Disease Priority Review Voucher to encourage development of products for certain tropical diseases
  • Postmarketing requirements: QT/QTc trial, additional dose evaluation,
Image credits: Janssen, Sanofi, Novartis


News & Vews: Farewell Commissioner Gottlieb, Patient participation in cancer clinical trials, CDRH reorganization, Request to Connect for patients, Implanted Brain-Computer Interface devices, Safe Use alerts

Capture.JPGFarewell Commissioner Gottlieb

Sincere gratitude for your leadership and exemplary work during your current FDA tenure. You have been an inspiration.Capture.JPGEXIT INTERVIEW


New steps to broaden patient participation in cancer clinical trials

FDA issued new recommendations for broadening cancer trial eligibility criteria

  • More representative of patient population
  • Maximize the generalizability of the trial results
  • Maximize understanding of therapy’s benefit-risk profile across the patient population likely to receive the drug in clinical practice

Broadening eligibility criteria to include:  Pediatric patients, Patients with HIV, Hepatitis B and Hepatitis C Virus infections, Patients with brain metastases, organ dysfunction and prior or concurrent malignancies

New Guidances



Reorganization of CDRH

CDRH reorganization to implement efficiencies to integrate CDRH’s premarket and postmarket program functions

  • Reviewers, compliance officers and other experts would work in teams responsible for device oversight throughout the product’s development and commercialization
  • More integrated approach to device safety throughout the Total Product Life Cycle (TPLC) – already in pilot testing
  • Timeline: March 18, 2019 (begin) – September 30, 2019 (full implementation)

New Offices 

  • Office of Product Evaluation and Quality (OPEQ) :  Combines Office of Compliance, Office of Device Evaluation, Office of Surveillance and Biometrics, and  Office of In Vitro Diagnostics
  • Office of Policy – Two teams, the Guidance, Legislation and Special Projects Team and the Regulatory Documents and Special Projects Team
  • Office of Strategic Partnerships and Technological Innovation – Combines Science & Strategic Partnerships, Digital Health, Health Informatics and Innovation teams



“Request to Connect” – A New Way for Patients to Connect with FDA

“Request to Connect” portal is live
  • Gives patients and caregivers a single entry point to the Agency for questions and meeting requests
  • Co-developed by Patient Affairs Staff and the medical product centers
  • Will route inquiries to appropriate medical product center or office for responses in effective and efficient manner
  • Opportunity for FDA to better understand patient perspective and advance science of patient input

Implanted Brain-Computer Interface (BCI) Devices for Patients with
Paralysis or Amputation – Non-clinical Testing and Clinical

Implanted BCI devices increase ability to interact with environment and provide independence to patients with paralysis or amputation

  • Interface with nervous system to restore motor and/or sensory capabilities
  • Recommendations for non-clinical testing and study design considerations for IDE feasibility and pivotal clinical studies

Non-Clinical Bench Testing Considerations: Risk analysis, Electrodes, Leads and Connectors, Implanted casing and electronics, Output simulation measurements, Output simulation safety, Programmers/control unit, Radiofrequency transmitter and receiver, System level testing, factors for determining and design of animal studies

Clinical Study Considerations: Patient population, Home-Use, Duration and follow-up schedule, Inclusion/Exclusion criteria, Demographics, Treatment parameters, Endpoints including patient input (patient engagement. patient preference information, patient reported outcome measures)



SAFE USE ALERTS: Surgical Staplers and Staples, Contact Lenses

Surgical Staplers and Staples:

  • Increased number of adverse events reported to the FDA since 2011: 366 deaths, > 9,000 serious injuries, > 32,000 malfunctions
  • FDA Actions:
    • Letter to Healthcare Providers
    • Issue draft guidance on recommendations to manufacturers
    • Hold public meeting of  General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee  to reclassify as Class II (from Class I)
    • Require premarket notification and establish mandatory special controls to help mitigate known risks 

Contact lenses 

  • Risk of several serious conditions including eye infections and corneal ulcers
  • Can develop very quickly, be serious and can cause blindness
  • Video on safe and effective use

Image credits: FDA

News & Views: Flu vaccine supply, Rare Disease Day, Childhood Cancer Advocacy Forum, Heart Devices, Physiologically Based Pharmacokinetic (PBPK) Modeling

Capture.JPGEnsuring Supply of Influenza Vaccine

Starts well before the current flu season ends – a year-round initiative

  1. Vaccine composition changes every year as flu viruses are constantly evolving
  2. Collaboration of FDA, WHO, CDC to evaluate global circulating strains and disease trends
  3. FDA advisory committee recommend 3-4 strains to include in trivalent and quadrivalent influenza vaccines
  4. Manufacturers begin manufacturing process to include the newly selected flu strains and seek FDA approval for lot release – quality control tests, including testing for sterility


CaptureObservation of Rare Disease Day

Created to raise awareness about the 7,000 known rare diseases with theme of Bridging Health and Social Care


CaptureOncology Center of Excellence Childhood Cancer Advocacy Forum

Topics for Discussion:

  • FDA’s External Engagement and Patient Advocacy: A Dialogue to Better Inform FDA of Patient Needs and Priorities
  • Avoiding Pitfalls in Drug Development
  • Approved Cancer Drugs in Children
  • BPCA/WR Study Results
  • Expanded Access to Investigational Drugs
  • FDARA Implementation
  • Pediatric PROs: Are they feasible?

Register here for in-person or online attendance

CaptureHeart Devices regulated by FDA

  • Automated external defibrillators (AEDs): Portable and automatic,  to restore normal heart rhythm
  • Cardiac ablation catheters: Long, thin flexible tubes.  to treat abnormally rapid heartbeats
  • Cardiovascular angioplasty devices: Long, thin, flexible tubes threaded into  heart vessel to open narrowed or blocked areas
  • Cardiac pacemakers: Small, battery-powered, implanted permanently, monitor heart’s electrical impulses. deliver electrical stimulation if bradycardia
  • Implantable cardioverter defibrillators (ICDs): Monitor heart rhythms and deliver shocks if dangerous tachycardia
  • Prosthetic (artificial) heart valves: Replacing diseased or dysfunctional heart valves,
  • Stents: Small, lattice-shaped, metal tubes, some with drugs,  to improve blood flow
  • Ventricular assist devices (VADs): Mechanical pumps for short-term or long term use

Warning signs and symptoms of a heart attack 

CaptureSupporting Drug Development Through Physiologically Based Pharmacokinetic (PBPK) Modeling

PBPK Models to Mechanistically Predict Drug Pharmacokinetics

  • Grounded in human physiology – describe time course of absorption, distribution, metabolism, and elimination of one or more drugs
  • Includes anatomical or physiological parameters such as blood flow, tissue composition, enzyme abundance, drug-specific values, such as tissue-to-plasma concentration ratios, metabolism and clearance
  • Make predictions on drug concentrations achieved in the absence of clinical data
  • Focus to improve accuracy of predictions and incoporate PBPK models in drug development


image credit: FDA