FDA Guidances: Antimicrobial Drug/Device Coordination, Computational Modeling, Total Kidney Volume

FDA BRIEF: Week of September 19, 2016



SCOPE : For coordinated development of new antimicrobial drug and an antimicrobial susceptibility test (AST) device to streamline CDER and CDRH reviews and approvals

  • Interactions between drug sponsors and device manufacturers
  • Considerations for submitting separate applications to CDER and CDRH
  • Clarify independent review of drug product and device
  • Maximize  likelihood of coinciding device and drug approvals


  • Submit coordinated development plans to CDER and CDRH, respectively, for review and comment
  • Joint meetings with  drug sponsor and device manufacturer and personnel from both CDER and CDRH
  • Use CDRH pre- submission process
  • CDRH communicate with CDER and review the 510(k) submission during the NDA review process




  • Computational Modeling and Simulation (CM&S) studies to support device design/development and CDRH submissions
  • Provide recommendations formatting, organization, and content of  CM&S reports
  • Improve consistency and predictability of FDA review


  • Fluid dynamics
  • Solid mechanics
  • Electromagnetics and optics
  • Ultrasound propagation
  • Thermal propagation


  •  Executive Report Summary
  • Background/Introduction
  • Code Verification
  • System Configuration
  • Governing Equations/Constitutive Laws
  • System Properties
  • System Conditions
  • System Discretization
  • Numerical Implementation
  • Validation
  • Results
  • Discussion
  • Limitations
  • Conclusions




  • TKV: Sum of the volume of the left and right kidneys
  • Qualified context of use (COU) for TKV in studies for the treatment of autosomal dominant polycystic kidney disease (ADPKD)


  • Use Statement:  Prognostic enrichment biomarker,  TKV-based patient selection






FDA BRIEF: Week of September 19, 2016

FDA approved

EXONDYS 51 (eteplirsen) injection

Sarepta Therapeutics, Cambridge, MA, USA  

Image result for exondys 51

Image result for exondys 51

INDICATION: Treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping.

A clinical benefit of EXONDYS 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.


  • Duchenne muscular dystrophy (DMD) is a rare and devastating disease
  • Occurs in 1 out of every 3,600 male infants worldwide
  • Progressive muscle deterioration and weakness; most common type of muscular dystrophy
  • Need for an approved treatment


  • Accelerated Approval
  • However, FDA internal Scientific Dispute on Approval between CDER Review Division and CDER Director
  • Key disagreement on the amount of dystrophin protein produced in sufficient to be ‘reasonably likely’ to predict clinical benefit.
  • FDA Commissioner deferred to CDER Director’s assessment of granting accelerated approval
  • Sponsor required to conduct a clinical trial to  to assess whether Exondys 51 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.
  • If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

FDA Commissioner Memo

MECHANISM OF ACTION: Accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51.  Eteplirsen  binds to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.


  • 3 clinical studies, patients with confirmed mutation of DMD gene amenable to exon 51 skipping, Exondys vs,. placebo, or open label
  • Primary Endpoint: dystrophin production
  • Clinical outcome measure: 6-minute walk test (6MWT)
  • No significant difference in change in 6MWT for EXONDYS 51 vs. placebo (Study 1)
  • Not possible to estimate dystrophin production in response to EXONDYS 51 (Study 2)
  • Dystrophin level: Pretreatment level 0.16% ± 0.12%  of level in healthy subject vs. and 0.44% ± 0.43% after 48 weeks of EXONDYS 51 (p < 0.05).

SAFETY: Most common side effect: Balance disorder and vomiting.


 AMJEVITA (adalimumab-atto)

Image result for biosimilar

INDICATION: In adult patients with

  • moderately to severely active rheumatoid arthritis;
  • active psoriatic arthritis;
  • active ankylosing spondylitis (an arthritis that affects the spine);
  • moderately to severely active Crohn’s disease;
  • moderately to severely active ulcerative colitis; and
  • moderate to severe plaque psoriasis.

Also indicated for moderately to severely active polyarticular juvenile idiopathic arthritis in patients four years of age and older.

REG PATHWAY: Biosimilar to Humira®


  • Structural and Functional characterization
  • Animal study data
  • Human Pharmacokinetic and Pharmacodynamics data
  • Clinical immunogenicity data
  • Other clinical safety and effectiveness data

Bioresearch Monitoring Information System (BMIS)


WHAT: Bioresearch monitoring web site that makes clinical research information available to the public.


WHY:  To foster transparency and encourage information sharing within the clinical research community. Contains information on clinical investigators, contract research organizations, and institutional review boards involved in the conduct of IND studies with human investigational drugs and therapeutic biologics.

HOW: Extracted from IND-related documents  for whom FDA has received Form FDA 1572


FDA NEWS: Naloxone App Competition, CDRH Priorities, NEST Report, ClinTrials.gov Requirements

FDA BRIEF: Week of September 19, 2016


Image result for 2016 Naloxone App Competition,

  • Public contest on developing innovative technologies to combat opioid overdose epidemic
    1. For: Computer programmers, public health advocates, clinical researchers, entrepreneurs, innovators from all disciplines
    2. Create: App to connect opioid users experiencing overdose with nearby naloxone (antidote) carriers
  • Goal to develop a low-cost, scalable, crowd-sourced App to increase accessibility
  • Registration Deadline : Oct. 7, 2016
  • Code-a-thon: Oct. 19-20, 2016, @ FDA campus
    1. Code: Open-source, publicly accessible; collaboration
  • Submission Deadline: Nov. 7, 2016. Submit video of functional prototype along with concept summary
  • Judging: FDA, NIDA, and SAMHSA
  • Award:  $40,000 + application for NIDA SBIR grant



  • Leverage “Big Data” for regulatory decision-making
  • Modernize biocompatibility and biological risk evaluation of device materials
  • Leverage real-world evidence in regulatory decision-making
  • Advance methods for predicting/monitoring medical device clinical performance
  • Improve and streamline clinical trial design
  • Develop computational modeling technologies  for regulatory decision-making
  • Enhance performance of Digital Health and strengthen medical device cybersecurity
  • Reduce healthcare associated infections by better understanding antimicrobials, sterilization, reprocessing of medical devices
  • Collect and use patient input in regulatory decision-making
  • Leverage precision medicine and biomarkers for predicting medical device performance, disease diagnosis and progression


National Evaluation System for health Technology (NEST) Report

Image result for A NEST Planning Board Report



  • Collaborative system leverages real-world evidence from  different sources (see above) to better understand how medical devices perform
  • Contribute to regulatory decisions, promote device innovation, provide timely and meaningful information directly to patients and health care providers


  • Published by  Duke-Margolis Center for Health Policy through cooperative agreement with FDA
  • Goals for Phase 1
    1. Balancing of pre- and postmarket device evidence development
    2. Active surveillance system
  • Goals for Phase 2
    1. Class 2 devices: Enhanced data collection and integrating health IT systems
    2. Patient-mediated data sharing
    3. Measuring device value



Image result for clintrial gov

Final rule on requirements for registering certain clinical trials and summary results  to ClinicalTrials.gov.

Legal requirements for submitting registration and results information for clinical trials involving FDA -regulated drug, biological and device products.

  • Access is good for patients, the public and science
  • Maximize value of clinical trials
  • Honor commitments to trial participants

Key elements:

  • Checklist for trial eligibility and responsibility
  • Expanded scope for summary results information
  • Additional registration and summary results information data –  race, ethnicity of trial participants, if collected, and the protocol
  • Additional types of adverse event information
  • List of potential legal consequences for non-compliance.


FDA National Evaluation System for health Technology (NEST)


WHAT:  Foundation to efficiently generate evidence for medical device evaluation and regulatory decision-making

WHY: National evaluation system would generate evidence across the total product lifecycle (TPLC), by leveraging real-world evidence (RWE)and applying advanced analytics

WHO:  Link and synthesize data across the medical device landscape – clinical registries, electronic health records and medical billing claims

HOW: High quality RWE  for health care providers and patients to make better informed treatment decisions; strike right balance between safety vs innovation and patient access




FDA Guidances, MaPPs : Multi-Regional Clinical Trials, 510(k) Third-Party Review, Drug Safety Oversight Board

FDA BRIEF: Week of September 12, 2016

fda guidances

Image result for ICH



  • Multi-regional clinical trials (MRCTs) to address increasing globalization of drug development
  • General and Strategic principles for planning and design of MRCTs  for global regulatory submissions


  • Value in Drug Development
  • Basic Requirements and Key Considerations
  • Scientific Consultation Meetings with Regulatory Authorities
  • Clinical Trial Design and Protocol-related Issues
  • Regional Variability and its Potential Impact on Efficacy and Safety
  • Subject Selection
  • Dose Selection of Doses
  • Endpoint Selection
  • Comparator Selection
  • Statistical Analysis Plan
  • Overall Sample Size and Allocation to Regions
  • Efficacy and Safety Information Collecting and Handling
  • Handling Concomitant Medications


third party.JPG


  • Third Party (TP) Review Program authorized under section 523 of FD&C Act
  • Recognition, Rerecognition, Denial, and Withdrawal processes and criteria
  • Harmonized with International Medical Device Regulators 114 Forum’s (IMDRF) regulatory assessment program – Medical Device Single Audit 115 Program (MDSAP)


  • Device Eligibility
  • Relevant FDA guidance(s) and information
  • FDA Branch Chief Consult
  • Administratively complete submission
  •  Product Specialist(s) and Technical Expert(s) selection
  • Substantive review
  • Identifying deficiencies
  • Documenting review
  • TP Review documentation
  • Additional information per FDA request
  • Dispute resolution


  • Operational considerations..
  • Management of impartiality
  • Personnel
  • External Technical Experts
  • Outsourcing
  • Confidential information
  • Complaints
  • Record keeping


Initial recognition

  • Administrative information
  • Prevention of conflicts of interest
  • Personnel qualifications.
  • Certification statements.


Recognition or rerecognition denial

Recognition Suspension or Withdrawal



Image result for FDA manual of policy and procedures


MaPP: Drug Safety Oversight Board

  • Drug Safety Oversight Board (DSB) in 2005
  • Provide oversight for management of drug safety issues,  internal deliberations,   review disputes regarding Risk Evaluation and Mitigation Strategies (REMS)
  • Internal management council providing advice to CDER Director


  • Policy
  • Responsibilities – Chairperson, Executive Director, Members, Staff
  • Procedures – Referrals, Attendance, Decision-Making, Conflict of Interest




FDA Approvals & Consumer Information: AERA system, VISUMAX Laser, BARD stent, COBAS test, IMAGE READY system, JUVEDERM Volbella, RAINDROP inlay, OBALON Balloon

FDA BRIEF: Week of September 12, 2016

FDA approved


AERA Eustachian Tube Balloon Dilation System

Acclarent, Inc., Irvine, CA, USA

Image result for Aera Eustachian Tube

INDICATION FOR USE: To treat persistent Eustachian tube dysfunction (ETD), a condition in which pressure, pain or clogged or muffled sensations occur in the ear.


  • Eustachian tube supports hearing by maintaining pressure inside the ear
  • ETD results in discomfort, impaired hearing, persistent ear infections, ringing in the ears (tinnitus) or other symptoms
  • Need for new treatment option for ETD

REG PATHWAY: De Novo classification process


  • Catheter to insert a small balloon through the patient’s nose and into the Eustachian tube
  • Once inflated, balloon opens up pathway for mucus and air to flow through the Eustachian tube
  • After Eustachian tube dilated, doctor deflates and removes the balloon.


  • Randomized clinical trial, n=299, patients with chronic ETD, Aera vs. conventional medical management (nasal spray).
  • Primary Endpoint: Middle ear function was tested using tympanogram, 6 weeks post-procedure
    •  52%  with tympanogram results within a normal functioning vs. 14%
  • Most common adverse event: Small tears of the lining of the Eustachian tube, minor bleeding and worsening of ETD


VISUMAX  Femtosecond Laser 

Carl Zeiss Meditec Inc., Dublin, CA, USA

Picture of the device.

INDICATION FOR USE: For the small incision lenticule extraction (SMILE) procedure to reduce or eliminate nearsightedness in certain patients 22 years of age or older.


  • Nearsightedness, or myopia, is a common vision condition
  • Can be due to the shape of the cornea being too steep and/or the length of the eyeball being too long
  • Need for expansion of surgical treatment options available to patients for correcting nearsightedness



  • Laser removes small amount of eye tissue to permanently reshape cornea
  • Femtosecond (very fast, short-pulsed) laser makes cuts within cornea, creating disc-shaped piece of tissue  removed by surgeon
  • Tissue removal causes changed shape of cornea, corrects nearsightedness


  • Clinical study, n=328,
  • Primary endpoint :  Stable vision correction at six month
  • >99% :Uncorrected (without glasses or contacts) visual acuity of 20/40 or better
  • 88% : Uncorrected visual acuity of 20/20 or better
  • Common complications during surgery: Difficulty removing corneal tissue, loss of suction that keeps laser aligned with eye
  • Common complications after surgery: Debris at the site of tissue removal, dry eye, moderate to severe glare and moderate to severe halos




BARD ® LifeStent® Vascular Stent System

Bard Peripheral Vascular, Inc.Tempe, AZ, USA

Image of the device.

INDICATION FOR USE: T is intended to improve luminal diameter in the treatment of symptomatic de novo or restenotic lesions up to 240 mm in length in the native superficial femoral artery (SFA) and popliteal artery with reference vessel diameters ranging from 4.0 – 6.5 mm.

Consumer Information

COBAS ® EGFR Mutation Test v2
Roche Molecular Systems, Inc., Pleasanton, CA, USA

cobas® EGFR Mutation Test v2

INDICATION FOR USE: Real-time PCR test for the qualitative detection of defined mutations of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) patients. Defined EGFR mutations are detected using DNA isolated from formalin-fixed paraffin-embedded tumor tissue (FFPET) or circulating-free tumor DNA (cfDNA) from plasma derived from EDTA anti-coagulated peripheral whole blood. The test is indicated as a companion diagnostic to aid in selecting NSCLC patients for treatment with the targeted therapies  in accordance with the approved therapeutic product labeling:

Consumer Information

ImageReady MR Conditional Pacing System and Ingevity Pace/Sense Lead
Boston Scientific Corporation, St. Paul, MN, USA


ImageReady MR Conditional Pacing System

INDICAIONS FOR USE: Symptomatic paroxysmal or permanent second- or third-degree AV block ,  Symptomatic bilateral bundle branch block, Symptomatic paroxysmal or transient sinus node dysfunction with or without associated AV conduction disorders (i.e., sinus bradycardia, sinus arrest, sinoatrial [SA] block), Bradycardia-tachycardia syndrome, to prevent symptomatic bradycardia or some forms of symptomatic tachyarrhythmias,  Neurovascular (vaso-vagal) syndromes or hypersensitive carotid sinus syndromes

Consumer Information

Allergan, Irvine, CA, USA

Image result for Juvéderm Volbella® XC

INDICATION FOR USE: For injection into the lips for lip augmentation and for correction of perioral rhytids in adults over the age of 21.

Consumer Information

RAINDROP® Near Vision Inlay
ReVision Optics, Lake Forest, CA,USA

Image of Raindrop Near Vision Inlay

INDICATION FOR USE: Intrastromal implantation to improve near vision in the non-dominant eye of phakic, presbyopic patients, 41 to 65 years of age, who have manifest refractive spherical equivalent of +1.00 diopters (D) to -0.50 D with less than or equal to 0.75 D of refractive cylinder, who do not require correction for clear distance vision, but who do require near correction of +1.50 D to +2.50 D of reading add.

Consumer Information

OBALON Balloon System
Obalon Therapeutics, Inc., Carlsbad, CA, USA
Picture of the device, indicating the Obalon Balloon System and three balloons in the stomach with radiopaque markers.

Consumer Information



FDA News: Oncology Center of Excellence, Drug Pricing, Alzheimer’s Disease

FDA BRIEF: Week of September 12, 2016

FDA Voice


Evaluating FDA’s Approach to Cancer Clinical Trials
By: Richard Pazdur, M.D., Acting Director, FDA Oncology Center of Excellence

Dr. Richard Pazdur


FDA Oncology Center of Excellence (OCE) announced 2 months ago

 OCE and  Cancer Moonshot focus

  • leverage combined expertise in drugs, biologics, and device
  • most innovative approaches for new oncology prod

Commitment to optimally designed clinical trials

  • Emphasis on design for increased efficiency
  • Stakeholder engagement across government and industry to revisit eligibility criteria and enhance generalizability
  • Transition from Phase 1/2/3 paradign to a more seamless approach – expedire regulatory pathway
  • Use of ‘common control trials- with a common control arm and multiple different drugs with same indication and different companies
  • Use of ‘large simple trials’  with easily-measured endpoints safety or secondary efficacy endpoints
  • Public meetings to interact with patients and stakeholders.

NEJM Publication


FDA and Access to Medications

By: Janet Woodcock, M.D., Director, CDER

Janet Woodcock

Recent news about the price spike of EpiPen has caused concern about medications become prohibitively expensive  and some people losing access to a potentially life-saving treatment.
FDA’s Role
  • doesn’t regulate drug prices – prices are set by the drug makers or distributors.
  • does approve new drugs, including generic versions of a drug, to improve competition in the marketplace.
  • Office of Generic Drugs prioritizes and expedites our review of applications for first generics
  • roadmap developed for expedited access


FDA Facilitates Research on Earlier Stages of Alzheimer’s Disease

Alzheimer’s disease is a nightmare 

  • > 5 million diagnosed, 6th leading cause of death,  most common cause of dementia
  • limited treatment options

New Paths for New Alzheimer’s Drugs


  • focus clinical trials on stages before the onset of overt dementia
  • earlier and more precise identification of patients with early brain changes
  • earlier interventions, before further extensive brain damage, more successful




FDA Division of Biology, Chemistry, and Materials Science



A scientist working with test tubes.

WHAT: Part of  Office of Science and Engineering Laboratories (OSEL), CDRH


  • Determine effects of implanted devices, potential device adverse effects,  source and impact of device degradation
  • Develop experimental data, test methods, and protocols
  • Develop measurements, methods, and analytical procedures to support CDRH pre-market and post-market activities.

WHO: Experts in biology, biomaterials science, biomedical and chemical engineering, chemical physics, materials science, pharmacology, physical chemistry, polymer science, and toxicology

HOW: Focus on

  • analytical chemistry and electrochemistry
  • biocompatibility, toxicology, and biological risk assessment
  • biosensors and biomarkers
  • extractables, leachables, and chemical contamination
  • genomic and genetic technologies
  • immune and cellular responses
  • infection control, sterility, and biofilms
  • materials characterization, processing, and materials degradation
  • modeling of physiological processes
  • multicomponent mass transfer and reaction kinetics
  • nanotechnology

Clinical Pharmacology Cards: JADENU, SYNJARDY



Image result for JADENU


Mechanism of Action


Orally active chelator that is selective for iron (as Fe3+) for the treatment of chronic iron overload due to blood transfusions.
Pharmacodynamics (PD)





Deferasirox (10, 20,and 40 mg per kg per day) was able to induce a mean net iron excretion (0.119, 0.329,and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1 to 0.5 mg per kg per day). Iron excretion was predominantly fecal.

The effect of 20 and 40 mg per kg per day of deferasirox (tablets for oral suspension) as single dose showed no evidence of prolongation of the QTc interval.

Pharmacokinetics (PK)













Linear PK with mean elimination half-life ranged from 8 to 16 hours and mean steady state volume of distribution was of 14.37 L. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension was 70%. The bioavailability of JADENU was 36% greater than with deferasirox tablets for oral suspension.

AUC and Cmax were slightly decreased after a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and Cmax were increased by 18% and 29%, respectively. It is recommended that JADENU should be taken on an empty stomach or with a light meal.

Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.

Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin.

Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose).

Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3.

PK-PD Analysis Not reported
Population PK Not reported
Special Populations





Compared to patients with myelodysplastic syndrome (MDS) and CLCr greater than 60 mL/min, patients with MDS and CLCr 40 to 60 mL/min had approximately 50% higher mean deferasirox trough plasma concentrations.

In children less than 6 years of age, systemic exposure was about 50% lower than in adults, However, the safety and efficacy of deferasirox in pediatric patients was similar to that of adult patients.

Drug Interactions





Deferasirox may induce CYP3A4 and inhibit CYP2C8 and CYP1A2.

The concomitant use of JADENU with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in JADENU efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with JADENU due to a possible decrease in deferasirox concentration.

Source https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/jadenu.pdf


Image result for synjardy

Mechanism of Action







SYNJARDY combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a member of the biguanide class.

Empagliflozin, by inhibiting SGLT2, reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacodynamics (PD)







In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of empagliflozin and was maintained at the end of a 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily.

In a 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of empagliflozin 25 mg once daily treatment.

No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

Pharmacokinetics (PK)

























SYNJARDY (empagliflozin/metformin hydrochloride) 5 mg/500 mg, 5 mg/1000 mg, 12.5 mg/500 mg, and 12.5 mg/1000 mg combination tablets are bioequivalent to coadministration of corresponding doses of empagliflozin and metformin as individual tablets.

Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.

There is a lack of dose proportionality with increasing Metformin doses, which is due to decreased absorption rather than an alteration in elimination. Plasma and blood elimination half-lives of Metformin are approximately 6.2 and 17.6 hours, respectively. The apparent volume of distribution of metformin following single oral dose of immediate-release metformin hydrochloride tablets 850 mg averaged 654±358 L.

Food has no clinically relevant effect on AUC or Cmax of empagliflozin or metformin.

Empagliflozin partitioned approximately 36.8% to red blood cell. Its plasma protein binding was 86.2%. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas (SUs), which are more than 90% protein bound.

Systemic exposure of each of 3 glucuronide conjugate metabolites of empagliflozin was less than 10% of total drug-related material.

Metformin excretes as unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.

The majority of drug-related radioactivity recovered in feces was unchanged empagliflozin and approximately half of drug-related radioactivity excreted in urine was unchanged empagliflozin.

Renal clearance of metformin is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. The change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

PK-PD Analysis Not reported
Population PK




The apparent steady-state volume of distribution of empagliflozin was estimated to be 73.8 L. The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis.

Body mass index, gender and race do not have a clinically meaningful effect on pharmacokinetics of empagliflozin.

Special Populations






Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin

In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively.

In healthy elderly subjects, the total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased.

Drug Interactions





PK drug interaction studies with SYNJARDY have not been performed; however, such studies have been conducted with the individual components empagliflozin and metformin.  No dose adjustment of empagliflozin is recommended when coadministered with commonly prescribed medicinal products based on results of the described PK studies.

Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin.

Source http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206111lbl.pdf




FDA News: Traumatic Brain Injury, MDSAP Pilot, MDUFA III Metrics

FDA BRIEF: Week of September 5, 2016

Traumatic Brain Injury (TBI): FDA Research and Actions

Causes of Traumatic Brain Injury - 4 Photos (350x350)

TBI and Unmet Need

  • Often caused by bump, blow, jolt, or explosive blast to the head, or a penetrating head injury that disrupts the brain’s normal function
  • ~ 2.5 million TBI emergency department visits /year; 30% all injury-related deaths
  • Hard to diagnose
  • Can cause short- or long-term complications
  • Need for sensitive and objective diagnostic methods

FDA Research

  • Diagnostic measures of mild TBI
  • Studying biomarkers e.g. brain imaging, biofluid, physical indicators such as eye tracking and electroencephalography

FDA Regulations

  • Cleared devices to help determine need for imaging following head injury
  • Recent approval of  ImPACT and ImPACT Pediatric (review) to assess cognitive function following a possible concussion.
  • NO cleared medical products intended to specifically diagnose or treat TBI.

FDA Collaboration

  • Working with research and clinical community to develop better-designed clinical studies
  • Hosted  public meeting in March 2016
  • Plans to provide recommendations to address challenges in biomarker development


Medical Device Single Audit Program’s Regulatory Authority Council (MDSAP – RAC)

Image result for MDSAP image

FDA joined MDSAP RAC  to participate in pilot


  • Envisioned by International Medical Device Regulators Forum (IMDRF)
  • In collaboration with Australia, Brazil, Canada, and Japan regulatory authorities
  • Enables medical device manufacturers to contract with an MDSAP-authorized Auditing Organization (AO) to conduct a single audit
  • Learning Modules posted (Link and Learn )


MDUFA Performance Report

mdufaGuidance Documents issued: 37

FY 2016 User Fee collections: $137,677,000 (authorized)

Metrics for:

  • PMA Originals and Panel Track Supplements
  • PMA 180 Day Supplements
  • PMA Real Time Supplements
  • Pre-Market Report Submissions
  • PMA Annual Metrics and Goals
  • 510(k) MDUFA III Performance
  • 510(k) Annual General Metrics
  • Annual Metrics for De Novo Requests
  • Pre-Submissions
  • CLIA Waiver Annual Metrics
  • Investigational Device Exemptions (IDEs)
  • Dual (510(k) and CLIA Waiver) Annual Metrics

Internal Training:

  • Premarket Reviewer Training
  • Leadership Training


FDA CERSI Lecture Series, MDSAP Pilot

CERSI Lecture Series

Science and Research at FDA

WHAT: Lecture series to present current research and advancements in regulatory science related to pre-clinical evaluation of safety and efficacy of medical products, emerging technologies, and assessing diverse data sets through information sciences to improve health outcomes.

WHO:  Centers of Excellence in Regulatory Science and Innovation

WHEN: CERSI Workshops & Meetings

HOW: Presented by scientists from the CERSI academic institutions or collaborators of CERSI investigators.



Medical Device Single Audit Program (MDSAP)

Slide 1


WHAT : Invitation to manufacturers to participate in innovative regulatory single audit program.

WHO: MDSAP Regulatory Authority Council

HOW: Learning modules in CDRH Learn – see links below

Inspections – Global Harmonization  (New modules 9/8/16)

Primer – International Medical Device Regulators Forum (IMDRF) Medical Device Single Audit Program (MDSAP) Pilot
Presentation Closed Captioned   Printable Slides   Transcript

1. Introduction to MDSAP

2. MDSAP Management

3. MDSAP Device Marketing Authorization and Facility Registration

4. MDSAP Measurement, Analysis and Improvement

5. MDSAP Medical Device Adverse Events and Advisory Notices Reporting

6. MDSAP Design and Development

7. MDSAP Production and Service Controls, part 1

8. MDSAP Production and Service Controls, part 2

9. MDSAP Production and Service Controls, part 3

10. MDSAP Purchasing


FDA MDUFA IV Reauthorization commitments, New Logo

FDA BRIEF: Week of August 29, 2016




Image result for MDUFA IV image



Industry attendees: MITA, AdvaMed,  ACLA, MDMA

FDA Commitments:

  • Improve consistency, predictability through enhanced supervisory oversight, audits
  • Establish  dedicated premarket Quality Management team
  • Improve quality and consistency of Additional Information and Major Deficiency letters
  • Reduce average total time to decision: 108 days (510(k)s), 290 days (PMAs) FY2022
  • Improve CLIA waiver process, offer CLIA Waiver vendor days, timelines
  • Implement IT improvements
  • Participate in independent assessment of CDRH review process
  • Implement more effective recruiting and hiring strategy
  • Improve employee retention
  • Implement complete time reporting by the end of MDUFA IV
  • Seek authority to eliminate the fifth-year fee offset
  • Improve Pre-Submission process and written feedback
  • Ramp up performance goal for 70% of De Novo within 150 days in FY2022
  • Issue MDUFA decision within 60 days of Advisory Committee recommendation for PMA
  • PMA decision  within 60 days of the sponsor’s response to the Approvable letter
  • Strengthen  Third Party Premarket Review program
  • Improve consistency in review of software as device, other Digitial Health activities
  • Develop expertise on patient engagement, PPI, PRO
  • Establish value of real world evidence to accelerate patient access
  • Etablish conformity assessment program for accredited testing laboratories
  • Enhance IT infrastructure
  • Treat LDTs no less favorably than other devices



FDA Guidances: UDI Enforcement, Patient-Specific Information Dissemination

FDA BRIEF: Week of August 29, 2016

fda guidances


UNIQUE DEVICE IDENTIFICATION (UDI) rule, published 9/2013, for medical devices

  • Standardized identification system to rapidly and definitively identify device and key attributes
  • Phased enforcement over 7 years based primarily on device classification

RESCINDS legacy identifiers

  • NHRIC or NDC numbers on  labels and packages
  • 11-digit reimbursement number, typically using an NHRIC or NDC number


  • Pharmacies and payers rely on NHRIC and NDC numbers for reimbursement
  • Removal could cause disruption to existing reimbursement, supply chain, and procurement processes

REVISED FDA Enforcement Policy

  • Provide additional time to remove dependence on NHRIC/NDC
  • Labeler may continue use of previously assigned FDA labeler code under a system for the issuance of UDIs – for use in reimbursement numbers
  • New UDI implementation compliance dates
  • UDI Webpage Webpage.JPG




<Guidance posted in June 2016)

APPROPRIATE & RESPONSIBLE dissemination of patient-specific information

  • Recorded, stored, processed, retrieved, and/or derived from medical devices
  • From manufacturers to patients
  • To empower patients to be more engaged with their healthcare providers in making sound medical decisions


  • Any information unique to an individual patient or unique to patient’s treatment or diagnosis
  • May include recorded patient data, device usage/output statistics, healthcare provider inputs, alarms, records of device malfunctions/failures
  • Does not include data interpretations


  1.  Data from healthcare provider to record status and ongoing treatment of patient
  2. Information stored by device to record usage, alarms, or outputs


  • No additional premarket review if consistent with cleared label
  • Does not impact HIPAA Privacy Rule
  • Content:
    • Interpretable and useful to patient
    • Prevent confusing or unclear information that could be misinterpreted
    • Consider  intended audience characteristics that may affect interpretability
    • May provide supplementary information to aid patient understanding
  • Context:
    • Include relevant context to avoid misinterpretation, incorrect conclusions
    • Information on contact for follow-up information – healthcare provider at a minimum.


Drug Safety Labeling Changes


Drug safety.JPG

WHAT: Drug Safety Labeling Changes (SLC) database provides approved safety labeling changes

WHEN: Data from from January 2016 forward. Prior information at MedWatch website.

WHO: CDER’s Office of Communications – OCOMM

WHY:To more efficiently gather, organize and distribute information related to drug safety label changes. Prompt access to  health care providers and consumers to better promote patient health.

HOW: Visit site, Sign up for updates


FDA Approvals, Evaluations: LIGHTMIX ZIKA test, ERELZI biosimilar, TREVO clot retrieval, De Novo Summaries

FDA BRIEF: Week of August 29, 2016

FDA approved


Roche Molecular Systems, Pleasonton, CA, USA

Image result for LightMix Zika test image


INTENDED USE: Real-time RT-PCR test intended for the qualitative detection of RNA from the Zika virus in serum or EDTA plasma from individuals meeting CDC Zika virus clinical criteria (e.g., clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (e.g., history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiologic criteria for which Zika virus testing may be indicated). Testing is limited to CLIA certified  laboratories to perform high complexity tests, or by similarly qualified non-U.S. laboratories

REG PATHWAY: Emergency Use Authorization

TEST PRINCIPLE: Zika virus primers and probe set detects RNA from the Zika virus in serum or EDTA plasma from patients presenting signs and symptoms of the Zika virus infection in conjunction with epidemiological risk factors.


  • LightMix® Zika rRT-PCR Test PSR: Pathogen-specific reagent (PSR) to specifically detect Zika viral RNA
  • LightMix® Zika rRT-PCR Test ivRNA Positive Control: Lyophilized synthetic RNA, designed to react with the LightMix® Zika rRT-PCR Test PSR to indicate whether the LightMix® Zika rRT-PCR Test has worked properly.


  • Negative Process Control, :Negative rRT-PCR Control, Positive Control, Extraction Control


ERELZI (etanercept-szzs) injection

Sandoz Inc., Princeton, NJ, USA

Image result for Erelzi image

INDICATION: Multiple inflammatory diseases

  • moderate to severe rheumatoid arthritis, either as a standalone therapy or in combination with methotrexate (MTX);
  • moderate to severe polyarticular juvenile idiopathic arthritis in patients ages two and older;
  • active psoriatic arthritis, including use in combination with MTX in psoriatic arthritis patients who do not respond adequately to MTX alone;
  • active ankylosing spondylitis (an arthritis that affects the spine); and
  • chronic moderate to severe plaque psoriasis in adult patients (18 years or older) who are candidates for systemic therapy or phototherapy.

PRODUCT DESCRIPTION: Biosimilar to ENBREL (etanercept), which was originally licensed in 1998

REG PATHWAY: Biosimilar pathway – not an interchangeable product.

DATA to demonstrate biosimilarity to Enbrel:

  • Structural and Functional characterization
  • Animal study
  • Human pharmacokinetic and pharmacodynamics
  • Clinical immunogenicity
  • Clinical Safety and Effectiveness data


TREVO clot retrieval devices

Concentric Medical Inc. (Stryker) Mountain View, CA, USA

Image result for trevo clot removal images

INDICATION FOR USE: Clot retrieval devices as an initial therapy for strokes due to blood clots (ischemic) to reduce paralysis, speech difficulties and other stroke disabilities. These devices should be used within six hours of symptom onset and only following treatment with a clot-dissolving drug (tissue plasminogen activator or t-PA), which needs to be given within three hours of symptom onset.


  • ~ 130,000 Americans killed by stroke each year; 85% ischemic strokes
  • Only first-line treatment for acute ischemic stroke was iv t-PA
  • Need for devices alongside t-PA
  • Potential to help further reduce the devastating disabilities associated with strokes compared to t-PA alone
  • Another tool for treating stroke and potentially preventing long-term disability

REG PATHWAY: De Novo. Prior 510(k) clearance in 2012 for patient ineligible for t-PA or failed t-PA therapy.


  • Clot removal device inserted through catheter into blood vessel to blood clot site
  • Shaped section at end fully expanded (3-6 mm diameter), grips clot
  • Clot retrieved by physician


  • Clinical trial, Trevo device (n=96) along with t-PA vs t-PA only (n=-249)
  • Functional independence (no symptoms- slight disability) 3 m0. post-treatment: 29% vs. 19%
  • Risks: Failure to retrieve the blood clot, device malfunctions including breakage and navigation difficulties.


de novo


ImPACT Applications, Inc, Pittsburgh, PA, USA

Image result for impact images


ImPACT is intended for use as a computer-based neurocognitive test battery to aid in the
assessment and management of concussion.
ImPACT is a neurocognitive test battery that provides healthcare professionals with
objective measure of neurocognitive functioning as an assessment aid and in the
management of concussion in individuals ages 12-59.
ImPACT Pediatric is intended for use as a computer-based neurocognitive test battery to
aid in the assessment and management of concussion.
ImPACT Pediatric is a neurocognitive test battery that provides healthcare professionals
with objective measure of neurocognitive functioning as an assessment aid and in the
management of concussion in individuals ages 5-11.


  • De Novo, Class II
  • Regulation Number: 21 CFR 882.1471
  • Regulation Name: Computerized Cognitive Assessment Aid for Concussion
  • Product Code: POM

PRODUCT DESCRIPTION: Prescription device that uses an individual’s score(s) on a battery of cognitive tasks to provide an indication of the current level of cognitive function in response to concussion. The computerized cognitive assessment aid for concussion is used only as an assessment aid in the management of concussion to determine cognitive function for patients after a potential concussive event where other diagnostic tools are available and does not identify the presence or absence of concussion. It is not intended as a stand-alone diagnostic device.


  • User discomfort (e.g., visual or mental fatigue) – Labeling
  • False positive, False negative – Clinical performance testing, Software verification, validation, hazard analysis, Labeling


  • Software, including proprietary algorithm(s): Software requirements specification (SRS) and software design specification (SDS), software verification, validation, and hazard analysis
  • Clinical performance: Device functioning, clinical interpretation, test-retest reliability, inclusion and exclusion criteria, statistical methods and model assumptions
  • Labeling: Clinical testing summary, device functioning, testing summary, warnings, instructions for use


PERMASEAL Apical Closure Device

Micro Interventional Devices, Inc., Newtown, PA, USA

Image result for permaseal apical closure device image

INDICATION FOR USE: Soft tissue approximation of cardiac apical tissue during transcatheter valve replacement procedures.


  • De Novo, Class II
  • Regulation Number: 21 CFR 870.4510
  • Regulation Name: Apical Closure Device
  • Product Code: PNQ

PRODUCT DESCRIPTION: Prescription device consisting of a delivery system and implant component that is used for soft tissue approximation of cardiac apical tissue during transcatheter valve replacement procedures.


  • Infection – Sterilization Validation,  Shelf Life Testing, Labeling
  • Adverse Tissue Reaction – Biocompatibility Evaluation,  In vivo Performance Testing
  • Bleeding – Non-clinical Performance Testing,  In vivo Performance Testing Labeling
  • Tissue Damage – Non-clinical Performance Testing,  In vivo Performance Testing, Labeling, Training
  • New Hypokinesia or Akinesis of Apex – In vivo Performance Testing, Labeling
  • Thromboemboli and Full Thickness Injury – In vivo Performance Testing, Labeling, Training
  • Pericardial TamponadeL In vivo Performance Testing, Labeling


  • Biocompatibility of patient contacting materials
  • Sterility of the patient-contacting components
  • Shelf life by continued sterility, package integrity, and device functionality
  • Non-clinical performance testing of performance
  • In vivo evaluation of performance
  • Labeling