FDA Guidances: Zika, Device Benefit-Risk, Device Patient Preference, Antibacterial Drugs

FDA BRIEF: Week of August 22, 2016

fda guidances


UNIVERSAL TESTING of donated Whole Blood and blood components for Zika virus in the U.S. and its territories.


  • Transfusion-Transmitted Infection (TTI) under 21 CFR 630.3(1)
  • Relevant Transfusion-Transmitted Infection (RTTI) under 21 CFR 630.3(h)(2).

Determination based on

  • severity of disease
  • risk of transfusion-transmission by blood and blood components
  • availability of appropriate screening measures
  • significant incidence and prevalence affecting the potential donor population


  •  Testing and Pathogen Reduction
  • Donor and Product Management
  • Labeling of Whole Blood and Blood Components Intended for Transfusion


PRINCIPAL FDA FACTORS for benefit-risk determinations for PMA and De Novo


  • RASE- Reasonable Assurance of Safety and Effectiveness
  • De Novo devices : May not need to confer as substantial a benefit;  should sufficiently explain  risks-benefits; risks appropriately mitigated by general and/or special controls


  • Clinical: Randomized, well-controlled, in target population
  • Non-Clinical: Performance testing for safety/reliability/characterization, human factors and usability engineering, animal, cell-based studies


  • Type, Magnitude, Probability, Duration


  • Severity, type, number, rate,probability, duration,


  • Uncertainty, Disease characterization, Patient-Centric assessments, Patient Preference, Availability of alternative treatments, Risk Mitigation, Poatmarket data. Novel Technology, Unmet Need




PATIENT PREFERENCE INFORMATION (PPI) can provide a unique and important perspective on benefits-risks of certain medical devices; part of FDA’s Partner with Patients CDRH 2016-2017 Strategic Priority.

  • Definition: Qualitative/Quantitative assessments of relative desirability or acceptability to patients of specified alternatives or choices …
  • Estimates of how much different outcomes valued by patients vs. tradeoffs
  • Only for certain devices :  Direct patient interface, yield significant health and appearance benefits, treat a rare disease, novel technology


  • Voluntary submission for PMA, HDE, De Novo pathways –
  •  Linking to new Benefit-Risk guidance (described above)-  PPI part of totality of evidence from clinical and nonclinical testing
  • Quantitative Methods : Stated preference, Revealed preference
  • Recommended Study Qualities : Patient Centeredness, Generalizability, Heterogeneity, Good Research Practices, Benefit/Harm/Risk/Uncertainty Communication,  Cognitive Bias, Relevance, Robustness of Analysis, Study Conduct, Comprehension by Study Participants:
  • Additional Considerations:   Integrity,  Conditions of Approval
  • FDA Engagement and Submission: Pre-Submission meeting discyussion, Labeling

EXAMPLES are provided





ANTIBACTERIAL DRUG DEVELOPMENT and  development, analysis, and presentation of microbiology data


  • Antibacterial Spectrum of Activity
  • Mechanism of Action
  • Intracellular Antimicrobial Concentration Assessment
  • Resistance Studies
  • In Vitro Antimicrobial Susceptibility Test Methods During Drug Development


  • Provisional Antibacterial Susceptibility Test Interpretive Criteria
  • Establishing In Vitro Antibacterial Susceptibility Test Interpretive Criteria
  • Quality Control Parameters


  • First and Second Lists of Target Bacteria in Labeling
  • Antibacterial Interactions and Fixed Combination Studies
  • Additional Nonclinical Studies of Antibacterial Drugs
  • Animal Models of Infection
  • Microbiology Information Collected in Clinical Trials
  • Electronic Submission of Microbiology Information
  • Postmarketing Microbiology Information










FDA Reviews, Approvals: iPRO2 monitor, iMPACT cognitive test

FDA BRIEF: Week of Aug 22, 2016

FDA approved

iPro2 Continuous Glucose Monitoring System 

Medtronic MiniMed, Northridge, CA, USA


Image result for iPro2 Continuous Glucose Monitoring System image

INDICATION FOR USE: The iPro2 Recorder is to be used with either Enlite sensor or Sof-Sensor and is intended to continuously record interstitial glucose levels in pesons with diabetes mellitus.

This information is intended to supplement, not replace, blood glucose information obtained using a standard home glucose-monitoring device.

The information collected by the iPro2 Recorder may be uploaded to a computer (with Internet access) and reviewed by healthcare professionals.

This information may allow identification of patterns of glucose level excursions above or below the desired range, facilitating therapy adjustments which may minimize these excursions.


PMA. The iPro2 CGM system previously approved for use with the Sof-sensor . This approval is for use with  Enlite sensor.

Device Procode: MDS

Classification: Sensor, Glucose, Invasive


(1) iPro2 Digital Recorder

  • Portable electrical current meter, data storage, and wired data communication system
  • Continuous glucose recorder (measure, process, store, and upload glucose data ) for use under a physician’s direction
  • Intended only for retrospective review and analysis by a healthcare professional

(2) Enlite Sensor

  • Single-use, disposable component, to continuously monitor glucose levels
  • Inserted into subcutaneous tissue  with sensor insertion device
  • Connects to the iPro2 Digital Recorder to permit continuous glucose recording


Based on : (1) Pre-clinical bench testing results and (2) Re-analysis of clinical data

  • Tests performed: Environmental exposure, functional testing, electro-magnetic compatibility (EMC), biocompatibility, cleaning/disinfection, packaging/shelf-life, software verification and validation, and human factors/usability
  • Bench testing data confirmed system capability of sensing, storing, and uploading data


Based on post-market data (MDR analysis) and non-clinical data

  • CGM values masked – User cannot make treatment decisions
  • Device-related, non-serious: Local infection, Skin inflammation, Pain or discomfort, Bleeding, Bruising, Itching, Scarring or skin discoloration, Allergic reactions to adhesive, Sensor or needle fracture during insertion, wear or removal


ImPACT computerized cognitive test & ImPACT Pediatric

ImPACT Applications, Pittsburgh, PA, USA

Image result for impact images

INTENDED USE: Assess cognitive function following a possible concussion. They are intended as part of the medical evaluation that doctors perform to assess signs and symptoms of a head injury.


  • > 2 million emergency room visits  due to traumatic brain injuries;  50,000 deaths
  • Significant number of  injuries are mild – ‘concussion’
  • Need for tool to aid in the evaluation of patients experiencing possible signs of a concussion
  • But clinicians should not rely on these tests alone to rule out a concussion or determine whether an injured player should return to a game

REG PATHWAY: De Novo, Class II


  • ImPACT software runs on desktop or laptop for ages 12 to 59
  • ImPACT Pediatric runs on an iPad for ages 5 to 11
  • Licensed health care professionals perform test and interpret the results.
  • Test cognitive skills such as word memory, reaction time and word recognition, all of which could be affected by a head injury
  • Results compared to an age-matched control database or to a patient’s pre-injury baseline scores, if available.


  • 250 peer-reviewed articles, half were independently conducted clinical research studies
  • Analyzed devices’ validity, reliability and ability to detect evidence of cognitive dysfunction that might be associated with a concussive head injury


FDA-CDC Free Webinars

Heater-Cooler Device

WHAT: Free Continuing Education Webinars from CDC for Healthcare Providers. CE is available! There are no fees for CE.

WHEN: August 29, 2016 : Invasive Nontuberculous Mycobacterium Infections Associated with Exposure to Heater-Cooler Units during Cardiac Surgery

WHY: Recent reports of suggest that heater-cooler units used in cardiopulmonary bypass procedures, are putting patients at risk for invasive nontuberculous mycobacterium (NTM) infections. CDC offering expert panel to discuss

  • Evidence
  • Clinical manifestations, diagnosis, and treatment strategies
  • Risk identification and mitigation strategies


FDA Review: Obesity Medical Devices

FDA BRIEF: Week of August 15

Medical Devices that Treat Obesity

losing weight together (350x233)

Currently,  4 types of devices FDA approved for patients age 18 and older

Gastric Bands

  • Surgically implanted around the stomach
  • Limit amount of food that can be eaten

Electrical Stimulation System

  • Surgically implanted into abdomen to block brain-stomach nerve activity
  • Specific reasons for weight loss

Gastric Balloons

  • Temporary devices that fill stomach space

Gastric Emptying System

  • Tube placed in stomach via endoscope
  • Port lies against skin of the abdomen to drain portion of stomach contents

Risks vary for each device but can include nausea or vomiting, bleeding, or infection.


FDA Approvals and Reviews: SAPIEN Heart Valves, ZIKV Detect

FDA BRIEF: Week of August 15, 2016

FDA approved

SAPIEN XT and SAPIEN 3 Transcatheter Heart Valves 

 Edwards Lifesciences, Irvine, CA, USA

Edwards Sapien 3


Relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis who are judged by a heart team, including a cardiac surgeon, to be at intermediate or greater risk for open surgical therapy (i.e., predicted risk of surgical mortality ≥ 3% at 30 days, based on the Society Thoracic Surgeons (STS) risk score and other clinical co-morbidities unmeasured by the STS risk calculator).


  • Aortic valve stenosis increases with age –  need for heart valve replacement to improve blood flow through their aortic valve
  • Gold standard –  open-heart surgery.  ~ 30% patients at “intermediate risk”
  • Transcatheter aortic valve replacement (TAVR) minimally invasive procedure
  • First time in  U.S. for a transcatheter aortic valve  use in intermediate risk patients
  • Significantly expands access to patients for less invasive procedure


  • PMA approved in 2015
  • Supplemental PMA for expanded indication
  • Priority Review status because availability is in the best interest of the patients


  • First Study: Randomized, intermediate risk aortic stenosis patient, SAPIEN3 TAVR (n=1,011) vs traditional aortic valve replacement during open-heart surgery (n=1,021)
  • Second study : Intermediate risk patients (n=1,078)  implanted with the Sapien 3 vs.  surgical control patients in study 1
  • Primary endpoint:  Non-hierarchical composite of all-cause death, all stroke, or aortic insufficiency (AI) ≥ moderate at 1 year.s 13.0% vs. 23.2%
  • Sapien 3 group showed significantly lower rates of mortality (1.1%), disabling stroke at 30 d (1.0%), and moderate or severe aortic regurgitation after one year
  • Also improvement in valve hemodynamics  – improvements in 6MWT distance, NYHA classification and QoL


  • Potential risk: Serious complications from device/implantation procedure, such as death, stroke, acute kidney injury, heart attack, bleeding, and the need for a permanent pacemaker
  • Contraindication: Patients who cannot tolerate blood thinning medication, being treated for a bacterial or other infection

POST-APPROVAL REQUIREMENT: Monitor safety and effectiveness in patients in both studies for 10 years.



Zika Virus Emergency Use Authorization

Vials of flu vaccine

ZIKV DetectTM IgM Capture ELISA

InBios International, Seattle, WA, USA

INTENDED USE: Presumptive detection of Zika virus IgM antibodies in human sera collected from individuals meeting CDC Zika virus clinical criteria  and/or CDC Zika virus epidemiological criteria. Intended for use in US CLIA certified laboratories, or by similarly qualified non-U.S. laboratories

REG PATHWAY: Emergency Use Authorization (EUA)


  • Uses purified antibody specific for human IgM that is immobilized on a test plate to capture IgM antibodies from human specimen
  • Kit contains:  Coated Microtiter Test Strips for IgM, ZIKV Sample Dilution Buffer, Ready-To-Use ZIKV Recombinant Antigen for IgM (Zika Ag), Cross-reactive Control Antigen for ZIKV IgM (CCA),  Normal Cell Antigen for ZIKV IgM,  100X Conjugate, Conjugate Diluent for ZIKV,  10X Wash Buffer, Liquid Tetramethylbenzidine Substrate, Stop Solution, ZIKV IgM Positive Control:&  ZIKV IgM Negative Control


  • Possibility of false positive results
  • Additional testing and/or consideration of test results for other patient-matched specimens, using the latest CDC guideline





Web-based Orange book, HIPAA @ 20


WHAT: Web-based version of the Orange Book, which identifies drug products approved on the basis of safety and effectiveness by the FDA, first appeared as a published list in October 1980.

WHY: Updated design with new, user-friendly search options that help users customize their research experience.

HOW :  Redesigned web page conveniently collects search and browse options onto the home page to improve access of these commonly used features.



WHEN: August 21, 1996, a bipartisan legislation called the Health Insurance Portability and Accountability Act or HIPAA

WHAT:  More than medical privacy and security law.  Allows transfer and continue health insurance after change or job loss – under Consolidated Omnibus Budget Reconciliation Act (COBRA). Further developed to Affordable Care Act (ACA) amendment and expansion of original HIPAA consumer protections.


FDA Guidances: Bipolar Electrosurgical Vessel Sealers, Electrosurgical Devices, CDER 2016 guidances

FDA BRIEF: Week of August 8, 2016

fda guidances



Bipolar electrosurgical vessel sealers are designed to seal isolated blood and lymphatic vessels for hemostasis (as an alternative to ties) through the use of high-frequency electrical current between two electrodes in close proximity.

CONTENT: 510(k) submissions for  intended for use in general surgery.

  • Device Description: Indications for Use, Device Design
  • Substantial Equivalence Comparison:  Indications for Use, Electrosurgical Unit (ESU), Active Components/Accessories, Miscellaneous Accessories, Vessels
  • Performance Data: ESU,  Active Components/Accessories,  Miscellaneous Components/Accessories, System Testing, Chronic Animal Study
  • Clinical Testing
  • Labeling:  Instructions for Use (User Manual), Device Labels, Package, Special Components



Electrosurgical devices intended for use in general surgery are designed to cut and/or remove tissue and control bleeding through the use of highfrequency electrical current. Devices may also be called radiofrequency (RF) devices or high-frequency (HF) devices.

GUIDANCE:  510(k) submissions for  intended for use in general surgery.

  • Device Description.: Indications for Use,  Device Design
  • Substantial Equivalence Comparison
  • Software
  • Biocompatibility
  • Sterility.
  • Reprocessing.
  • Pyrogenicity
  • Shelf Life
  • Performance Data: ESU, Active Components/Accessories, Neutral Electrodes,  Miscellaneous Components/Accessories System Testing
  • Electrical Safety and Electromagnetic Compatibility
  • Clinical Testing
  • Labeling






  • Advertising: e.g. Health Care Economic Information in Labeling and Advertising,  Internet/Social Media Advertising , Presenting Risk Information in Prescription Drugs and Medical Devices Promotion; Revised Draft
  • Biopharmaceutics: e.g. Bioavailabiolity/Bioequivalence studies, food effect
  • Biosimilarity:  e.g. Interchangeability, Labeling, Statistical Approaches
  • Clinical/Antimicrobial: e.g.  Inhalation Anthrax, HIV-1 Infection, Bacterial Vaginosis, Chronic Hepatitis C,  Herpes Labialis, Vulvovaginal Candidiasis
  • Clinical/Medical: e.g. Allergic Rhinitis, Exocrine Pancreatic Insufficiency,  Natural History Studies for Rare Disease,  Nonallergic Rhinitis, Pediatric Oncology , Pregnant Women in Clinical Trials,  Varicose Vein,  Ulcerative Colitis
  • Clinical Pharmacology: e.g. Drug Interactions,Lactation Trials,  In vitro Metabolism-and-Transporter Mediated,  Impaired Renal Function, Pregnancy and the Postpartum Period,  Population Pharmacokinetics
  • Labeling : e.g. Child Resistant Closures, Gluten, Hormonal Contraceptives
  • Pharmaceutical Quality/CMC: e.g. Immunogenicity Testing,  Comparability Protocols,  Elemental Impurities, Compendial Standards,  Abuse Deterrent Properties
  • Pharmaceutical Quality/Manufacturing Standards (CGMP)
  • Pharmacology/Toxicology
  • Procedural


DEA Actions: Marijuana Rescheduling, Industrial Production for R&D

FDA BRIEF: Week of August 8, 2016



DENIAL : Petitions to Reschedule Marijuana

  • 2 petitions to reschedcule marijuana from Schedule I (high abuse risk, no therapeutic value) to Schedule II (high abuse risk, with therapeutic value) based on:
    • Accepted medical use in US
    • Safe for use under medical supervision

    • Low abuse potential for medical use

  • DEA consulted with FDA and NIDA on scientific evaluation of efficacy/safety and scheduling recommendation
  • DENIED rescheduling requests:
    • Marijuana has a high potential for abuse. Based on additional data gathered by DEA

    • Marijuana has no currently accepted medical use in treatment in US. Chemistry is not known and reproducible; no adequate studies on safety and efficacy; not accepted by qualified experts, scientific evidence is not widely available

    • Marijuana lacks accepted safety for use under medical supervision. No FDA-approved marijuana product, no NDA under FDA review. Known risks outweighed by specific benefits in well-controlled clinical trials that scientifically evaluate safety and efficacy

  • Product needs to be approved by FDA prior to rescheduling

Federal Register responses  READ  AND READ

INCREASE: Number of Authorized Marijuana Manufacturers Supplying Researchers

  • Policy change to expand DEA- registered marijuana manufacturers
  • Consistent with the CSA and U.S. treaty obligations
  • Allow additional entities for DEA registration to grow and distribute marijuana
  • Facilitate research and development of products


FDA Views: Pre-RFD for Combination Products, Naloxone Access, Cardiovascular Medicine future, Zika Safety, BIA 10-2474

FDA BRIEF: Week of August 8, 2016


Making Continuous Improvements in the Combination Products Program: The Pre-Response For Designation (RFD) Process

Thinh Nguyen, Director, Office of Combination Products

Rachel E. Sherman, M.D., M.P.H., FDA’s Associate Deputy Commissioner 

Thinh Nguyen

Rachel Sherman

Agency making changes to internal procedures for responding to RFD communications from Office of Combination Products (OCP)

  • Pre-RFD process: Similar to RFD process;  OCP’s goal for Pre-RFDs  to respond to sponsors within 60 days following
  • Can be used at any point during medical product development
  • FDA preliminary feedback based on structured and efficient process


FDA Supports Greater Access to Naloxone to Help Reduce Opioid Overdose Deaths

By: Karen Mahoney, M.D., Deputy Director, Division of Nonprescription Drug Product

Overdose deaths involving prescription opioids tripled since 1999 –28,000 deaths in 2014

Tragedies avoided with immediate administration of  naloxone (injection, nasal spray) to stop or reverse overdose effects

FDA is exploring options to make naloxone more available: FDA’s opioid action plan 

  • Pursue approval of OTC naloxone product
  • Label with consumer-friendly instructions
  • Label comprehension testing


The Future of Cardiovascular Medicine From the Regulatory Perspective 

By: Robert M. Califf, MD

The field of cardiovascular medicine has been an exemplary partner with the FDA

Entering  new era in medicine characterized by dramatic accelerations in biological and information sciences and near-ubiquitous uptake of social media and personal devices

Need for integration of complex measurement and decision support with traditional devices, drugs, and biologics. Must involve entire ecosystem of which the FDA is a part. Efforts in:

  • Evidence Generation
  • Phenotyping
  • Integrative Biomarkers And Monitoring
  • Targeted Therapy
  • Devices
  • Regenerative Medicine
  • Nutrition And Diet
  • Lifecycle
  • Disparities

FDA Working to Keep the U.S. Blood Supply Safe from Zika and other Emerging Threats

 By: Peter Marks, M.D., Ph.D., Director, CBER

Luciana Borio, M.D., Acting Chief Scientist


  • Top priority to help assure that the blood supply is safe
  • Close collaboration with other government agencies, e.g. Centers for Disease Control and Prevention (CDC), and non-governmental partners, e.g. blood collection establishments and screening test developers.
  • Recommendations to reduce the risk of its transmission through blood
  • Working with manufacturers to speed development of Zika screening tests
  • Working with the Biomedical Advanced Research and Development Agency (BARDA) to facilitate evaluation of tests and other measures




First phase 1 clinical trial of BIA 10-2474, fatty acid amide hydrolase (FAAH) inhibitor

  • In France in Jan 2016
  • One death
  • Five hospitalization – Four with neurological injury

FDA received information from European Medicines Agency (EMA) and French national medicines agency (ANSM)

  • Comprehensive review of safety information
  • BIA 10-2474 exhibits a unique toxicity that does not extend to other FAAH drugs
  • No BIA 10-2474 trials in US;  will establish the appropriate path forward for FAAH inhibitors under investigation in the U.S.



FDA BRIEF: Week of August 8, 2016

FDA approved

KEYTRUDA (pembrolizumab) injection

Merck Sharp & Dohme Corp. Whitehouse Station, NJ, USA

SUPPLEMENTARY INDICATION:  Treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy


REG PATHWAY: Supplementary BLA, Accelerated Approval, Priority Review


  • Single multicenter, nonrandomized, open-label, multicohort study(n=174, HNSCC)
  • KEYTRUDA, 10 mg/kg every 2 weeks or 200 mg every 3 weeks,  until unacceptable toxicity or disease progression
  • Major efficacy outcome measures: Objective Response Rate ( ORR), RECIST 1.1 and Duration of Response
  • ORR : 16% (95% CI: 11, 22) with a complete response rate of 5%
  • Median Duration of Response had not been reached (range 2.4+ to 27.7+ months)
  • Continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials


  • Most common adverse reactions: Fatigue, decreased appetite, and dyspnea
  • Similar to previously approved indications of melanoma or NSCLC
  • Increased incidence of facial edema (10% all grades, 2.1% grades 3-4), new or worsening hypothyroidism (14.6% all grades).


SUSTOL (granisetron) extended-release injection

Heron Therapeutics, Redwood City, CA, USA

INDICATION: ndicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

REG PATHWAY: NDA, 505 (b)(2). Initial applications rejected in 2010, 2013.

MECHANISM OF ACTION: Selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist Blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin.


  • Randomized, multicenter, double-blind, parallel group study (n=733), SUSTOL vs. palonosetron hydrochloride, cancer patients with MEC or AC
  • Primary Endpoint:  Complete Response defined as no emetic episodes and no use of rescue medications.
  • Non-inferiority of SUSTOL to palonosetron hydrochloride in acute and delayed phases of MEC and of AC combination chemotherapy

SAFETY: Injection Site reactions, gastrointestinal disorders, hypersensitivity reactions, serotonin symdrome









WHAT: Work collaboratively  with a network of 250 hospitals, nursing homes and home health facilities in US


WHY: To assist in detecting, understanding, and sharing information on safety of devices

WHEN: Launched in 2002

HOW: Secure, on-line system for reporting problems with the use of medical devices.




FDA Guidance: IRBs, 510(k)s for device change/software change

FDA BRIEF, Week of August 1, 2016

fda guidances


Prepared by : Office for Human Research Protections (OHRP) and FDA

For: IRBs and institutions responsible for review and oversight of human subject research

Required Written procedures:

  • Conducting initial and continuing review of research
  • Reporting findings and actions to investigator/institution
  • Determining which projects require review more often than annually
  • Determining which projects need verification from sources other than investigator
  • Ensuring prompt reporting to the IRB of proposed changes in a research activity
  • Ensuring prompt reporting to the IRB, OHRP, FDA of any unanticipated risks, noncompliance,  suspension or termination of IRB approval

IRB Written Procedures Checklist 



510k changes.JPG

Clarify: When a  medical device change would trigger submission a new premarket notification – 510(k)

Guiding Principles:

  • Modifications significantly affect safety or effectiveness
  • “Could significantly affect” evaluation and the role of testing
  • Unintended consequences of changes
  • Use of risk management
  • Evaluating simultaneous changes
  • Appropriate comparative device and cumulative effect of changes
  • Documentation requirement
  • Submissions for modified devices
  • Substantial equivalence determinations

Considerations for:

  • Labeling changes
  • Technology, Engineering, Performance changes, Materials Changes for In Vitro Diagnostic Devices
  • Risk Assessments of Modified Devices

Flowcharts provided

WEBINAR  on Aug 25th



Clarify: When a software (including firmware) change to a 510(k)-cleared device may require new 510(k)

Software modifications:

  •  Adaptive – modification of software to keep it usable in a changed or changing 197 environment
  • Corrective – reactive modification of software to address discovered faults
  • Perfective – modification of software to improve performance or maintainability.

Guiding Principles:

  • Modifications significantly affect safety or effectiveness
  • “Could significantly affect” evaluation and the role of testing
  • Unintended consequences of changes
  • Use of risk management
  • Evaluating simultaneous changes
  • Appropriate comparative device and cumulative effect of changes
  • Documentation requirement
  • Submissions for modified devices
  • Substantial equivalence determinations


  • Solely to strengthen cybersecurity
  • Solely to return system into specification of the most recently cleared device
  • Introduce a new cause or modify an existing cause of a hazardous situation
  • Introduce a new hazardous situation or modify an existing hazardous situation
  • Create or necessitate a new risk control measure or modification of existing measure
  • Significantly affect clinical functionality or performance specifications associated with intended use

Common Software Change Types: Infrastructure, Architecture, Algorithm, Core algorithm, Clarification of Requirements – No change to Functionality, “Cosmetic Changes – No change to Functionality, “Reengineering” and “refactoring”


Flowcharts and Examples provided

WEBINAR  on Aug 25th



FDA Views: Intercenter Consult, Clinical Holds, CDER Co-Sponsorship, 2017 MDUFA Fees

FDA BRIEF: Week of Aug 1, 2016



Piloting an Improved Intercenter Consult Process


Michael Rappel, Ph.D., Senior Science Advisor, CDER and Member, Lean Management Team

Rachel E. Sherman, M.D., M.P.H., Associate Deputy Commissioner 

Michael Rappel

Rachel Sherman

FDA’s efforts to improve review of combination product (combine drugs, devices, and/or biological products)

Important ICCR improvements:

  • Establishing timelines for consults
  • Streamline and Optimize interactions across centers
  • Clear roles and responsibilities for Lead Center, Consulted Center(s), Office of Combination Products (OCP), and Combination Product Council
  • User-friendly ICCR form t.

Continuous learning:

  • Collect quantitative and qualitative data to evaluate success
  • Refine ICCR process
  • ICCR pilot  comprised of three phases, phase 1 planned for two months
  • Iterative approach to ensure robust process

Feedback appreciated: combinationproductICCRpilot@fda.hhs.gov.


How do clinical holds impact drug development programs?

by: Larissa Lapteva, M.D., CDER


Larissa Lapteva, M.D.


Do clinical holds impact drug development – especially potential treatments for rare diseases?

Q/A with Dr. Lapteva

Investigational Drug Application( IND):  By companies/academia to test investigational drug effects

Clinical Hold:  If FDA finds issues with safety or quality; hold will last until sponsor adequately addresses all issues

FDA’s research into clinical holds:

  • Objective and informative assessment to identify and avoid common pitfalls
  • Clinical holds not frequent; ~ 9% INDs
  • Off Hold : >50% within 1 yr; . ~76% rare disease INDs  vs. 40% for common disease
  • Most common deficiencies: Quality issues, clinical, toxicology issues
  • Similar issues for  rare vs. common diseases
  • Recommended Reg strategies: Read applicable guidances, Early FDA communication



  • CDER engages in not-for-profit events (including conferences, meetings, symposia, webinars, and workshops) co-sponsored with organization(s)
  • Provide relevant expertise and share a mutual interest and benefit in the subject matter
  • May participate as a  speaker




  • The Medical Device User Fee Amendments (MDUFA) require payment of user fee for  medical device applications
  • Fees are lower compared to FY2016  fees 
  •  “small business” (sales no more than $100 million/yr) eligible for reduction in fees
  • guidance for “foreign business”





FDA Approvals & Reviews: TAMIFLU generic, CDRH PMA Summaries

FDA BRIEF: Week of Aug 1, 2016

FDA approved


TAMIFLU (oseltamivir phosphate) First GENERIC version

Natco Pharma , Pine Brook, NJ, USA

INDICATION:  Treatment of acute, uncomplicated illness due to influenza A and B infection in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours.


  • Tamiflu approved in 1999
  • First generic approved based on same high-quality and strength as branded Tamiflu




AXIUM Neurostimulator System
Spinal Modulation, Menlo Park, CA, USA
Approval Date: February 26, 2016

Image of Axium Neurostimulator System

INDICATION FOR USE: Spinal column stimulation via epidural and intra-spinal lead access to the dorsal root ganglion as an aid in the management of moderate to severe chronic intractable pain of the lower limbs in adult patients with Complex Regional Pain Syndrome (CRPS) types I and II  SUMMARY

BLAZER  Open-Irrigated Ablation Catheter
Boston Scientific Corporation, San Jose, CA, USA
Approval Date: February 24, 2016

Image of Blazer Open-Irrigated Ablation Catheter

INDICATION FOR USE:Hhen used with a Maestro 4000 Radiofrequency (RF) Controller and MetriQ Irrigation Pump, is indicated for cardiac electrophysiological mapping, delivering diagnostic pacing stimuli and radiofrequency ablation of sustained or recurrent Type 1 Atrial Flutter in patients age 18 or older.  SUMMARY

SORIN PERCEVAL Sutureless Heart Valve
Sorin Group Canada Inc., Bumaby, BC, CANADA 
Approval Date: January 8, 2016

Image of Sorin Perceval Sutureless Heart Valve

INDICATION FOR USE: Bioprosthesis  indicated for the replacement of diseased, damaged, or malfunctioning native or prosthetic aortic valvesSUMMARY

STORZ Medical Duolith SD1 Shock Wave Therapy Device
Storz Medical AG, Tagerwilen, Switzerland
Approval Date: January 8, 2016

Image of Storz Medical Duolith SD1 Shock Wave Therapy Device

INDICATION FOR USE: Extracorporeal shock wave treatment of heel pain due to chronic proximal plantar fasciitis for patients of age greater than 18 years with a history of failed alternative conservative therapies for at least 6 months. Chronic proximal plantar fasciitis is defined as traction degeneration of the plantar fascial band at the origin on the medial calcaneal tuberosity that has persisted for six months or more. SUMMARY

OMNIGRAFT Dermal Regeneration Matrix
Integra LifeSciences Corporation, Plainsboro, NJ, USA 
Approval Date: January 7, 2016

INDICATION FOR USE: Treatment of partial and full-thickness neuropathic diabetic foot ulcers that are greater than six weeks in duration, with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care. SUMMARY

CLOSER Vascular Sealing System (VSS)
Rex Medical, Conshohocken, PA 
Approval Date: February 12, 2016

Photo of Closer Vascular Sealing System

INDICATION FOR USE: Percutaneous closure of femoral arterial access sites while reducing times to hemostasis and ambulation in patients who have undergone diagnostic or interventional endovascular catheterization procedures utilizing 5, 6, or 7Fr procedural sheaths. SUMMARY

PD-L1 IHC 28-8 pharmDx
Dako North America, Carpinteria, CA, USA
Approval Date: January 22 , 2016

Image of PD-L1 IHC 28-8 pharmDx

INDICATION FOR USE: Qualitative immunohistochemical assay using Monoclonal Rabbit Anti-PD-L1, Clone 28-8 intended for use in the detection of PD-L1 protein in formalin-fixed, paraffin-embedded (FFPE) melanoma tissue using EnVision FLEX visualization system on Autostainer Link 48. PD-L1 protein expression is defined as the percentage of tumor cells exhibiting positive membrane staining at any intensity.

PD-L1 expression as detected by PD-L1 IHC 28-8 pharmDx in non-squamous NSCLC may be associated with enhanced survival from OPDIVO ® (nivolumab).

Positive PD-L1 status as determined by PD-L1 IHC 28-8 pharmDx in melanoma is correlated with the magnitude of the treatment effect on progression-free survival from OPDIVO® SUMMARY

FDA Device Guidances: Real-World Evidence, UDI, Adaptive Design, General Wellness

FDA BRIEF: Week of July 29, 2016

fda guidances



Real-World Data (RWD): Data collected from sources outside of traditional clinical

Real-World Evidence (RWE): Evidence derived from aggregation and analysis of
RWD elements.

FDA’s National Evaluation System leverages RWD to identify safety problems, to better understand the benefit-risk profile, reduce the time and cost of evidence generation


  • Of sufficient quality to provide confidence in analyses for regulatory decision making
  • May be used in total product life cycle e.g. generating clinical study hypotheses, historical control, concurrent control group, expand labeling, public health surveillance


  • Relevance: Ddata adequately addresses applicable regulatory question/ requirement
  • Reliability: Data accrual, Data adequacy, Data assurance

Comment period : End October.




Defines expected content and forms of the Unique Device Identifier (UDI) to assist both labelers and FDA-accredited issuing agencies

UDI Rule:

  • Create a standardized identification system for medical devices in US
  • Adequately identify devices through distribution and use

UDI Forms:

  • Easily readable plain-text
  • AIDC

UDI Content, Data delimiters

Comment period: End September




How to plan and implement adaptive designs for clinical studies when used in medical device development programs

Adaptive Designs:

  • prospectively planned modifications based on accumulating study data without undermining the study’s integrity and validity
  • efficient, saving time, money, and resources
  • can improve the chance of trial success by employing sample size reassessment
  • may facilitate transition from premarket to postmarket follow-up
  • can enhance patient protection
  • can include a plan to modify the patient population during the study
  • can improve decision-making at milestones
  • Limitations: more effort at the design stage, can introduce operational or statistical bias, may confound the interpretation,


  • control of the chance of erroneous conclusions (positive and negative)
  • minimization of operational bias

Adaptations Using Unblinded Data:

  • Group Sequential Designs, Sample Size Reassessment, Bayesian Sample Size Adaptation,  Group Sequential Designs etc.

Special Considerations:

  • Not Preplanned chnages, Simulations, Safety Endpoints,  Open-Label Randomized Studies, Observational Comparative Studies, One-Arm Studies without a Control


  • Data Monitoring Committees,  Minimize Operational Bias, IRBs, Logisitcs

Regulatory Considerations:

  • FDA interactions, Sponsor Monitoring, Protect Study Blinding



POLICY for low risk general wellness products

CDRH does not intend to examine

  • whether they are devices
  • whether they comply with the premarket review and post-market regulatory requirements for devices
  • whether they are implementing regulations : registration and listing, premarket notification, labeling, good manufacturing practice,  Medical Device Reporting

Must meet factors

  • intended for only general wellness use AND
  • present a low risk to the safety of users and other persons

Intended Use

  • Maintaining or encouraging a general state of health or a healthy activity
  • Relates the role of healthy lifestyle with helping to reduce the risk or impact of certain chronic diseases or conditions


Sustaining or offering general improvement to functions with general health

  • weight management, physical fitness, relaxation or stress management, mental acuity, self-esteem, .sleep management, sexual function

Sustaining or offering general improvement to functions associated with a general state of health while making reference to diseases or conditions

  • may help to reduce the risk of certain chronic diseases or conditions
  • may help living well with certain chronic diseases or conditions

QUESTIONNAIRE to determine fit






FDA Approvals/Final Orders: ADLYXIN, VIEKIRA XR, CYPASS, Iontophoresis Devices

FDA BRIEF: Week of July 29, 2016

FDA approved

ADLYXIN (lixisenatide) injection

Sanofi Aventis, Bridgewater, NJ, USA

Add Alt Text Here

INDICATION: Adjunct to diet and exercise for the treatment of adults with type 2 diabetes.


  • > 29 million , >90% diabetes cases in US
  • Can increase the risk for serious complications, including heart disease, blindness and nerve and kidney damage.
  • Need to add to available treatment options to control blood sugar levels

REG PATHWAY: Standard review. Post-marketing studies required – Pediatric, Immunogenicity.

MECHANISM OF ACTION: Glucagon-like peptide-1 receptor agonist (GLP-1 RA). GLP-1  suppresses glucagon secretion from pancreatic alpha cells and stimulate glucose-dependent insulin secretion by pancreatic beta cells. Increases glucose-dependent insulin release, decreased glucagon secretion, and slows gastric emptying.


  • GetGoal clinical program:  13 clinical trials,  5,400 patients with type 2 diabetes
    • Standalone therapy and in combination with other FDA-approved diabetic medications, including metformin, sulfonylureas, pioglitazone and basal insulin.
    • Primary efficacy endpoint of HbA1c reduction – Achieved
  • Cardiovascular Outcomes Trial: > 6,000 patients with type 2 diabetes at risk for atherosclerotic cardiovascular disease

    • Adlyxin vs. placebo

    • No increase the risk of cardiovascular adverse events


  • Severe hypersensitivity reactions, including anaphylaxis
  • Most common side effects: Nausea, vomiting, headache, diarrhea and dizziness.

 VIEKIRA XR (dasabuvir, ombitasvir, paritaprevir and ritonavir) tablets



INDICATION:  Treatment of patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection, including those with compensated cirrhosis (Child-Pugh A).

NEW FORMULATION: Extended-release co-formulation of the active ingredients in VIEKIRA PAK® (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets)

REG PATHWAY: Approval based on comparability of bioavailability for each of the components in VIEKIRA XR compared to that of the previously approved formulations in VIEKIRA Pak.


  • Components  studied in 7 Phase 3 clinical trials, n=1076
  • 95-100%  achieved SVR12, hepatitis C virus is not detectable in the blood three months after treatment ends



CYPASS System (Model 241-S)

Alcon Laboratories, Inc., Fort Worth, TX, USA

Image of the device. The Micro-Stent illustrates its 6.35mm length, three retention rings, proximal collar, and lumen. The applier (model 241-S) illustrates its front button (retracts guidewire), guidewire tube, guidewire, and rear button (extends guidewire).

INDICATION FOR USE: Minimally invasive glaucoma surgical device (MIGS) approved for use in combination with cataract surgery. ThE device helps to reduce intraocular pressure (IOP) in adult patients with mild to moderate primary open-angle glaucoma (POAG).



  • Small stent (CyPass Micro-Stent) contained within a loading device, and a stent delivery tool (CyPass® Applier).
  • Designed for placement in the angle of the eye, with the proximal end extending into the anterior chamber (AC), and the distal end residing in the supraciliary space
  • Allows outflow of fluid from the AC through the distal end into the supraciliary and suprachoroidal spaces.



  • Clinical trail in patients diagnosed with POAG (n=505)
  • Iimplanted with the CyPass® (n=74) vs. cataract surgery alone (n= 131 )
  • Primary Endpoint: % patients with 20%reduction in mean diurnal IOP  for 24 months after implantation.
  • Significant lowering of their IOP: 72.5 % vs. 58%; maintined in 2 year followup


  • Most serious AEs: Hypotony maculopathy, peripheral anterior choroidal effusion, intraocular lens (IOL) subluxation and corneal compromise
  • Most common safety concerns: Bleeding, inflammation, and damage to angle tissue (i.e., iridodialysis, larger than expected cyclodialysis cleft, ciliary body edema)
  • No reports: Loss of light perception, endophthalmitis, suprachoroidal hemmorrhage, diplopia, wound leak, flat anterior chamber, or bleb complications



Final Order:

  • Class II (special controls)
  • reclassify iontophoresis devices intended for any other purpose
  • Not covered: Devices intended to deliver  specific drugs
  • Required Performance Testing and Labeling



FDA Views: Orphan Drug Designation, Patient Representative Voice, Clinical Trial Diversity

FDA BRIEF: Week of July 29, 2016


The Rise in Orphan Drug Designations: Meeting the Growing Demand 

by: Gayatri Rao, M.D., J.D., Director for The Office of Orphan Products Development

Dr. Gayatri Rao

Rare Disease drug development became reality with Orphan Drug Act in 1983

  •  Orphan Drug Designation Program
  • Financial incentives to encourage companies
  • Major tax credits to defray the cost of clinical trials
  • Seven years of market exclusivity
  • No user fee

Continued growth of  FDA’s Office of Orphan Products Development – 30% increase in 2016 vs. 2015

  • Strive to review 75%  designation requests within 90 days
  • Designated drugs need to satisfy criteria for designation and the financial incentives

Sponsors play a critical role in ensuring high quality and complete designation requests


The Unique Voices of Our Patient Representatives

by: Robert M. Califf, M.D., Commissioner &  Heidi C. Marchand, Pharm.D., Assistant Commissioner, Office of Health and Constituent Affairs

Robert Califf

Heidi Marchand

Patient Representative Workshop

  • Met with 21 inspirational patients and patient caregivers who are FDA patient representatives
  • Patients add context and content to the science – important in regulatory decision-making
  • Include perspectives and voices in entire medical product continuum : development to review and evaluation to post-market surveillance
  • Training patient representatives to serve on FDA advisory committees, meetings and workshops

Unique skill set and experiences

  • Elite world class athlete – benefit/risk experience with anticoagulants
  • Caregivers for rare disease  – advocates to find a cure
  • Parent of child with two craniotomies – importance of opioids for pain

2016 FDA Patient Representative Group photo

FDA looking for new and better ways to integrate patient voice







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