News & Views: Duodenoscope concerns, Biomarker qualification framework, Device classification procedures, Data integrity, NASH guidance, Non-device software report, To eat or not to eat?


Interim Results of Duodenoscope Reprocessing Studies Conducted in Real-World Settings: FDA Safety Communication

FDA ordered all U.S. duodenoscope manufacturers (Olympus, Fujifilm, Pentax) to conduct 2 postmarket surveillance studies on whether health care facilities were able to properly clean and disinfect devices

  • Study to sample and culture reprocessed duodenoscopes
  • Study to nassess how effectively the trained hospital staff follow the manufacturer reprocessing instructions (human factors)
  • At least 10% of the samples have been collected assuming <0.4% contamination rate

Interim results indicate higher-than-expected contamination rates after reprocessing

  • Up to 3% samples testing positive for enough low concern organisms
  • Up to 3% of samples testing positive for high concern organisms- E. coli,  Pseudomonas aeruginosa
  • Root cause analyses are underway;  final results in 2019

Safety communication to hospitals and health care providers

  • Following the manufacturer’s reprocessing and maintenance instructions not sufficient to avoid all infections
  • FDA been working with developers on new product designs, including disposable components



Biomarker Qualification: Evidentiary Framework

Evidentiary framework to support biomarker qualification with recommended components

  • Type and level of evidence
  • Broadly applicable regardless of the type of biomarker or context of use (COU)
  • Qualified biomarker can be used across multiple drug development programs

Framework consists of 

  • Drug development need
  • Defining the COU
  • Potential benefits if the biomarker is qualified for use
  • Potential risks of biomarker in drug development program

Biomarker validation




Medical Device Classification Procedures: Incorporating Food and Drug Administration Safety and Innovation Act Procedures


  • Medical device classification procedures for certain devices and requiring premarket approval applications for preamendments to Class III devices by using administrative orders, rather than rulemaking
  • Do not affect the classifications of previously cleared or approved devices

Principle benefits

  • Reduction in regulatory and economic burden and decreased timelines by eliminating paperwork filing requirements
  • Enhanced consistency and uniformity across reclassification proceedings
  • Cost and time savings will accrue to both medical device manufacturers and to Agency.



Data Integrity and Compliance With Drug CGMP

Clarify role of data integrity in current good manufacturing practice (CGMP) for drugs

  • All data expected to be reliable and accurate
  • Flexible and risk-based strategies to prevent and detect data integrity issues
  • Consider design, operation, monitoring based on risk to patient, process, product
  • Management’s involvement essential in preventing and correcting conditions that lead to data integrity problems.
  • Create a quality culture with data integrity as core value

Q & As on broad range of topics provided



Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry

Guidance for clinical development of drugs for treatment of noncirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis

  • Necessary components of drug development program


  • General Considerations
  • Phase 2 Development Considerations: Early and Late trials
  • Phase 3 Development Considerations: Inclusion / Exclusion criteria,  trial design and efficacy endpoints, safety considerations, pediatric considerations

NASH guidance


Report on Non-Device Software Functions 

Certain software functions excluded from definition of device under section 201(h) FD&C Act (21 U.S.C. 321(h))

  • Administrative support of a health care facility
  • Maintaining or encouraging a healthy lifestyle and unrelated to the diagnosis, cure, mitigation, prevention, or treatment of disease or condition
  • Serving as electronic patient records; not intended to interpret or analyze
  • Transferring, storing, converting formats, displaying data
  • Certain types of clinical decision support to a health care provider unless interpreting or analyzing

Report based on information from: DHHS offices, representatives of patients, consumers, health care providers, startup companies, health plans or other third-party payers, venture capital investors, information technology

Analysis based on: Impact to patient safety, Benefits and risks to health, Best practices to promote safety, education, and competency

Findings: More benefits than risks to patient safety and health related to these software functions

Details best practices: Implementation, training techniques, and use, which could promote safety, education, and competency related to these software functions


Image credit: FDA



FDA News & Views: Real-World Evidence framework, Women’s Health Research roadmap, Clinical Testing advances, Human Genetic Variant databases, De Novo pathway improvement, Collaborative Community toolkit, Opioid Use Disorder challenge, Blood Glucose Monitors safety/accuracy, Patient Engagement Advisory Committee


Framework for Real-World Evidence Program

Framework for evaluating potential use of real-world evidence (RWE) to help support the approval of a new indication for a drug
  • Already approved under section 505(c) of the FD&C Act
  • Adding or modifying indication, adding new population, adding comparative effectiveness or safety information
  • Help satisfy postapproval study requirements
  • Does not apply to medical devices

Three-part approach for assessing  use of real world data (RWD) to generate RWE

  •  Are the RWD fit for use?
  • Can study design used to generate RWE provide adequate relevant scientific evidence?
  • Does study conducted meet FDA regulatory requirements for study monitoring and data collection?

Women’s Health Research Roadmap

FDA Office of Women’s Health (OWH) research priority areas to advance the science of women’s health

  1. Advance Safety and Efficacy of FDA-regulated products used by women
  2. Improve Clinical Study Design and Analyses to better identify and evaluate possible sex differences
  3. Novel Modeling and Simulation Approaches  to aid in regulatory evaluation
  4. Advances in Biomarker Science to identify, evaluate, qualify clinical and non-clinical biomarkers and surrogate endpoints
  5. Expand Data Sources and Analysis  to identify, develop, evaluate data sources to assess postmarket toxicity or safety and effectiveness
  6. Improve Health Communications to develop, evaluate, use tools to make informed health-related decisions
  7. Emerging Technologies for identification of sex differences to use of emerging technologies



New Steps to Advance Clinical Testing to Deliver New Cures



FDA Recognition of Public Human Genetic Variant Databases

Genetic variant database collect, organize, publicly document evidence supporting links between human genetic variant and disease

  • Better understanding relationships between genotypes and diseases can aid in the diagnosis and treatment of individuals with genetic conditions
  •  Mechanism for test developers to leverage publicly accessible databases to support  regulatory review of genetic and genomic tests

Clinical Genome Resource (ClinGen) consortium’s ClinGen Expert Curated Human Genetic Data is first FDA-recognized publicly-available genetic variants database




Improvements to the De Novo pathway for novel medical devices to advance safe, effective, and innovative treatments for patients

Establish procedures and criteria for medical device De Novo classification process

  • For new medical devices with no legally marketed predicates
  • Vehicle for establishing new predicates reflecting modern standards for performance and safety
  • Make pathway significantly more efficient and transparent
  • Expecting more use of pathway for new devices

De Novo request granted

  • new device is legally marketed and in compliance with regulatory controls
  • new classification regulation established
  • new device serves as predicate device for 510(k) submissions of same type devices
  • Federal Register notification of new classification regulation, new special controls
  • posting of granting order and decision summary.

De Novo request decline

  • general/special controls  insufficient to provide reasonable assurance of safety and effectiveness
  • data insufficient to determine whether controls can provide reasonable assurance of safety and effectiveness of the device
  • probable benefits do not outweigh probable risks
  • device remains in class III and may not be legally marketed



Collaborative Community Toolkit

Collaborative community is continuing forum with private- and public-sector members, including FDA, work together on medical device challenges

  • Challenges ill-defined or no consensus
  • Challenges and outcomes are complex
  • Partners are interrelated
  • Incremental or unilateral efforts to address challenge have been ineffective
  • Partners seek to optimize efforts, including preventing duplication of efforts
  • Better outcomes with integrating different perspectives, experiences, resources, expertise



Selections for FDA Innovation Challenge for Devices to Prevent and Treat Opioid Use Disorder

Over 250 applications received for Opioid Use Disorder (OUD) challenge; selections include

  • prediction of risk of OUD
  • detection of  opioid overdose
  • dispensing medication
  • providing pain treatment alternatives to opioids

Selected applicants receive Breakthrough Device designation



Steps to advance safety and accuracy of blood glucose monitors

Two revised draft guidances regarding blood glucose monitors used in health care and home settings

  • Based stakeholder feedback requesting more clarification on design considerations and recommended standards
  • To improve development of new blood glucose meters based on feedback from both patients and health care providers especially on usability of glucose monitors

Blood Glucose Monitoring Test Systems for Prescription Point-of-Care Use

Self-Monitoring Blood Glucose Test Systems for Over-the-Counter Use



Patient Engagement Advisory Committee (PEAC)

PEAC held on Nov 15, 2018, to discuss topic “Connected and Empowered Patients: e-Platforms Potentially Expanding the Definition of Scientific Evidence”

  • Leveraging  patient-generated health data, such as social media, sensors, patient-driven registries, to better engage patients
  • Social media and other web platform  for virtual patient communities
  • Resource for postmarket study design, performing surveillance for adverse events, issuing recalls, communicating signals to public

FDA needs to take following steps 

  • Standardize how data is collected, used and applied
  • Ensure language communicated to patients be clear and understandable
  • Ensure data collected is de-identified
  • Ensure a high level of integrity with the data collected


Image credits: FDA

FDA Market Authorizations: AEMCOLO for travelers’ diarrhea, YULPERI for COPD, GAMIFANT for rare immune disease, DAURISMO for AML


AEMCOLO (rifamycin) AEMCOLO (rifamycin) delayed-release tablets

Cosmo Technologies, Ltd

INDICATION: Treatment of travelers’ diarrhea (TD) caused by non-invasive strains of Escherichia coli in adults

  • Limitations of Use: Not recommended for use in patients with diarrhea complicated by fever and/or bloody stool or due to pathogens other than noninvasive strains of E. coli.


  • Travelers’ diarrhea affects 10–40 % travelers worldwide each year
  • Highest-risk destinations in most of Asia as well as the Middle East, Africa, Mexico, and Central and South America

MECHANISM OF ACTION: Antibacterial drug


  • Multi-center, randomized, double-blind, placebo (Guatemala, Mexico)  and active-controlled (India, Guatemala and Ecuador) trials
  • Primary endpoint: Time to last unformedstool (TLUS) before achieving clinical cure
  • AEMCOLO significantly reduced the TLUS compared to placebo (p=0.0008); supportive outcome ina ctive controlled trial.


  • Most common adverse reactions (incidence > 2%): Headache and constipation


  • Qualified Infectious Disease Product (QIDP) designation under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act
  • Priority Review
  • Deferred pediatrkc studies: Treatment of travelers’ diarrhea in children from 6 – 11 years of age and 12-17 years of age



YUPELRI™ (revefenacin) inhalation solution

Theravance and Mylan

INDICATION: Mtreatment of patients with chronic obstructive pulmonary disease (COPD)

MECHANISM OF ACTION: Long-acting muscarinic antagonist, inhibition of M3 receptor at the smooth muscle leading to bronchodilation


  • Two dose-ranging trials, two replicate 12-week, Phase 3 confirmatory clinical trials, and a 52-week safety trial
  • Confirmatory Trials: n=1,229 subjects, YUPELRI vs. placebo once daily
  • Primary endpoint: Change from baseline in trough (predose) Forced Expiratory Volume in One Second or FEV1  at Day 85
  • Significant improvement in lung function vs placebo


  • Most common adverse reactions (incidence greater than or equal to 2% and more common than placebo):  Cough, nasopharyngitis, upper respiratory tract infection, headache, back pain
  • Worsening of narrow-angle glaucoma may occur


  • Pediatric requirements waived



Novimmune SA

INDICATION: Treatment of adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or
progressive disease or intolerance with conventional HLH therapy


  • Primary HLH is rare and life-threatening condition typically affecting children
  • Approval fills an unmet medical need for these patients

MECHANISM OF ACTION: Monoclonal antibody that binds to and neutralizes interferon gamma


  • Clinical trial of 27 pediatric patients,  with suspected or confirmed primary HLH,  intolerant of conventional HLH therapy
  • 63% experienced response and 70 % were able to proceed to stem cell transplant


  • Common side effects: Infections, hypertension, infusion-related reactions, low potassium and fever
  •  Patients should not receive any live vaccines and should be tested for latent tuberculosis
  • Patients should be closely monitored and treated promptly for infections


  • Orphan designation, Priority Review and Breakthrough Therapy designation



DAURISMO (glasdegib) tablets


INDICATION: In combination with low-dose cytarabine, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

  • Limitation of Use: Has not been studied in patients with the comorbidities of severe renal impairment or moderate-to-severe hepatic impairment

MECHANISM OF ACTION: Hedgehog pathway inhibitor, binds to and inhibits Smoothened, a transmembrane protein involved in hedgehog signal transduction


  • Multicenter, openlabel, randomized study, n=115 patients with newly-diagnosed AML, DAURISMO with low-dose Cytarabine va. low-dose Cytarabine
  • Primary Endpoint: Overall Survival; 8.3 mo. vs 4.3 mo, p=0.0002


  • Boxed warning: Can cause embryo-fetal death or severe birth defects
  • Most common adverse reactions (incidence ≥20%): Anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, rash


  • Orphan and Priority designations


Image credits: Cosma, Theravance, Novimmune, Pfizer

FDA News and Views: Transforming 510(k) Program, Increased Medical Device Inspections, Social Media Trends for Drug Use, Drug Use Software, Addressing Drug Shortages, Waiver or Alteration of Informed Consent

CaptureTransformative new steps to modernize FDA’s 510(k) program to advance the review of the safety and effectiveness of medical devices

Changes to modernize  510(k) clearance pathway, which accounts for majority of FDA reviews

  • To keep pace with increasing complexity of rapidly evolving technology
  • To efficiently advance beneficial technology to patients, while solidifying FDA’s gold standard for safety

Reliance on more modern predicate devices or objective performance criteria

  • Predicates that are <10 years old
  • Public website on cleared devices with substantial equivalence to older predicates
  • Rename new approach the “Safety and Performance Based Pathway
    • Focus on advancing improved safety and performance of new products
    • Ensure novel device meets modern performance-based criteria that reflect current technological principles

Report on Strengthening the 510(k) program

  • Increased premarket expectations
  • Implemented a Refuse-To-Accept policy to improve the quality of submissions
  • Improved consistency and thoroughness of review
  • Eliminated use of 510(k) for Class III devices
  • Eliminated use of > 1000 510(k)s as legal predicates


CaptureFDA’s increased inspections of medical device manufacturers and targeted risk-based approach leads to improved compliance

FDA has increased its oversight through additional device inspections since 2007

  • Increase in annual number of device inspections by 46%
  • Increased annual inspections of foreign firms by 243%
  • Established Medical Device Single Audit Program to allow for a single audit on behalf of multiple countriesf  urther increased the FDA’s oversight of foreign manufacturing facilities
  • Targeted risk-based approach to addressing concerns with specific devices e.g. infusion pumps, automated external defibrillators
  • Increased compliance actions and voluntary recalls leading to better compliance, improved device quality, reduction in reported injuries and deaths
  • Identifying reporting deficiencies during inspections leading to increase in voluntary recalls and adverse event reporting
  • Case for Quality initiative that includes a voluntary quality maturity appraisal pilot launched this year.



 Monitoring Social Media to Better Understand Drug Use Trends

Proactive pharmacovigilance using nontraditional monitoring process is to identify and analyze content found in conversations occurring online and on social media sites

  • Inform prescription drug use or abuse – explore in greater depth through more detailed and rigorous primary data collection efforts
  • Use data gleaned from social media monitoring –  inform communications activities, identify potential new trends
  • Methods to monitor social media platforms – Twitter, Facebook, Instagram, also forums, blogs, discussion groups, news sites, and other nontraditional sites
  • Recognize benefits and limitations
  • EXAMPLE- Gabapentinoids use increase – focus on misuse and abuse based on online conversations



Prescription Drug-Use-Related Software

“Prescription drug-use-related software” refers to:

  • Software (e.g. App) disseminated by or on behalf of a drug sponsor
  • Accompanies one or more of the sponsor’s prescription drugs, including biological drug products

Proposed framework takes risk-based approach to prescription drug use-related software

  • Anticipated that output of such software will not require FDA review prior to dissemination
  • Dependent on whether software is a ‘device’ per CDRH assessment



New Efforts to Address Drug Shortages

Ensuring that necessary drug is available to patient involves a lot of stakeholders working together at key stages of the development, manufacturing, marketing, and distribution 

  • Immediate need: External factors (bioterror attacks, natural disasters)
  • Long-term need : Interagency Drug Shortages Task Force to investigate root causes  and take new approach to advance long-term solutions
  • Public engagement: Upcoming public meeting, Identifying the Root Causes of Drug Shortages and Finding Enduring Solutions



Institutional Review Board Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations

Allow responsible IRB to approve an informed consent procedure that does not include or that alters some or all of the elements of informed consent or waives requirement to obtain informed consent 

  • Clinical investigation involves no more than minimal risk to subjects
  • Waiver or alteration of informed consent will not adversely affect rights and welfare of subjects
  • Clinical investigation could not practicably be carried out without waiver or alteration of informed consent
  • Whenever appropriate, subjects will be provided with additional pertinent information after participation


Image credits: FDA

FDA Market Authorization: ADCETRIS for peripheral T-cell lymphoma, DPP Ebola Test, picoAMH Test for Menopause, INNOVO electrical stimulatory for incontinence

Capture.JPGAdcetris (brentuximab vedotin) injection

Seattle Genetics

EXPANDED INDICATION: Previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), in combination with cyclophosphamide, doxorubicin, and prednisone


  • First approval for treatment of newly diagnosed PTCL
  • Use of new Real-Time Oncology Review (RTOR) program to complete approval more quickly; access key data prior to the official submission of application allowing review team to begin review prior to the application’s actual submission


  • Trial, n=452 patients with certain PTCLs who received either Adcetris plus chemotherapy or a standard chemotherapy (CHOP) as first-line treatment
  • Progression-free survival:  Significantly longer (hazard ratio 0.71, P-value 0.01) in the Adcetris arm (median 48 months, compared to 21 months with CHOP)
  • Survival and overall response rates were also significantly better in the Adcetris arm


  • Boxed Warning: JC virus infection resulting in PML
  • Most common side effects: Peripheral neuropathy, nausea and vomiting, diarrhea, low white blood cell counts, fatigue, mouth sores, constipation, hair loss, fever and anemia
  • Monitor for infusion reactions, life-threatening anaphylaxis, neuropathy, fever, gastrointestinal complications and infections, tumor lysis syndrome,  serious skin reactions, pulmonary toxicity and hepatotoxicity.


Capture.JPGDPP Ebola Antigen System

ChemBio Diagnostic

INTENDED USE: The is a rapid, single-use immunochromatographic test intended for the qualitative detection of VP40 protein from Ebola virus (species Zaire ebolavirus and hereafter referred to as Ebola virus) in capillary “fingerstick” whole blood, EDTA venous whole blood, and EDTA plasma


  • Rapid, single-use test for the detection of Ebola virus (Zaire ebolavirus)
  • Second Ebola rapid antigen fingerstick test available
  •  Collaboration with  Federal, international and industry partners to assist in global response to Ebola outbreak in Democratic Republic of Congo


  • Single-use immuno-chromatographic, rapid test developed on Chembio’s patented DPP® technology
  • DPP® Micro Reader which is used to interpret test results

REGULATORY PATHWAY: Emergency Use Authorization


CapturepicoAMH ELISA Menopause Test

Ansh Labs

INDICATION FOR USE: Enzyme-linked immunosorbent assay (ELISA) for the in vitro quantitative measurement of anti-Müllerian hormone (AMH), also known as Müllerian Inhibiting Substance (MIS), concentrations in human serum. It is intended to be used as an aid in the determination of menopausal status in women between 42 and 62 years of age. This assay should only be used in conjunction with other clinical and laboratory findings and results from this test alone should not be used to make diagnostic or treatment decisions. It is intended for in vitro diagnostic use and for prescription use only


  • Diagnostic results about a woman’s menopausal status may prompt discussions about preventative care for women experiencing menopausal symptoms
  • Can help inform discussions about preventative care e.g. prevent loss in bone mineral density or to address cardiovascular disease, both of which increase after menopause

GENERIC DEVICE TYPE: Menopause test system

  • In vitro diagnostic device intended to measure hormones or other analytes in human clinical specimens as an aid in the determination of menopausal status in women



  • Data from multi-center, longitudinal Study of Women’s Health Across the Nation (SWAN), n= 690 women, aged 42 to 62
  • PicoAMH Elisa test performed reasonably well
    • determining AMH levels of AMH in blood
    • identifying women who had their last menstrual period
    • identifying women who were more > five years away from last menstrual period


  • Incorrect test results: General controls and special controls
  • Incorrect interpretation of test results: General controls and special controls


  • Regulation Number: 21 CFR 862.1093
  • Regulation Name: Menopause test system
  • Regulatory Class: Class II
  • Product Code: QDH




Atlantic Therapeutics Group

INDICATION FOR USE: Transcutaneous electrical stimulator indicated for the treatment of stress urinary incontinence in adult females. Indicated for prescription use only.

GENERIC DEVICE TYPE: Transcutaneous electrical continence device

  • Consists of cutaneous electrodes that are used to apply external stimulation to reduce urinary incontinence


  • Two randomized controlled trials in EU and US
  • US trial: 87.2% of patients were dry or mild of after a 12-week treatment period1, with 93% of patients experiencing improvement in 4 weeks


  • Pain or tissue damage due to overstimulation: Non-clinical performance testing
    Software verification, validation, and hazard analysis, Electrical safety testing, Labeling
  • Adverse tissue reaction: Biocompatibility evaluation
  • Electrical shock or burn: Electrical safety testing, Software verification, validation, and hazard analysis, Labeling
  • Device failure due to electromagnetic interference: Electromagnetic compatibility (EMC) testing, Software verification, validation, and hazard analysis, Labeling
  • Use error that may result in user discomfort, injury, or delay in treatment: Software verification, validation, and hazard analysis, Labeling


  • Regulation Number: 21 CFR 876.5330
  • Regulation Name: Transcutaneous electrical continence device
  • Regulatory Class: Class II
  • Product Code: QAJ


Image Credits: Seattle Genetics, ChemBio, Ansh Labs, Atlantic Therapeutics

FDA News & Views: MyStudies App, Asthma and OTC Treatment, Improving Expanded Access, Modernizing Sterile Drug Inspections

Capture.JPGFDA MyStudies app

MyStudies app will aid researchers and industry in collecting real world patient level data

  • When linked to existing electronic health data
  • Will promote efficiencies in drug development and drug safety monitoring processes
  • Patients can securely enroll and participate in large scale pragmatic clinical trials or registries
  • Comply with FDA guidance and regulations regarding data authenticity, integrity, and confidentiality (21 CFR Part 11 compliant clinical trials)

Two versions of the app

  • Apple ResearchKit (iOS) framework
  • Open source ResearchStack framework, which runs on Google’s Android

App (iOS and Android), web configuration portal (WCP), and storage environment posted on GitHub to allow customization and use 




Asthma Management and OTC Treatment Option

About 8.3 percent of Americans — nearly 27 million people — have asthma

  • No cure for asthma and, in most cases, don’t know causes
  • Can reduce the number and severity of attacks
  • Develop an asthma action plan – with right medications

OTC Primatene Mist for temporary relief for symptoms of mild, intermittent asthma

  • Original OTC Primatene Mist taken off market in 2011- contained chlorofluorocarbon (CFC) propellants known to deplete the ozone layer
  • New version recently approved
  • Uses same active bronchodilator ingredient (epinephrine)
  • Redesigned device for use n people ages 12 years and older




New efforts to strengthen FDA’s expanded access program

Expanded Access (EA) program provides pathway for patients to gain access to investigational drugs, biologics and medical devices for serious diseases and immediately life-threatening conditions outside of clinical trials

Steps taken for improvement

  •  streamlining the required supporting documentation
  • simplified the process for Institutional Review Board (IRB) review
  • guidance on use of safety data

Additional improvements based on independent assessment

  • mproving FDA’s public website content and investing in resources to support patient/physician program navigation
  • formally establish an agency-wide Patient Affairs Staff and Health Care Provider Affairs Program,
  • Implementing Right to Try legislation



New Inspection Protocol Project (NIPP) to strengthen and modernize  inspections for sterile injectable drugs

New Inspection Protocol Project (NIPP) uses standardized electronic inspection protocols to collect data in a structured manner for more consistent oversight

  • Quickly assess state of quality in drug manufacturing facilities while maintaining flexibility to adapt inspections based on constraints e.g.  time or seriousness of violations
  • Easier to analyze data to find anomalies and inform decisions that can reduce risks to patients
  • Ensure more streamlined and consistent coverage and reporting of inspectional activities
  • Multiple pilots of NIPP protocols conducted
  • Integrate learnings into field activities – goal to have full implementation within two years


Image credit: FDA

FDA Market Authorizations: VISUMAX Laser, BIOMIMICS 3D Stent, PERSONAL GENOME SERVICE Pharmacogenetic Reports, FLUOBEAM 800 Clinic Imaging Device, Biosimilars: UDENCYA, HYRIMOZ


VisuMax Femtosecond Laser

 Carl Zeiss Meditec, Inc.

INDICATION FOR USE: In small incision lenticule extraction (SMILE) for the reduction or elimination of myopia with or without astigmatism:

  • For spherical refractive error (in minus cylinder format) from -1.00 diopters through -10.00 diopters
  • For cylinder from -0.75 diopters through -3.00 diopters
  • When refraction spherical equivalent is no greater in magnitude than 10.00 diopters, in patients 22 years of age or older with documentation of stable manifest refraction over the past year as demonstrated by a change in sphere and cylinder of ≤ 0.50 D in magnitude


  • Precision ophthalmic surgical laser designed for creation of incisions in cornea
  • Mimics cutting action of mechanical or blade-based keratomes
  • Accomplishes this by scanning tightly focused patterns of femtosecond laser pulses in cornea at precise and predefined positions and depths
  • Each laser pulse produces micro-photodisruption in tissue of only a few microns in size
  • Patterns of contiguous, focused laser pulses results in the creation of continuous cut surfaces in cornea


  • 12-month, prospective, multi-center, open-label, non-randomized clinical trial, 360 eyes of 360 consecutive subjects for reduction or elimination of myopia from ≥ -1.00 D to ≤ -10.00 D with ≤ -3.00 D cylinder (myopia with or without astigmatism) and MRSE ≤ -11.50 D
  • The key effectiveness variables : Predictability: the percentage of eyes achieving MRSE within ± 1.00 D of the intended outcome,  Improvement in UCVA following treatment: the percentage of eyes that achieve uncorrected visual acuity (UCVA) of 20/40 or better
  • Predictability of MRSE: 99.1%
  • Improvement in UCVA: 98.6%
  • Most serious types of adverse events : 3 cases of intraoperative cap tears, several of the cases of epithelium in the interface, all objective types of adverse events occurred at rates less than 1%, no objective findings resulted in long-term serious sequelae


  • Device Procode: OTL



BioMimics 3D Vascular Stent System

Veryan Medical Limited

INDICATION FOR USE: To improve luminal diameter in the treatment of symptomatic de novo or restenotic lesions in the native superficial femoral artery and/or proximal popliteal artery, with reference vessel diameters ranging from 4.0 – 6.0 mm and lesion lengths up to 140 mm


  • Comprised of two components; (i) a Nitinol stent with a 3D helical profile in a range of lengths and diameters and (ii) an over-the-wire stent delivery system
  • 3D stent is a peripheral self-expanding nickel-titanium alloy (Nitinol)stent with 3D helical centerline geometry
  • Stent is laser cut from a straight Nitinol tube and 3D helical geometry is stored in the Nitinol shape memory
  • Three tantalum radiopaque markers are located at both ends of the stent to increase visibility of the stent to aid in placemen
  • 3D stent is mounted on a 6F over-the-wire stent delivery system (SDS) for use with a 0.035” guidewire


  • Prospective, single-arm, multicenter clinical trial,  in patients with intermittent claudication due to atherosclerotic disease of the femoropopliteal artery
  • Primary effectiveness endpoint: Primary stent patency rate at 12 months: 73%
  • Freedom from Major Adverse Event (MAE) comprising death, any major amputation performed on the target limb through 30 days: 99.6%


  • Device Procode: NIP
  • Device Generic Name: Stent, Superficial Femoral Artery



 Personal Genome Service (PGS) Pharmacogenetic Reports


INDICATION FOR USE: Qualitative genotyping assessment system applied to genomic DNA isolated from human saliva collected using the Oragene Dx OGD500.001 to simultaneously detect, report, and interpret genetic variants in a broad multigene test. The assessment system is intended to enable users to access information about their genetics that could aid discussions with a healthcare professional.

The 23andMe Personal Genome Service Pharmacogenetic Reports are indicated for reporting of the following variants:

Gene Variant(s)
CYP2C19 *2, *3, *17
CYP2C9 *2, *3, *5, *6, rs7089580
CYP3A5 *3
UGT1A1 *6, *28
DPYD *2A, rs67376798
TPMT *2, *3C
SLCO1B1 *5
CYP2D6 *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *15, *17, *20, *29, *35, *40, *41


  • Making information about genetic variants available directly to consumers
  • Better inform their discussions with their health care providers

GENERIC DEVICE TYPE: Pharmacogenetic assessment system

Qualitative in vitro molecular diagnostic system intended to detect nucleic acid variants isolated from human specimens for the purpose of identifying pharmacogenetic associations for the detected variants. The intended use of the device must not include an indication for use in supporting or sustaining human life, being of substantial importance in preventing impairment of human health, or presenting a potential, unreasonable risk of illness or injury.


  • Data to show that the test is accurate (i.e., can correctly identify the genetic variants in saliva samples)
  • Provide reproducible results
  • Data on user comprehension studies that demonstrated that the test instructions and reports were understood by consumers
  • Test report provides information describing what the results might mean, what the test does not do and how to interpret results.


  • Incorrect test results (false positive or false negative results): Special controls
  • Incorrect interpretation of test results: Special controls
  • Incorrect action based on test results: Special controls

REGULATORY PATHWAY: De Novo classification request

  • Regulation Number: 21 CFR 862.3364
  • Regulation Name: Pharmacogenetic assessment system
  • Regulatory Class: Class II
  • Product Code: QDJ



Fluobeam 800 Clinic Imaging Device


INDICATION FOR USE:  To provide real-time near infrared (NIR) fluorescence imaging of tissue during surgical procedures. The Fluoptics Fluobeam® Imaging system is indicated for use in capturing and viewing fluorescent images for the visual assessment of blood flow in adults as an adjunctive method for the evaluation of tissue perfusion, perfused organs, and related tissue-transfer circulation in tissue and free flaps used in plastic, micro- and reconstructive and organ transplant surgeries.

The Fluoptics Fluobeam® Imaging system can also be used to assist in the imaging of parathyroid glands and can be used as an adjunctive method to assist in the location of parathyroid glands due to the auto-fluorescence of this tissue.

Use of the Fluobeam® device is intended to assist, not replace, experienced visual assessment, and biopsy with conventional histopathological confirmation per standard of care. The system is not to be used to confirm the absence of parathyroid tissue or glands and is only to be used to assist in locating visually identified gland/tissues.

ADDRESSING UNMET NEED:  Provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy (surgery to remove all or part of the thyroid) and parathyroidectomy (surgery to remove one or more parathyroid glands).

GENERIC TYPE OF DEVICE: Autofluorescence detection device for general surgery and dermatological use.

  • Adjunct tool that uses autofluorescence to detect tissues or structures. This device is not intended to provide a diagnosis.


  • Data from five peer-reviewed published studies, including one study that compared the rate of postoperative hypocalcemia (PH), or a temporary reduction in calcium in the blood, that occurs when healthy parathyroid tissue is inadvertently removed, n=93
  • 5 % experienced fluctuating PH following surgery (n=93) vs  21 % (n=153) patients who had surgery without the device


  • Electrical, mechanical, or thermal hazards leading to user injury or discomfort:  Electromagnetic compatibility testing Electrical, mechanical and thermal safety testing, Software verification, validation, and hazard analysis, Labeling
  • Tissue, skin burn, or eye injury due to light and laser exposure: Light and laser exposure safety testing, Labeling
  • Infection and cross-contamination: Sterilization validation, Shelf life testing, Labeling
  • Adverse tissue reaction: Biocompatibility evaluation
  • False identification of target tissues or structures leading to errors in patient
    management (e.g., removal of healthy tissue or not removing diseased tissue): In vivo performance testing, Software verification, validation, hazard analysis, Labeling

REGULATORY PATHWAY: De Novo classification request

  • Previously cleared, via 510(k) pathway, as an imaging system used to capture and view fluorescent images for the visual assessment of blood flow as an adjunctive method for the evaluation of tissue perfusion
  • De Novo pathway for new indication
  • Regulation Number: 21 CFR 878.4550
  • Regulation Name: Autofluorescence detection device for general surgery and dermatological use
  • Regulatory Class: Class II
  • Product Code: QDG



Biosimilars: UDENCYA (pegfilgrastim-cbqv), HYRIMOZ (adalimumab-adaz)

Biosimilar product: Biological product that is approved based on a showing that it is highly similar to an already-approved biological product, known as a reference product. The biosimilar also must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product.

UDENCYA (pegfilgrastim-cbqv) injection, biosimilar to NEULASTA (pegfilgrastim)

INDICATION: To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia

HYRIMOZ (adalimumab-adaz) injection, biosimilar to HUMIRA (adalimumab)

  • Rheumatoid Arthritis: Reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HYRIMOZ can be used alone or in combination with methotrexate or other non- biologic disease-modifying anti-rheumatic drugs (DMARDs).
  • Juvenile Idiopathic Arthritis: Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older. HYRIMOZ can be used alone or in combination with methotrexate.
  • Psoriatic Arthritis: Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HYRIMOZ can be used alone or in combination with non-biologic DMARDs.
  • Ankylosing Spondylitis: Reducing signs and symptoms in adult patients with active ankylosing spondylitis.
  • Adult Crohn’s Disease: Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HYRIMOZ is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.
  • Ulcerative Colitis: Inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP).
  • Plaque Psoriasis: Treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.


Image credits: Carl Zeiss Meditec, Veryan Medical Limited, 23andMe, Fluoptics, FDA

FDA News and Views: Cybersecurity, Digital Health Advisor, Stakeholder update, Dsuvia Opioid Approval, E-cigarette cessation drugs, ASCA pilot, FDA-DoD collaboration


The Medical Device Ecosystem and Cybersecurity — Building Capabilities and Advancing Contributions

Medical device cybersecurity is shared responsibility across the medical device ecosystem

  • In context of total product lifecycle
  • As part of interconnected cyber — physical infrastructure among people, processes, data and information and communication technologies
  • Identify and prepare for cyber intrusions, reduce medical device vulnerabilities, mitigate patient impact, enable timely restoration of devices and systems

Applying a best-teams approach  (with Dept. of Homeland Security, FDA Medical Device Safety Action Plan, Guidances on Premarket cybersecurity)

Building strategic alliances (with MITRE, MDIC)

Fortifying long-term commitment (Center of Excellence for Digital Health)



FDA Seeking Digital Health Advisor

Primarily serve as expert on  digital health technologies during FDA’s review and evaluation of digital health technologies

  • Review of first-of-a-kind digital health technology, precedent-setting research
  • Create preconditions and incentives informing digital health policy proposals
  • Provide advice, consultations and training
  • Assist with technology solutions to enhance CDRH internal processes


Stakeholder Update: FDA’s 2018 Strategic Policy Roadmap

Update on priority areas to advance public health

Reduce the burden of addiction crises 

  • Address growing epidemic of youth e-cigarette use, including potential new therapies to support cessation Read
  • Industry meetings on epidemic rates in youth e-cigarette use Read

Leverage innovation and competition to improve health care and access

  • Medical Device Ecosystem and Cybersecurity  Read
  • Authorization of first direct-to-consumer test for detecting genetic variants for medication metabolism



Approval of Dsuvia and the FDA’s future consideration of new opioids

Dsuvia approval considerations in the context of the overall therapeutic armamentarium

  • Sublingual with restricted use in certified medically-supervised health care settings
  • Ideally suited for special circumstances where patients not able to swallow oral medication and access to intravenous pain relief is not possible
  • Potential uses on the battlefield – Department of Defense (DoD) worked closely with  sponsor on the development of opioid
  • Very tight restrictions on distribution and use with REMS
  • Quickly make regulatory adjustments if problems arise



Growing epidemic of youth e-cigarette use, including potential new therapies to support cessation

Public hearing on Dec. 5, to  focus on potential role of drug therapies to support cessation

  • Obtain input from across the medical and research fields, the pharmaceutical and tobacco industries, and public health stakeholders
  • Approaches to eliminate youth e-cigarette use
  • Exploring potential drug therapies to support youth e-cigarette cessation



Accreditation Scheme for Conformity Assessment (ASCA)

Piloted under CDRH’s Standards and Conformity Assessment Program

  • Enhance predictability of the medical device review process
  • Reducing premarket questions on conformity activities
  • Conformance declarations
  • Increase consistency of submissions and saving FDA resources

Pilot will ensure appropriate interaction between FDA, accreditation bodies, and testing labs



FDA and DoD formalize collaboration to advance medical products in support of American military personnel

New Memorandum of Understanding aligns agency efforts to foster the development and use of safe and effective medical products for members of the U.S. military

  • Evaluate how best to foster access to safe and effective medical products
  • Expedite review of priority DoD medical products
  • Provide technical  to aid rapidly  develop and manufacture medical products
  • Determine opportunities to streamline review and expedite availability
  • Authorize emergency uses of medical products to reduce deaths and severity of injuries caused by chemical, biological, radiological or nuclear (CBRN) agents


Image credit: FDA

Market Authorizations: ARIKAYCE, clonoSEQ Assay, XOFLUZA



ARIKAYCE (amikacin liposome inhalation suspension) oral

with LAMIRA nebulizer system 

Insmed, Inc

INDICATION: LIMITED POPULATION: Adults, who have limited or no alternative  treatment options, for the treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy.

As only limited clinical safety and effectiveness data for ARIKAYCE are currently available, reserve ARIKAYCE for use in adults who have limited or no alternative treatment options. This drug is indicated for use in a limited and specific population of patients.


  • Need to encourage the development of drugs to treat resistant infections
  • First approval under Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) to  spur development of drugs targeting infections that lack effective therapies

MECHANISM OF ACTION: Antibacterial drug


  •  Randomized, controlled clinical trial, n=336 patients with refractory  MAC lung disease, ARIKAYCE plus a background regimen or background regimen alone
  • Surrogate efficacy endpoint: Culture conversion (3 consecutive monthly negative sputum cultures) by Month 6
  • 29% with Arikayce vs.  9% without Arikayce


  • Boxed Warning: Increased risk of respiratory conditions including hypersensitivity pneumonitis, bronchospasm, exacerbation of underlying lung disease, hemoptysis
  • Common side effects: Dysphonia, cough, ototoxicity, upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.


  • Fast Track, Breakthrough Therapy, Priority Review, Accelerated Approval, Qualified Infectious Disease Product (QIDP) designations
  • Accelerated approval requirements :Randomized, double-blind, placebo-controlled clinical trial to describe clinical benefit in patients with nontuberculous mycobacterial (NTM) lung disease caused by MAC




clonoSEQ Assay

Adaptive Biotechnologies

INDICATION FOR USE:  In vitro diagnostic that uses multiplex polymerase chain reaction (PCR) and next-generation sequencing (NGS) to identify and quantify rearranged IgH (VDJ), IgH (DJ), IgK, and IgL receptor gene sequences, as well as translocated BCL1/IgH (J) and BCL2/IgH (J) sequences in DNA extracted from bone marrow from patients with B-Cell acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).

The clonoSEQ Assay measures minimal residual disease (MRD) to monitor changes in burden of disease during and after treatment. The test is indicated for use by qualified healthcare professionals in accordance with professional guidelines for clinical decision-making and in conjunction with other clinicopathological features.

The clonoSEQ Assay is a single-site assay performed at Adaptive Biotechnologies Corporation.


  • Determining whether patient has residual cancer cells remaining after treatment provides information on how well patient responded to therapy and how long remission may last
  • Highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care
  • FDA applying novel regulatory approaches to make sure rapidly evolving NGS tests are accurate and reliable

GENERIC DEVICE TYPE: DNA-based test to measure minimal residual disease in hematological malignancies

  • Prescription in vitro diagnostic device that identifies and quantifies specific nucleic acid sequences within human tissues to estimate the percentage of cells that harbor the specific sequence(s). The test is intended to be used as an aid to measure Minimal residual disease to assess the change in burden of disease during Monitoring of treatment. The test is indicated for use by qualified healthcare professionals in accordance with professional guidelines for clinical decision-making, in conjunction with other clinicopathological features.


  • Retrospective analysis of samples obtained from three previously conducted clinical studies- N=273 patients with ALL, N=323 patients with multiple myeloma (ongoing), N=706 patients with multiple myeloma
  • ALL: MRD level correlated with event-free survival
  • Multiple myeloma: MRD level correlated with progression-free survival


  • Incorrect test results: General controls and special controls 
  • Incorrect interpretation of test results: General controls and special controls


  • Regulation Number: 21 CFR 866.6100
  • Regulatory Class: Class II
  • Product Code: QDC




XOFLUZA (baloxavir marboxil) tablets

Shionogi & Co, Genentech USA

INDICATION:  Treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours.


  • First new antiviral flu treatment with novel mechanism of action approved by FDA in nearly 20 year
  • Provides an important, additional treatment option

MECHANISM OF ACTION: Prodrug that is converted by hydrolysis to baloxavir that inhibits endonuclease activity of the polymerase acidic protein required for viral gene transcription resulting in inhibition of influenza virus replication


  • Two randomized controlled clinical trials, n=1,832 patients,  Xofluza, vs. placebo, or vs. another antiviral flu treatment (oseltamivir) within 48 hours of experiencing flu symptoms
  • Primary endpoint: Time to alleviation of all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue)
  • Statistically significant shorter time to alleviation of symptoms vs placebo
  • No difference in time to alleviation of symptoms vs. oseltamivir


  • Most common adverse reactions: Diarrhea and bronchitis


  • Priority Review
  • Required Pediatric Assessments: Studies in from birth – < 12 months  and from 12 months to <12 years of age with acute uncomplicated influenza
  • Material Threat Countermeasure (MCM) Priority Review Voucher – Denied
    • no form of influenza is listed as a material threat


Image credits: Insmed, Adaptive Biotechnologies, Shionogi/Genentech

FDA News and Views: SUPPORT Law for Substance Use Disorder, Global Crackdown on Illegal Drug Websites, Civil Money Penalties, Standing with Pittsburgh’s Jewish Community


Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act

President signed into law the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act

  • Require certain opioid packaging for shorter durations of use,  reduce number of 30-day prescriptions, address problem of excess supply
  • Require opioids be dispensed with mail-back pouch or other safe disposal option
  • Promote development of evidence-based opioid prescribing guidelines for treating acute pain resulting from specific conditions or procedures
  • Support developing pain drugs that are not addictive, as well as better understanding of safety/efficacy profile of existing opioids



Global operation to crack down on websites selling illegal, potentially dangerous drugs; including opioids

Action against target 465 websites illegally selling dangerous, unapproved versions of opioid, oncology, antiviral prescription drugs to U.S. consumers

  • Global cooperative effort, led by Interpol
  • Target illegal online pharmacies that knowingly and unlawfully distribute illicit drugs both on the surface and dark web
  • Consumers at risk by individuals who put financial gains above patient safety
  • Information on how to buy medicine safely online: BeSafeRx: Know Your Online Pharmacy



Civil Money Penalties Relating to the Data Bank

Civil money penalties for violating 42 CFR Part 11, to submit registration
and/or results information to the data bank 

  • Identification of violators
  • Circumstances for seeking civil money penalty
  • Procedures for seeking civil money penalty

Civil money penalties may be assessed for

  1. failing to submit required clinical trial registration
  2. submitting false or misleading information to the data bank
  3. failing to submit required certification to FDA
  4. knowingly submitting a false certification to FDA

Maximum penalties not more than $10,000 for all violations adjudicated in single proceeding, if a violation is not corrected within 30 days – not more than $10,000 for each day that violation continues 



♥ we stand with the Tree of Life Synagogue and with the Jewish community of Pittsburgh ♥

Image credits: FDA, Interpol

News and Views: Organs-on-Chips, DTC promotional labeling/advertisements, Critical Mitochondrial Functions of Cancer Cells, FDA-DHS coordination for Cybersecurity Threats, Cybersecurity Guidance, Targeted Therapies innovation, Fall 2018 Unified Agenda


Organs-On-Chips for Radiation Countermeasures

Organs-on-chips mimic the structure, function, interactions between living tissues within human organs on chips

Use for development of medical countermeasures (MCMs)

  • Develop models of radiation damage in lung, gut, and bone marrow organs-on-chips
  • Use models to test candidate medical countermeasures to treat such damage

Understand how sex differences impact body’s response to MCMs for radiological and nuclear preparedness

  • Assess differences in sex-specific responses to radiation exposure and chemotherapeutic agents
  • Effect of MCMs on that response in the bone marrow chip



Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements

Recent research on Direct-to-consumer (DTC) promotional labeling/advertisements for prescription and OTC drugs indicates

  • Consumers can recall and comprehend efficacy and risk information when it is provided quantitatively
  • Quantitative information can improve consumers’ accuracy in estimating the drug’s benefits and risks

Recommendations for presenting quantitative efficacy and risk information in DTC promotional materials: 

  • Probability information in terms of absolute frequencies, percentages, and relative frequencies
  • Formatting quantitative efficacy or risk information
  • Using visual aids to illustrate quantitative efficacy or risk information
  • Providing quantitative efficacy or risk information for the treatment group and the control group



CDER Scientists Investigate Critical Cellular Functions That Can Be Targeted to Kill Cancer Cells

Scientists in the CDER Office of Pharmaceutical Quality studying biochemical reactions of cancer cells to certain drugs designed to penetrate mitochondria 

  • Mitochondria are  “powerhouses” of the cell
  • Drugs that selectively enter and damage the mitochondria of cancer cells are of interest
  • However, cancer cells may thwart this strategy by employing a multi-step process, called mitophagy
  • Understand how removal of damaged mitochondria by mitophagy contributes to drug resistance during chemotherapy



FDA and DHS increase coordination of responses to medical device cybersecurity threats under new partnership

FDA and Dept of Homeland Security (DHS) signed memorandum of agreement to implement a new framework for addressing cybersecurity in medical devices

  • DHS will continue as central medical device vulnerability coordination center
  • DHS will continue to coordinate and enable information sharing between medical device manufacturers, researchers and the FDA
  • FDA will continue to engage with DHS and advise DHS regarding the risk to patient health and potential for harm posed by identified cybersecurity threats and vulnerabilities



Draft Recommendations on Premarket Submissions for Management of Cybersecurity in Medical Devices

Provide recommendations regarding cybersecurity device design, labeling, and documentation  for devices with cybersecurity risk

  • General Principles & Risk Assessment
  • Designing a Trustworthy Device: Application of NIST Cybersecurity Framework
  • Labeling Recommendations for Devices with Cybersecurity Risks
  • Cybersecurity Documentation
  • Recognized Standards



FDA’s new steps to modernize drug development, improve efficiency and promote innovation of targeted therapies

Focus on modernizing approach to design of clinical trials,  making drug development process efficient and less costly, while maintaining regulatory standards

  • New pilot program to encourage use of complex innovative trial designs, particularly in areas with small patient populations or unmet need
  • Use of  master protocols in oncology trials and one on the use of adaptive designs for clinical trials

Two new guidances



Fall 2018 Unified Agenda: FDA’s New Regulatory Work to Advance Health and Safety

Federal government published Fall 2018 Unified Agenda,  on government’s top regulatory priorities including FDA priorities

  • Combating Nicotine Addiction and Preventing Use among Youth
  • Modernizing Nutrition Claims, Labels and Standards of Identity
  • Prioritizing Medical Device Innovation and Safety
  • Advancing Drug Safety, Accessibility and Affordability



Image credit: FDA

Marketing Authorizations: Bose Hearing Aid, JIVI, LIBTAYO, VIZIMPRO



Bose Corporation

INDICATION FOR USE: To amplify sounds for individuals 18 years or older with perceived mild to moderate hearing impairment (hearing loss)


  •  37.5 million adults aged 18 and over report having some trouble hearing without a hearing aid
  • First hearing aid authorized for marketing by the FDA that enables users to fit, program and control the hearing aid on their own, without assistance from a health care provider


  • User-fitted wireless air conduction hearing aid
  • Captures sound vibrations through one or more microphones
  • Signal is processed, amplified, and played back through an earphone placed in the ear canal
  • Patients can adjust aid through mobile application on phone
  • Enables users to fit the hearing aid settings themselves, in real-time and in real-world environments without the assistance of a health care professional


  • Clinical data from 125 patients
  • Self-fitting of the Bose Hearing Aid comparable to those with professional fitting
    • Amount of amplification selected, speech in noise testing and overall benefit
  • Patients preferred those hearing aid settings over professionally-selected settings
  • Labeling to inform consumer when to consult a hearing health care professional



JIVI [antihemophilic factor (recombinant), PEGylated-aucl]

Bayer Healthcare

INDICATION FOR USE: For use in previously treated adults and adolescents (12 years of age and older) with hemophilia A (congenital Factor VIII deficiency) for: on-demand treatment and control of bleeding episodes; perioperative management of bleeding; and routine prophylaxis to reduce the frequency of bleeding episodes.


  • Option for : On-demand treatment and control of bleeding episodes; Perioperative management of bleeding;  Routine prophylaxis to reduce the frequency of bleeding episodes.

MECHANISM OF ACTION: Site-specifically PEGylated recombinant antihemophilic factor [see Description (11)], temporarily replaces the missing coagulation Factor VIII. The site-specific PEGylation in the A3 domain reduces binding to the physiological Factor VIII clearance receptors resulting in an extended half-life and increased AUC



  • On-demand JIVI is effective for treatment of and prevention of spontaneous or traumatic bleeding in patients with Hemophilia A
  • JIVI is effective in the perioperative setting for reduction of bleeding during surgery
  • JIVI is effective in patients over years of age


  • Hypersensitivity reactions and development of anti-PEG antibodies which resulted in loss of efficacy in patients <12 years of age
  • Risk of development of inhibitory antibodies is considered an expected adverse event




LIBTAYO (cemiplimab-rwlc) injection

Regeneron Pharmaceuticals

INDICATION:  Treatment of patients with metastatic cutaneous squamous cell
carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation


  • First  approval of a drug specifically for advanced CSCC
  • CSCC is the second most common human cancer in the United States with an estimated annual incidence of approximately 700,000 cases
  • Immune checkpoint inhibitors targeting the the PD-1 / PD-L1 pathway for treating a variety of tumors, from bladder to head and neck cancer, and now advanced CSCC


  • Two open label clinical trials, n=108 patients (75 with metastatic disease and 33 with locally-advanced disease)
  • Primary endpoint: Objective response rate, or the percentage of patients who experienced partial shrinkage or complete disappearance of their tumor(s) after treatment
  • 47.2% patients had tumors shrink or disappear


  • Severe and Fatal Immune-Mediated Adverse Reactions
  • Infusion-Related Reactions, Embryo-Fetal Toxicity
  • Common side effects: Fatigue, rash and diarrhea
  • Must be dispensed with a patient Medication Guide


  • Breakthrough Therapy and Priority Review designations



VIZIMPRO (dacomitinib) tablets


INDICATION FOR USE:  First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test

MECHANISM OF ACTION:  Irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation)


  • Randomized, multicenter, open-label, active controlled trialm n= 452 patients with unresectable, metastatic NSCLC,  dacomitinib vs gefitinib
  • Significant improvement in progression-free survival; no improvement in overall response rate or overall survival were demonstrated
  • Median progression-free survival; 14.7 vs. 9.2 months p<0.0001


  • Warnings & Precautions: Interstitial Lung Disease (ILD), Diarrhea, Dermatologic Adverse Reactions, Embryo-Fetal Toxicity


  • Priority Review and Orphan Drug Designation
  • Postmarketing study:  Pharmacokinetic trial to determine an appropriate dose of dacomitinib to minimize toxicity in patients with severe hepatic impairment


Image credit: Bose, Bayer, Regeneron, Pfizer


News and Views: CDRH 2019 guidances, ‘Gaming’ of Generics, Master Protocols, Antimicrobial Resistance, Medical Device Cybersecurity


Medical device guidance documents intended to be published in 2019

To meet quantitative and qualitative goals intended to help get safe and effective medical devices to market more quickly

  • List of prioritized device guidance documents (the “A-list”);
  • List of guidances to be published as resources permit (the “B-list”)
  • Update website in a timely manner
  • Provide stakeholders an opportunity to provide feedback
  • Finalize, withdraw, reopen the comment period,

The ‘A’ List- Final Guidances

  • Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions
  • Unique Device Identification: Policy Regarding Compliance Dates for Class I and Unclassified Devices and Direct Marking of Inventory
  • Breakthrough Devices Program
  • Expansion of the Abbreviated 510(k) Program: Demonstrating Substantial Equivalence through Performance Criteria
  • The Least Burdensome Provisions: Concept and Principles
  • Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act
  • Clinical and Patient Decision Support Software
  • Multiple Function Device Products:  Policy and Considerations
  • Humanitarian Device Exemption (HDE) Program
  • Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program
  • The Special 510(k) Program




New agency actions to further deter ‘gaming’ of the generic drug approval process by the use of citizen petitions

Drug Competition Action Plan for steps to increase competition and help facilitate entry of lower-cost affordable alternatives 

Address practices by branded firms to “game” system and extend monopoly

  • Make it hard for generic manufacturers to get access to  branded drug
  •  Use of citizen petitions (Section 505(q), FD&C Act)  to block generic entry

Revised draft guidance to allow for more efficient approach to 505(q) petitions and allow  reviewer resources on scientific reviews.



Master Protocols- Efficient Clinical Trial Design Strategies to Expedite Development of Cancer Drugs and Biologics.

Design and conduct of clinical trials intended to simultaneously evaluate more than one investigational oncology drugs

  •  More than one cancer type within the same overall trial structure (master protocols) in adult and pediatric cancers
  • The recommended phase 2 dose (RP2D) has been established
  • Focus for continued discussions among FDA, pharmaceutical sponsors, academic community, public
  • Describes aspects of master protocol designs and trial conduct and related considerations, such as biomarker codevelopment, statistical analysis considerations

Types : Single Investigational Drug or Investigational Drug Combination Across Multiple Cancer Populations, Investigational Drugs or Investigational Drug Combination(s) in Single Cancer Type

Specific Design Considerations: Single Common Control Arm, Novel Combination of Two or More Investigational Drugs, Drugs Targeting Multiple Biomarkers, dding and Stopping Treatment Arms, Biomarker development

Statistical Considerations: Nonrandomized, Activity-Estimating Design, Randomized Designs., Adaptive/Bayesian Design, Biomarker-Defined Subgroups



Antimicrobial Resistance Information from FDA

Antimicrobial resistance (AMR)—the ability of a microorganism (bacteria, virus, fungi, parasite) to resist the effects of a drug—is serious, complex, costly public health problem

  • At least two million people develop serious infections caused by AMR each year in US, the United States a, and at least 23,000 people die as a result. Combating AMR re

Proactively addressing complex challenges associated with growing threat of AMR by

  • Facilitating efficient product development: development of new antimicrobials, diagnostic tests, and vaccines
  • Promoting appropriate and responsible use of antimicrobials :promoting interventions to slow development of resistance
  • Supporting development and enhancement of tools for conducting surveillance:  better track, treat, or respond to AMR outbreaks
  • Advancing regulatory science:  translation of breakthrough discoveries in science and technology into innovative, safe, and effective medical products



FDA’s efforts to strengthen the agency’s medical device cybersecurity program as part of its mission to protect patients

FDA working hard with various stakeholders to stay ahead of constantly evolving cybersecurity vulnerabilities

  • Created a Cybersecurity Working Group within CDRH
  • Guidance to establish framework to address cybersecurity regulatory considerations:  Premarket and Postmarket
  • Create shared responsibility with diverse stakeholders, including other government agencies, industry, health care delivery organizations, cybersecurity researchers
  • MITRE Corporation, with support from the FDA, released a Medical Device Cybersecurity Regional Incident Preparedness and Response Playbookdisclaimer icon.
  •  Memoranda of understanding with multiple stakeholder groups to create information sharing analysis organizations (ISAOs)
  • Participating with manufacturers in the DefCon Biohacking Village – Medical Device Hacking Lab in 2018
  • Issued Medical Device Safety Action Plan for advancing medical device cybersecurity


Image credit: FDA


News and Views: Digital Health Innovation, Facilitating Third Party Review, Drug Supply Chain Security, Flu Vaccinations, Rare Diseases Grants, Collaborative Communities Toolkit


FDA Budget Matters: Advancing Innovation in Digital Health

Digital health tools have vast potential to diagnose and treat disease, enhance delivery of health care for the individual

  • modern, flexible, risk-based approaches to regulation
  • launched our Digital Health Innovation Action Plan
  • committed to launching the digital health software precertification pilot program

Sought additional resources as part of the FDA’s FY2019 Budget

  • Create Center of Excellence for Digital Health (CoE) to advance pre-certification model
  • Building a new capacity to evaluate third-party certifiers of digital technologies
  • Create cybersecurity unit to complement the advances in software-based devices,


Capture.JPGEliminating Routine FDA Re-Review of Third Party 510(k) Reviews

Updating 510(k) Third Party (3P) Review Program to avoid routine re-review of 510(k) submissions already reviewed by a 3P Review Organization (3PRO)

  • Ensuring eligible device types are appropriate
  • Giving 3PRO reviewers tools needed to succeed
  • Providing way to demonstrate successful application of FDA’s 510(k) criteria
  • Implementing comprehensive framework for processing of submission packages
  • Using program measures to monitor 3P Review Program



FDA advances policies related to bolstering security of drug products in the U.S. supply chain

Guidances  to ensure that prescription drug products are identified and traced properly as they move through the supply chain in compliance with federal law


Preparations for the upcoming flu season and vaccinations

FDA has a key role in selecting strains to be included in seasonal flu vaccines

  • Designed to target three or four of the most likely viruses:  two influenza A types (H1N1 and H3N2) and one (trivalent formulation) or two (quadrivalent formulation) types of influenza B
  • FDA, World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC) review data collected on globally circulating strains
  • Vaccines and Related Biological Products Advisory Committee (VRBPAC) met in March 2018 to select strains for upcoming season
  • Addressed last year’s challenges with selection of  less protective strains
  • Ensures released lots meet appropriate standards including testing for sterility.

Seasonal flu vaccine one of the most effective and safest ways to protect



FDA awards 12 grants to advance rare diseases medical products 

FDA awarded grants through Orphan Products Clinical Trials Grants Program for clinical studies for treatment of rare diseases

  • Reviewed and evaluated for scientific and technical merit by more than 100 rare disease experts (academia, NIH, FDA)
  • Created in 1983, has provided > $400 million to fund > 600 new clinical studies

Grant recipients 

  • Alkeus Pharmaceuticals, Inc., Arizona State University-Tempe Campus, Cedars-Sinai Medical Center, Columbia University of New York,  Emory University,  Fibrocell Technologies, Inc.,  Johns Hopkins University,  Oncolmmune, Inc.,  Patagonia Pharmaceuticals, LLC,  The General Hospital Corporation, University of Minnesota, University of North Carolina at Chapel Hill


CaptureCollaborative Communities Toolkit 

Collaborative community is private- and public-sector forum (including FDA)  to work together on medical device challenges

  • Challenges are ill-defined or there is no consensus on the definition
  • Challenges and outcomes are complex
  • Partners are interrelated
  • Incremental or unilateral efforts to address the challenge have been ineffective
  • Partners seek to optimize efforts, including preventing duplication of efforts
  • Better outcomes could be achieved with integrating different perspectives, experiences, resources, and expertise


  • Collection of materials designed to help a community become established, to encourage effective collaboration, and foster rich communities to take on healthcare challenges


Image credit: FDA



News and Views: Digital Health Innovation, Development of New Antibacterial Drugs, Opioid REMS, Civil Money Penalties Related to


Efforts to work with tech industry to spur innovation in digital health


Development of New Antibacterial Drugs Active Against Multi-Drug Resistant Bacteria

Bacterial drug resistance is major threat to public health
  • Design and conduct of clinical trials to evaluate new antibacterial drugs challenging
  • Recruitment can be difficult
  • Delay in availability of information regarding identification and antibacterial susceptibility of the causal pathogen
Request for Information (RFI) to solicit input from public and private sectors into developing regulatory science initiatives specific for antimicrobial products


Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Approval of final Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

  • Several measures to help better communicate the serious risks about the use of opioid pain medications to patients and health care professionals
  • Applies to immediate-release (IR) opioid analgesics intended for use in an outpatient setting
  • Also applies to the extended-release and long-acting (ER/LA) opioid analgesics, which have been subject to a REMS since 2012

New requirements

  • Training for health care providers who are involved in the management of patients with pain, and not only to prescribers
  • Education cover broader information about appropriate pain management, including alternatives to opioids for the treatment of pain
  • New product labeling containing information about the health care provider education

New FDA Opioid Analgesic REMS Education Blueprint for Health Care Providers Involved in the Treatment and Monitoring of Patients with Pain (Blueprint)

  • Updated educational content
  • Ensure proper product is selected for the patient and used with appropriate clinical oversight



Civil Money Penalties Relating to the Data Bank

Describes civil money penalties against responsible parties and/or submitters on submission of regiatration and /or results information to the data bank and/or certain certifications to FDA

  • How do the Centers intend to identify whether
    • responsible parties have failed to submit required clinical trial registration and/or results information to the data bank
    • Submitted false or misleading information to the data bank
    • Failed to submit to FDA the certification
  • Under what circumstances may a Center decide to seek civil money penalties against a responsible party or submitter?
  • What procedures apply when a Center seeks civil money penalties?
  • What civil money penalty amounts may be assessed


Image credit: FDA

Market Authorizations: APPLE ECG App, APPLE Irregular Rhythm Notification Feature, LUMOXITI, PK Papyrus System, AJOVY





The ECG app is a software-only mobile medical application intended for use with the Apple Watch to create, record, store, transfer, and display a single channel electrocardiogram (ECG) similar to a Lead I ECG.

The ECG app determines the presence of atrial fibrillation (AFib) or sinus rhythm on a classifiable waveform. The ECG app is not recommended for users with other known arrhythmias.

The ECG app is intended for over-the-counter (OTC) use. The ECG data displayed by the ECG app is intended for informational use only. The user is not intended to interpret or take clinical action based on the device output without consultation of a qualified healthcare professional. The ECG waveform is meant to supplement rhythm classification for the purposes of discriminating AFib from normal sinus rhythm and not intended to replace traditional methods of diagnosis or treatment.

The ECG app is not intended for use by people under 22 years old.

GENERIC TYPE OF DEVICE: Electrocardiograph software for over-the-counter use

Creates, analyzes, and displays electrocardiograph data, and can provide information for identifying cardiac arrhythmias. This device is not intended to provide a diagnosis


  • Poor quality ECG signal resulting in failure to detect arrhythmia: Clinical performance testing, Human factors testing, Labeling
  • Misinterpretation and/or over-reliance on device output, leading to:  Failure to seek treatment despite acute symptoms, Discontinuing or modifying treatment for chronic heart condition: Human factors testing, Labeling 
  • False negative resulting in failure to identify arrhythmia and delay of further evaluation or treatment: Clinical performance testing, Software verification, validation, and hazard analysis, Non-clinical performance testing, Labeling
  • False positive resulting in additional unnecessary medical procedures: Clinical performance testing, Software verification, validation, and hazard analysis, Non-clinical performance testing, Labeling


  • Trade/Device Name: ECG App
  • Regulation Number: 21 CFR 870.2345
  • Regulation Name: Electrocardiograph software for over-the-counter use
  • Regulatory Class: Class II
  • Product Code: QDA



Irregular Rhythm Notification Feature


INDICATION FOR USE:  software-only mobile medical application that is intended to be used with the Apple Watch. The feature analyzes pulse rate data to identify episodes of irregular heart rhythms suggestive of atrial fibrillation (AFib) and provides a notification to the user.

The feature is intended for over-the-counter (OTC) use. It is not intended to provide a notification on every episode of irregular rhythm suggestive of AFib and the absence of a notification is not intended to indicate no disease process is present; rather the feature is intended to opportunistically surface a notification of possible AFib when sufficient data are available for analysis. These data are only captured when the user is still. Along with the user’s risk factors, the feature can be used to supplement the decision for AFib screening. The feature is not intended to replace traditional methods of diagnosis or treatment.

The feature has not been tested for and is not intended for use in people under 22 years of age. It is also not intended for use in individuals previously diagnosed with AFib.

GENERIC TYPE OF DEVICE: Photoplethysmograph analysis software for over-the-counter use.

Analyzes photoplethysmograph data and provides information for identifying irregular heart rhythms. This device is not intended to provide a diagnosis.


  • Poor quality incoming PPG signal resulting in failure to detect irregular heart rhythms: Clinical performance testing, Human factors testing, Labeling
  • Misinterpretation and/or over-reliance on device output, leading to: Failure to seek treatment despite acute symptoms (e.g., fluttering sensation in the chest,  lightheadedness, and irregular pulse), Discontinuing or modifying treatment for
    chronic heart condition: Human factors testing, Labeling
  • False negative resulting in failure to detect irregular heart rhythms and delay of further evaluation or treatment: Clinical performance testing, Software verification, validation, and hazard analysis, Non-clinical performance testing, Labeling
  • False positive resulting in additional unnecessary medical procedures: Clinical performance testing, Software verification, validation, and hazard analysis
    Non-clinical performance testing, Labeling


  • Trade/Device Name: Irregular Rhythm Notification Feature
  • Regulation Number: 21 CFR 870.2790
  • Regulation Name: Photoplethysmograph analysis software for over-the-counter use
  • Regulatory Class: Class II
  • Product Code: QDB



LUMOXITI (moxetumomab pasudotox-tdfk) for injection


INDICATION: Treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies, including treatment with a purine nucleoside analog (PNA).


  • HCL is a rare, slow-growing cancer of the blood
  • Approval fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies
  • Result of important research conducted by the National Cancer Institute

MECHANISM OF ACTION: CD22-directed cytotoxin, results in ADP-ribosylation of elongation factor 2, inhibition of protein synthesis, and apoptotic cell death


  • Single-arm, open-label clinical trial, n=80 patients who had received prior treatment for HCL with at least two systemic therapies
  • Endpoints: Blinded independent review committee (IRC)-assessed Durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR
  • Durable CR: 30%,
  • Overall response rate: 75%


  • Most common non-laboratory adverse reactions: Infusion related reactions, edema, nausea, fatigue, headache, pyrexia, constipation, anemia, and diarrhea
  • Most common grade 3 or 4 adverse reactions: Hypertension, febrile neutropenia, and hemolytic uremic syndrome (HUS)


  • Orphan, fast track and priority review designations
  • Postmarketing requirements: Safety  in patient who are 65 years of age and older and  in patients who have moderate renal impairment



PK Papyrus System 


INDICATION FOR USE: Treat acute coronary artery perforations, or tears in the blood vessels of the heart


  • Acute coronary artery perforation is a rare, but potentially life-threatening complication of heart vessel procedures
  • First device approved by the FDA for this indication in 17 years


  • Balloon-expandable covered coronary stent and delivery system
  • Advanced into the perforated coronary artery vessel using a balloon catheter
  • Once  implanted, it provides a physical barrier to seal the tear in the artery wall while still allowing blood to flow through the device to the heart muscle
  • Successful sealing can be a life-saving procedure without the need for open-heart surgery


  • Real-world survey data, n=80 patients who received PK Papyrus Stents to treat coronary artery perforations
  • Successfully delivered to the perforation site: 95%
  • Successfully sealed the perforation: 73%
  • Deaths: Two, occurred during the PCI procedure, post-procedure, in-hospital death occurred in five patients with perforations successfully sealed by PK Papyrus Stents and one patient in which the PK Papyrus Stent did not successfully seal the perforation

REGULATORY PATHWAY: Humanitarian Device Exemption

  •  Intended to benefit patients by treating or diagnosing a disease or condition that affects not more than 8,000 individuals in the U.S. per year
  • Classification Name: Coronary covered stent
  • Product Code: NIV



AJOVY (fremanezumab-vfrm) injection


INDICATION: Preventive treatment of migraine in adults

ADDRESSING UNMET NEED: Second FDA-approved preventive migraine treatment in a new class of drugs that work by blocking the activity of calcitonin gene-related peptide (CGRP), a molecule that is involved in migraine attacks


  • Two multicenter, randomized, 3-month, double-blind, placebo-controlled studies, n=875, 1130
  • Primary efficacy endpoint was the mean change from baseline in the monthly average number of migraine days during the 3-month treatment period
  • Statistically significant improvement vs placebo


  • The most common adverse reactions (≥5% and greater than placebo) were
    injection site reactions



Image credit: Apple, AstraZeneca, Biotronik, Teva

News and Views: Breast implant safety, E-Cig epidemic, Device submissions in eformat, Voluntary consensus standards for devices


Agency’s commitment to studying breast implant safety

FDA has worked over decades  to monitor, assess and take action to protect patients with regard to breast implant safety

  • Communicated risks such as capsular contracture, implant rupture and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)
  • However, disagree with claims of increased risk of certain connective tissue conditions, such as rheumatoid arthritis and scleroderma

Streamlining and modernizing postmarket actions to address device safety issues 

  • Coordinated with American Society of Plastic Surgeons and Plastic Surgeons Foundation to develop Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology
  • Development of the National Breast Implant Registry
  • Meet with patient advocacy group focused on breast implant related issues
  • Public meeting of the General and Plastic Surgery Devices Panel of our Medical Devices Advisory Committee in 2019


New steps to address epidemic of youth e-cigarette use

Didn’t predict epidemic of e-cigarette use among teenagers

  • Disturbing and accelerating trajectory of use in youth, and resulting addiction
  • Launched Youth Tobacco Prevention Plan earlier this year.

Series of compliance actions over the past year

  • In partnership with Federal Trade Commission, targeted misleadingly labeled or advertised e-liquids resembling kid-friendly foods like juice boxes, candy and cookies
  • Warning letters and civil monetary penalties to JUUL
  • >1000 warning letters to stores for illegal sale of e-cigarettes to minors
  • Re-examining the enforcement discretion currently exercised for other e-cig products currently on the market without authorization



Medical Device Submissions in Electronic Format

Proposed rule for medical device premarket submissions to be sent in electronic format, eliminating the need for multiple paper submissions

  • To improve efficiency of premarket submission program



Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical Devices

Appropriate use of national and international voluntary consensus standards (referred to as consensus standards) in the preparation and evaluation of premarket submissions

  • Provide clarity and explanation about the regulatory framework, policies, and practices regarding the appropriate utilization of consensus standards


  • Use of Consensus Standards
    • Use of Declarations of Conformity
    • General Use of Consensus Standards
  • Managing Product Development When Standards Change: Transition Periods
    • Where to Find Information on a Transition Period .
    • When Standards Change Prior to Review of a Premarket Submission .
    • When Standards Change During Active Review of a Premarket Submission
    • Transition Period Expiration
  • Promissory Statements
  • Limitations of Consensus Standards
  • When Devices or Standards Change After Marketing Authorization


Image credits: FDA

Market Authorizations: BRAINSWAY Stimulation System, ABBOTT RealTime IDH1, TAKHZYRO, OXERVATE, DIACOMIT


BRAINSWAY Deep Transcranial Magnetic Stimulation System

Brainsway Ltd.

INDICATION FOR USE: Adjunct for the treatment of adult patients suffering from Obsessive-Compulsive Disorder


  • Transcranial magnetic stimulation has potential to help patients suffering from depression and headaches
  • Another option for patients with OCD who have not responded to traditional treatments

GENERIC DEVICE TYPE: Transcranial magnetic stimulation system for neurological and psychiatric disorders and conditions

  • Prescription, non-implantable device that uses brief duration, rapidly alternating,
    or pulsed, magnetic fields to induce neural activity in the cerebral cortex. It is not intended for applying or focusing magnetic fields towards brain areas outside cerebral cortex (e.g., cerebellum). A repetitive transcranial magnetic stimulation system that is intended to treat major depressive disorder is classified in § 882.5805. A transcranial magnetic stimulation system for headache is classified in § 882.5808.


  • Multi-center study, n=100 patients receiving OCD treatments (medical management), Brainsway device vs. non-working (sham) device
  • Effectiveness endpoint: Reduction in Yale-Brown Obsessive Compulsive Scale (YBOCS) score; 38% on Brainsway with > 30% reduction vs. 11%
  • Adverse reactions: Headache,  application site pain or discomfort, jaw pain, facial pain, muscle pain, spasm or twitching, and neck pain


  • Seizure, Thermal injury, Hearing loss, Scalp discomfort, dizziness, nausea, pain in neck or jaw, headache, or other adverse effects due to treatment, Adverse tissue reaction, Electrical shock,  Device failure due to interference with other devices
  • Non-clinical performance testing, Labeling, Thermal safety testing, Electrical safety testing, Electromagnetic compatibility testing, Software verification, validation, and hazard analysis, Biocompatibility evaluation


  • Prior approvals in treatment for major depression (2008) and treating pain associated with certain migraine headaches (2013)
  • Regulation Number: 21 CFR 882.5802
  • Regulation Name: Transcranial magnetic stimulation system for neurological and psychiatric disorders and conditions
  • Regulatory Class: Class II
  • Product Code: QCI



Abbott RealTime IDH1

Abbott Molecular Inc.

INDICATION FOR USE:  In vitro polymerase chain reaction (PCR) assay for the qualitative detection of single nucleotide variants (SNVs) coding five IDH1 R132 mutations (R132C, R132H, R132G, R132S, and R132L) in DNA extracted from human blood (EDTA) or bone marrow (EDTA). Abbott RealTime IDH1 is for use with the Abbott m2000rt System.

Abbott RealTime IDH1 is indicated as an aid in identifying acute myeloid leukemia (AML) patients with an isocitrate dehydrogenase-1 (IDH1) mutation for treatment with TIBSOVO® (ivosidenib).

This test is for prescription use only.


  • Abbott RealTime IDH1 Amplification Reagent Kit
  • Abbott RealTime IDH1 Control Kit
  • Abbott mSample Preparation SystemDNA Kit
  • . Abbott RealTime IDH1 m2000rt Application CD-ROM


  • Accurate qualitative detection of single nucleotide variants (SNVs) coding five IDH1 mutations (R132C, R132H, R132G, R132S and R132L) in DNA extracted from human bone marrow or blood in patients with relapsed or refractory AML
  • Open-label, single-arm, international, multicenter clinical trial of TIBSOVO (ivosidenib), n=174 adult patients with relapsed or refractory AML and one of 5 IDH1 mutations in codon R132 detected by Abbott RealTime IDH1 assay
  • 32.8% exhibited complete remission or complete remission with partial hematological recovery


  • Potential mismanagement of patients resulting from false results
  • Failure to perform as expected or failure to correctly interpret test results
  • False positive test result may lead to TIBSOVO treatment in patient who is not expected to benefit, and suffer from any potential adverse side effects
  • False negative test result may lead to TIBSOVO (ivosidenib) treatment not being administered to a patient who may benefit from this drug




TAKHZYRO (lanadelumab-flyo) injection, for subcutaneous use

Dyax Corporation

INDICATION:  For prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older.


  • First monoclonal antibody approved to treat patients 12 years and older with types I and II HAE
  • HAE is rare and serious genetic disease that affects people with low levels of and poorly functioning C1-INH proteins; recurrent, unpredictable episodes of severe swelling in different areas of the body

MECHANISM OF ACTION:  Fully human monoclonal antibody (IgG1/κ-light chain) that binds plasma kallikrein (uncontrollably increased in HAE) and inhibits proteolytic activity which prevents angioedema attacks


  • Multicenter, randomized, double-blind, placebo-controlled, parallel-group study, n=125 patients with HAE
  • Takhzyro caused clinically meaningful and statistically significant reductions in the rate of investigator-confirmed HAE attacks vs. placebo over 6-month treatment period


  • Most common adverse drug reactions: Injection site reactions, upper respiratory infections, headache, rash, muscle pain, dizziness and diarrhea.


  • Priority Review, Breakthrough Therapy designation, Orphan Drug designation
  • Postmarketing commitment: Low endotoxin recovery (LER) study



OXERVATE (cenegermin-bkbj) ophthalmic solution for topical
ophthalmic use 

Dompé farmaceutici SpA.

INDICATION: Treatment of neurotrophic keratitis


  • First approved drug for neurotrophic keratitis, a rare degenerative disease affecting cornea
  • Loss of corneal sensation impairs corneal health and damage- corneal thinning, ulceration, and perforation in severe cases
  • Prevalence estimated to be less than five in 10,000 individuals

MECHANISM OF ACTION: Nerve growth factor is an endogenous protein involved in differentiation and maintenance of neurons which acts through nerve growth factor receptors in the anterior segment of the eye to support corneal innervation and integrity


  • Two, eight-week, randomized controlled multi-center, double-masked studies. n= 151 patients with neurotrophic keratitis
  • Across both studies, complete corneal healing in eight weeks was demonstrated in 70% of patients treated with Oxervate (containing cenegermin) vs. 28% treated without cenegermin


  • Most common adverse reactions: Eye pain, ocular hyperemia, eye inflammation and increased lacrimation (wat


  • Priority Review, Orphan Drug Designation
  • Postmarketing commitments:  Clinical study to determine systemic exposure following repeated topical ocular dosing, manufacturing and shipping validations



DIACOMIT (stiripentol) capsules and powder, for oral suspension


INDICATION: Treatment of seizures associated with Dravet syndrome (DS) in patients 2 years of age and older taking clobazam.

There are no clinical data to support the use of DIACOMIT as monotherapy in Dravet syndrome.

  • Treatment option for rare genetic condition leading ot seizures from first year of life

MECHANISM OF ACTION: Possible mechanisms include direct effects mediated through gamma-aminobutyric acid (GABA)A receptor and indirect effects involving inhibition of cytochrome P450 activity with resulting increase in blood levels of clobazam and active metabolite.

  • 2 multicenter placebo-controlled double-blind randomized studies, patients with Dravet syndrome inadequately controlled on clobazam and valproate, DIACOMIT vs placebo, n=64
  • Primary efficacy endpoint: Responder rate- patient who experienced > 50% decrease in frequency (per 30 days) of generalized clonic or tonic-clonic seizures
  • In both studies, responder rate significantly greater for DIACOMIT vs. placebo
  • Most common side effects: Somnolence, decreased appetite, agitation, ataxia, weight loss, hypotonia, nausea, tremor, dysarthria, insomnia
  • Must be dispensed with Medication Guide


Image credits: Brainsway, Abbott, Dyax, Dompé, Biocodex 

News and Views: Global Efforts for Product Quality, FDA-Payor Program, Uncertainty in Benefit-Risk  Determinations, 510(k) “Quik” Program


Global efforts to help assure product quality and transparency at foreign drug manufacturing facilities

FDA framework to help assure that all drug products meet the same high-quality standards, regardless of where they’re manufactured, brand or generic products, prescription or over-the-counter drugs


Capture.JPGNew Program with Payors Aims to Accelerate Patient Access to Medical Devices

FDA recognizes importance of working collaboratively with payor community to streamline the path from FDA market authorization to payor coverage and reimbursement.

Parallel Review Program: Piloted in 2011, fully adopted in 2016. Mechanism for decreasing time between FDA’s approval of a pre-market medical device application and CMS national coverage determination

  • Early feedback from the FDA and CMS on design of pivotal clinical trial in Pre-Submission Mtg
  • 75 inquiries into the process and 36 formal applications to participate in Parallel Review

Private Payor Program: Launched in 2016

  • Receive feedback from  FDA and other non-governmental health technology assessors/payors during the Pre-Submission mtg
  • Participants:  BlueCross BlueShield Association, Duke Evidence Synthesis Group, ECRI Institute, Humana, Kaiser Permanente, and the National Institute for Health and Care Excellence (NICE)
  • New Additions: CareFirst BlueCross BlueShield and United Health Group
  • 4 Pre-Submission mtgs with private payors
  • Program continues to gain momentum receiving new inquiries weekly

Payor engagement strategy particularly beneficial for manufacturers creating new and innovative devices 



Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions

Principles in guidance apply to FDA’s consideration of uncertainty in benefit-risk determinations for PMAs, De Novo requests, and HDE applications. Factors include:

  • Extent of probable benefits including the type, magnitude, probability, duration, frequency
  • Extent of probable risks including the severity, type, number, rates, probability,  duration
  • Extent of uncertainty regarding the benefit-risk profile of alternative treatments
  • Patients’ perspective on appropriate uncertainty about probable benefits and risks
  • Extent of the public health need (e.g., seriousness of the illness)
  • Feasibility of generating extensive clinical evidence premarket
  • Ability to reduce or resolve remaining uncertainty  postmarket
  • Likely effectiveness of postmarket mitigations, such as labeling
  • Type of decision being made
  • Probable benefits of earlier patient access to the device

Examples provided



Quality in 510(k) “Quik” Review Program Pilot

Launch of Quality in 510(k) (“Quik”) Review Program pilot

  • Simplify completion of  premarket notification (510(k)) submission for sertain moderate risk devices
  • Use free eSubmitter software for review efficiency
  • Not be subject to a Refuse to Accept (RTA) review; FDA interactive review and decision within 60 days
  • Does not change any requirements for the determination of substantial equivalence


Image credits: FDA, CMS




News & Views: Forcefully addressing Opioid Crisis, Complex Innovative Trial Designs, Initiatives to Modernize for Innovation


Agency’s ongoing work to forcefully address the opioid crisis

FDA addressing opioid crisis forcefully

  • Cut the rate of new addiction
  • Stepped up enforcement of marketing and sale of illicit opioids
  • Novel product innovation for opioid addiction treatment, non-addictive pain treatments
  • New Opioid Policy Steering Committee


  • Extension of risk evaluation and mitigation strategy program for immediate release formulations of opioid drugs
  • Broad effort to develop evidence-based guidelines for opioid prescribing
  • Protect children from unnecessary exposure to certain opioids in prescription cough and cold medicines
  • Requested market withdrawal of Opana ER based on risks that manifest only when  misused and abused
  • Enforcement actions collaboration with the Federal Trade Commission on unapproved product websites
  • Sharply expanded oversight of drugs being shipped illegally through international mail facilities
  • Expanded new pathways for the development of safe and effective treatments for addiction
  • New regulatory guidance to promote abuse-deterrent formulations of opioid drugs
  • Innovation challenge for medical devices and mobile applications as alternatives to oral opioids
  • Public meetings on Opioid Use Disorder and on Chronic Pain



Complex Innovative Trial Designs Pilot Program

Goal of facilitating and advancing the use of complex adaptive, Bayesian, and other novel clinical trial designs

  • Pilot program offers sponsors increased FDA interaction to discuss proposed  CID approach


  • Use of CID approaches in late-stage drug development
  • Publicly discuss trial designs to promote innovation


Capture.JPGFDA’s Comprehensive Effort to Advance New Innovations: Initiatives to Modernize for Innovation

Innovating new operating system to meet FDA goal for medical care – right drug or device delivered to right patient at right time

  1. Modernizing Clinical Trials for Drugs and Devices
  2. Modernizing FDA’s Organization and Breaking Down Outdated Silos
  3. Harnessing Real World Evidence
  4. FDA’s Role in Curating Standards for Novel Technologies


Image credit: FDA

News and Views: Evidence based prescription opioids, Additional tropical diseases for PRV, Quality Metrics Site Visit Program, Placebo controlled oncology clinical trials


New steps to advance the development of evidence-based, indication-specific guidelines to help guide appropriate prescribing of opioid analgesics

Need to reexamine how opioid analgesics are being prescribed

  • Arm health care providers with the most current and comprehensive guidance on  appropriate pain management
  • Work together with medical professional societies to develop  evidence-based guidelines

Contract with National Academies of Sciences, Engineering, and Medicine (NASEM)

  • Advance development of evidence-based guideline and understand needed evidence
  • Identification and prioritization of procedures and conditions associated with acute pain for which opioid analgesics are commonly prescribed
  • Scan existing opioid analgesic prescribing guidelines, how developed, gaps in evidence
  • Outline research needed to generate that evidence
  • Meetings and public workshops with broad range of stakeholders



FDA Adds Four Tropical Diseases to Priority Review Voucher (PRV) Program to Encourage Development

Addition of: 

  • Lassa fever
  • Chikungunya virus disease
  • Rabies
  • Cryptococcal meningitis

Applicants who submit drug/biological products applications may qualify for a  Priority Review Voucher (PRV)

  • Can be used to obtain priority review of a subsequent drug application that does not itself qualify for priority review




Quality Metrics Site Visit Program for CDER & CBER; Information Available to Industry; Extension of the Proposal Period

Quality Metrics Site Visit Program for FDA staff involved in development of FDA’s Quality Metrics Program

  • Gain exposure to robust quality metrics programs
  • Through on-site visits, tours of operations, discussions
  • Observe how quality metrics data are gathered, collected, reported to management

The intended timeframe of the on-location Quality Metrics site visits is from October 1, 2018 to  September 30, 2019



Hematologic Malignancy and Oncologic Disease: Considerations for Use of Placebos and Blinding in Randomized Controlled Clinical Trials for Drug Product Development

Placebo-controlled design only in selected circumstances

  • where surveillance is standard of care
  • with certain trial design features (e.g. if the trial uses an add-on design, when the
    endpoint intended to support a labeling claim has a high degree of subjectivity, such as patient reported outcomes


  • Rationale for the trial design
  • Justification in the setting of  sham surgical procedure or when invasive methods required for administration of the placebo (e.g., intrathecal administration, repeated 78 intravenous administration via an indwelling catheter)
  • No requirement of  patient-level maintenance of blinding at time of disease
  • Unblinding patient at time of documented disease recurrence or progression to ensure optimal patient management


Image credit: FDA

Authorizations: ONPATTRO, NATURAL CYCLES Mobile Medical App, BONEBRIDGE Hearing System, GALAFOLD, ANNOVERA vaginal system


ONPATTRO (patisiran) infusion 

Alnylam Pharmaceuticals

INDICATION: Treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults (hATTR)


  •  First FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease
  • Characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs
  • Also first FDA approval of new class of drugs called small interfering ribonucleic acid (siRNA) treatment

MECHANISM OF ACTION: Silencing portion of RNA involved in causing the disease  by encasing siRNA into lipid nanoparticle to deliver drug directly into the liver to alter or halt the production of disease-causing proteins


  • Randomized, double-blind, placebo-controlled, multicenter clinical trial, n=225  adult patients with polyneuropathy caused by hATTR amyloidosis,  ONPATTRO vs. placebo (N=77), 18 months
  •  Primary efficacy endpoint: Change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7);  objectively measures deficits in cranial nerve
    function, muscle strength, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, peripheral nerve electrophysiology
  •  Clinical meaningfulness assessed by change from baseline in Norfolk
    Quality of Life-Diabetic Neuropathy (QoL-DN) total score (patient reported
  • Both changes significantly favored ONPATTRO


  • Most common adverse reactions: infusion-related reactions including flushing, back pain, nausea, abdominal pain, dyspnea, headache
  • May also experience: vision problems including dry eyes, blurred vision and eye floaters (vitreous floaters)


  • Fast Track, Priority Review and Breakthrough Therapy designations. Onpattro also received Orphan Drug designation
  • Exempt from pediatric requirements
  • Postmarketing requirements: worldwide Pregnancy Surveillance Program
  • Postmarketing commitements: in vitro drug release, quality agreements



NATURAL CYCLES Mobile Medical App

Natural Cycles Nordic AB.

INDICATION FOR USE:  Stand-alone software application, intended for women 18 years and older, to monitor their fertility. Natural Cycles can be used for preventing a pregnancy (contraception) or planning a pregnancy (conception)


  • Consumers increasingly using digital health technologies to inform everyday health decisions
  • First Direct to Consumer App provides effective method of contraception if used carefully and correctly


  • Over-the-counter web and mobile-based standalone software application
  • Monitors menstrual cycle using information entered by the user and informs the user about her past, current and future fertility status
  • Following information entered by user
    • Daily basal body temperature (BBT) measurements
    • Menstruation cycle (i.e., start date, number of days)
    • Optional ovulation or pregnancy test results
  • Proprietary algorithm evaluates data and returns user’s fertility status
  • Three modes: Contraception, Conception, and Pregnancy

GENERIC DEVICE TYPE: Software application for contraception

  • Device that provides user-specific fertility information for preventing a pregnancy. This device includes an algorithm that performs analysis of patient-specific data (e.g., temperature, menstrual cycle dates) to distinguish between fertile and non-fertile days, then provides patient-specific recommendations related to contraception


  • Clinical studies  involved 15,570 women, used app for 8 months
  • “Perfect use” failure rate of 1.8%,
  • “Typical use” failure rate of 6.5%
  • Risk & Mitigation: Unintended pregnancy – Software verification, validation, and hazard analysis; Clinical performance testing; Human factors and usability testing; Labeling


  • New Regulation No.: 21 CFR 884.5370
  • Classification: Class II
  • Product Code: PYT



BONEBRIDGE Hearing System

MED-EL Elektromedizinische Geraete GmbH

INDICATION FOR USE:  Bone conduction hearing implant system for:

  • Patients 12 years of age or older
  • Patients who have a conductive or mixed hearing loss and still can benefit from sound amplification
  • The pure tone average (PTA) bone conduction (BC) threshold (measured at 0.5, 1, 2, and 3 kHz) should be better than or equal to 45 dB HL
  • Bilateral fitting of the BONEBRIDGE is intended for patients having a symmetrically conductive or mixed hearing loss
  • The difference between the left and right sides’ BC thresholds should be less than 10 dB on average measured at 0.5, 1, 2, and 3 kHz, or less than 15 dB at individual frequencies
  • Patients who have profound sensorineural hearing loss in one ear and normal hearing in the opposite ear (i.e., single-sided deafness or “SSD”)
  • The pure tone average air conduction hearing thresholds of the hearing ear should be better than or equal to 20 dB HL (measured at 0.5, 1, 2, and 3 kHz)
  • Any patient who is indicated for an airconduction contralateral routing of signals (AC CROS) hearing aid, but who for some reason cannot or will not use an AC CROS
  • Prior to receiving the device, it is recommended that an individual have experience with appropriately fit air conduction or bone conduction hearing aids.

GENERIC TYPE OF DEVICE: Active implantable bone conduction hearing system

  • Prescription device consisting of an implanted transducer, implanted electronics components, and an audio processor. The active implantable bone conduction hearing system is intended to compensate for conductive or mixed hearing losses by conveying amplified acoustic signals to the cochlea via mechanical vibrations on the skull bone


  • Dural erosion or compression, surgical complications, device software failure, implant failure, interference, adverse tissue reaction, infection



GALAFOLD (migalastat) capsule

Amicus Therapeutics

INDICATION: Treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data

  • Approved under accelerated approval based on reduction in kidney interstitial
    capillary cell globotriaosylceramide (KIC GL-3) substrate
  • Continued approval  contingent upon verification and description of clinical
    benefit in confirmatory trials


  • Rare Fabry disease causes slowly progressive kidney disease, cardiac hypertrophy (enlargement of the heart), arrhythmias (abnormal heart rhythm), stroke, early death
  • Galafold differs from enzyme replacement in that it increases the activity of the body’s deficient enzyme

MECHANISM OF ACTION:  Pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA), which is deficient in Fabry disease


  • Six-month, placebo-controlled clinical trial, n=45 adults with Fabry disease, 6 months, GALAFOLD vs placebo
  • Greater reduction in globotriaosylceramide (GL-3) in blood vessels of kidneys (as measured in kidney biopsy samples) with GALAFOLD


  • Most common adverse drug reactions: Headache, nasopharyngitis, urinary tract infection, nausea, pyrexia


  • Accelerated Approval, Priority Review, Orphan Drug Designation
  • Accelerated Approval requirements:
    • Randomized, double-blind, placebo-controlled clinical trial to verify and
      describe the clinical benefit in patients with Fabry disease
    • Prospective, longitudinal, observational study to evaluate efficacy and
      pharmacodynamic effects in patients with a confirmed diagnosis of Fabry disease and amenable, disease-causing GLA variants


Capture.JPGANNOVERA (segesterone acetate and ethinyl estradiol vaginal system)

Population Council, Inc.

INDICATION: For use by females of reproductive potential to prevent pregnancy


  • First vaginal ring contraceptive that can be used for an entire year

DESCRIPTION: Reusable donut-shaped (ring), non-biodegradable, flexible vaginal system, placed in vagina for three weeks followed by one week out of vagina, at which time women may experience a period (a withdrawal bleed). This schedule is repeated every four weeks for one year (thirteen 28-day menstrual cycles).


  • Three, open label clinical trials with healthy women ranging from 18 to 40 years of age
  • About two to four women out of 100 women may get pregnant during the first year they use Annovera
  • Most common side effects: (similar to those of other combined hormonal contraceptive products)- headache/migraine, nausea/vomiting, yeast infections, abdominal pain, dysmenorrhea (painful menstruation), breast tenderness, irregular bleeding, diarrhea, genital itching
  • Boxed Warning: Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use


  • Postmarketing studies: Risks of venous thromboembolism, effects of CYP3A modulating drugs and tampon use on pharmacokinetics
  • Part of FDA’s new pharmacovigilance system, Sentinel’s Active Risk Identification and Analysis (ARIA)


Image Credit: Alnylam, Natural Cycles, MED-EL, Amicus, Population Council

News and Views: Real World Data, CMS Blue Button Conference, Tech Companies and Healthcare Data Interoperability, Competitive Generic Therapy Approval


Use of real-world data (RWD) to enhance research efficiency and bridge evidentiary gap between clinical research and practice

  • Increasing accessibility of digital health data
  • Transition to electronic health records (EHRs)
  • Address rising costs and recognized limitations of traditional trials
  • Research collaborations with Flatiron Health and CancerLinQ for big oncology data
  • Need access to other large databases

FDA effort should be supported by CMS’ Blue Button 2.0 – see below


CaptureKeynote speaker, CMS Administrator Seema Verma, on  Blue Button 2.0 and the MyHealthEData initiative

  • Developers use Medicare claims data to facilitate cost-effective care
  • Aggregate genetic information, medical records, claims data and wearable data in one electronic health record people can share with doctors and researchers.
  • Release of Medicare Advantage data to speed interoperability between EHRs and PHRs
  • Plans to release Medicaid data next year
  • Among 600 companies partnering on Blue Button 2.0 initiative are Verily Life Sciences, Rush, Humetrix, Health Endeavors, Anthem, Massachusetts Institute of Technology, 23andMe, Medware, 3K Technologies

Blue Button

Capture.JPGTech Companies Joint Commitment to Improve Healthcare Data Interoperability

Amazon, Google, IBM, Microsoft, Oracle, Salesforce

  • Frictionless exchange of healthcare data
  • Open standards, open specifications, and open source tools
  • Actively engaging among open source and open standards



FDA approves first generic drug under new pathway aimed at enhancing market competition for sole source drugs

Potassium chloride oral solution USP

Apotex Inc

Several strengths of potassium chloride oral solution approved via  Competitive Generic Therapy (CGT) designation

  • New approval pathway
  • Expedite development and review of generic drug that lack competition

INDICATION: Treatment and prevention of hypokalemia (low potassium blood levels) in patients who are on diuretics, and when dietary management with potassium-rich foods is insufficient or diuretic dose reduction is not possible


  • Met approval standards that ensure an equivalent, high quality, safe and effective generic medicine
  • Review of manufacturing and packaging facilities


Image credits: JAMA, FDA. CMS

Authorizations: MAGTRACE/SENTIMAG Magnetic Localization System, SURPASS Flow Diverter, MOLECULIGHT i:X, POTELIGEO injection


Magtrace and Sentimag Magnetic Localization System

 Endomagnetics Inc.

INDICATION FOR USE: To assist in localizing lymph nodes draining a tumor
site, as part of a sentinel lymph node biopsy procedure, in patients with breast cancer undergoing a mastectomy. Magtrace™ is intended and calibrated for use ONLY with the Sentimag® system.


  • Sentinel lymph node biopsies are crucial for determining whether a patient’s breast cancer has spread and helping the provider determine the most appropriate course of treatment
  • System offers patients undergoing mastectomy an option for their sentinel lymph biopsy procedure that does not require the injection of radioactive materials


  • Sensitive magnetic sensing probe and base unit designed to detect small amounts of Magtrace, the magnetic tracer drug that is injected into breast tissue
  • Magtrace particles travel to lymph nodes, become physically trapped in them, facilitating magnetic detection of the lymph nodes
  • Following injection of Magtrace, the Sentimag probe is applied to the patients’ skin in areas closest to the tumor site containing the lymph nodes
  • Sensing of the magnetic particles is indicated by changes in audio and visual alerts from the base unit, enabling the surgeon to move the hand-held probe around the area of the lymph nodes, and locate the sentinel lymph node or nodes (if there are more than one)
  • Surgeon makes a small incision and removes the node, which is checked by a pathologist for the presence of cancer cell
  • Negative result: Suggests cancer has not spread to nearby lymph nodes
  • Positive result: May indicate cancer present in sentinel lymph node,  nearby lymph nodes and, possibly, other organs
  • Help determine stage of cancer and develop appropriate treatment plan


  • Trial of 147 patients with breast cancer, n=147, Sentimag System vs. control methodin sentinel lymph node detection ratw
  •  94.3% for Sentimag System vs. 93.5% for control
  • Overall, 98.0% same detection rate with both Sentimag System and control
  • Most common adverse event: Breast discoloration, cardiac disorder (bradycardia) and potential allergic reaction to the magnetic materials
  • Contraindication: Hypersensitivity to iron oxide or dextran compounds

REGULATORY PATHWAY: PMA, Combination Product

  • Product Code: PUV
  • Classification: III
  • Classification Name:  Lymph Node Location System during Sentinel Biopsy Procedure
  • Coordinated, cross-agency approach- Clinical review conducted by CDRH in consultation with CDER and with support from Oncology Center of Excellence. All other aspects of review and final product approval by CDRH


LABEL Part 2


Surpass Streamline Flow Diverter


INDICATION FOR USE: In the endovascular treatment of patients (18 years of age and older) with unruptured large or giant saccular wide-neck (neck width ≥ 4 mm or dome-to-neck ratio < 2) or fusiform intracranial aneurysms in the internal carotid artery from the petrous segment to the terminus arising from a parent vessel with a diameter ≥ 2.5 mm and ≤ 5.3 mm.


  • Self-expandable braided device preloaded into a delivery system. Each device is shipped sterile and labeled for single use only
  • Consists of the following major components: Surpass Flow Diverter (Implant),  Delivery Catheter, Pusher


  • Multi-center, prospective, non-randomized clinical study., n=180, follow-up at discharge, 30 days, 6 months, and 12-months post-procedure
  • Primary Safety endpoint: % experiencing neurologic death or major ipsilateral stroke through 12-months post-procedure
  • Major Effectiveness endpoint: % with complete (100%) occlusion (Raymond-Roy Class I) of the treated intracranial aneurysm without clinically significant stenosis
  •  62.8% achieved complete occlusion of their intracranial aneurysm within 1year post-procedure without re-treatment or clinically significant in-stent stenosis


  • Product Code: OUT
  • Classification: III
  • Generic Name: Intracranial Aneurysm Flow Diverter



MolecuLight i:X

MolecuLight Inc.

INDICATION FOR USE:  Handheld imaging tool that allows clinicians diagnosing and treating skin wounds, at the point of care, to:

  1. view and digitally record images of a wound, and
  2. view and digitally record images of fluorescence emitted from a wound when exposed to an excitation light

For prescription use only.

GENERIC DEVICE TYPE: Wound autofluorescence imaging device

Tool to view autofluorescence images from skin wounds that are exposed to an excitation light. The device is not intended to provide quantitative or diagnostic information


  • Classification: I
  • Product Code: QCR
  • Regulation Number: 21 CFR 878.4165
  • Regulation Name: Wound autofluorescence imaging device

IDENTIFIED RISKS: Electrical/mechanical/thermal, electromagnetic compatibility (EMC) and optical safety of the device, and the error in fluorescence detection from the wound.

  • No special controls



POTELIGEO (mogamulizumab-kpkc) injection 

Kyowa Hakko Kirin

INDICATION FOR USE: Treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy


  • Mycosis fungoides and Sézary syndrome are rare, hard-to-treat types of non-Hodgkin lymphoma
  • Fills an unmet medical need for these patients

MECHANISM OF ACTION: CC chemokine receptor type 4 (CCR4)-directed monoclonal antibody; CCR4 present in some cancern cells


  • Clinical trial, n=372 patients with relapsed MF or SS, Poteligeo vs. vorinostat
  • Progression-free survival:  Median 7.6 months vs. median 3.1 months


  • Most common side effects: Rash, infusion-related reactions, fatigue, diarrhea, musculoskeletal pain and upper respiratory tract infection
  • Serious warnings:  Risk of dermatologic toxicity, infusion reactions, infections, autoimmune problems,  complications of stem cell transplantation that uses donor stem cells (allogeneic) after treatment with the drug


  • Priority Review and Breakthrough Therapy designation, Orphan Drug designation
  • Postmarketing Requirements: Characterize complications after allogeneic hematopoietic stem cell transplantation
  • Exempt from pediatric assessments


Image credit: Endomagnetics, Stryker, MolecuLight Inc., Kyowa Hakko Kirin

News and Views: 2018-2019 Flu season, Transmucosal immediate-release fentanyl products, Electronic health record data in clinical investigations, Continuous manufacturing technology, Nicotine replacement drug therapies


Influenza Virus Vaccine for the 2018-2019 Season

Flu vaccine lots for 2018-2019 season have been released by FDA and are available for distribution by the manufacturers

  • Afluria, Afluria Quadrivalent, Fluad, Fluarix Quadrivalent, Flucelvax Quadrivalent, Flublok Quadrivalent, FluLaval Quadrivalent, Fluzone Quadrivalent

Selected by FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC)

  • Reviewed and evaluated surveillance data related to epidemiology and antigenic characteristics of recent influenza isolates, serological responses to 2017-2018 vaccines, and the availability of candidate strains and reagents



Continued, careful oversight of the REMS associated with transmucosal immediate-release fentanyl products

FDA Public Meeting with Drug Safety and Risk Management Advisory Committee (DSARM) and the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC)

  • Review data from Risk Evaluation and Mitigation Strategy (REMS) with Elements to Assure Safe Use (ETASU) for transmucosal immediate-release fentanyl (TIRF) products
  • Discuss findings from assessments conducted by manufacturers and  additional data about their use patterns and adverse events
  • Provide transparency around effectiveness of the REMS and whether changes might be necessary.

Significant decline in prescribing of TIRF products since REMS  implemented

  • How the TIRF REMS has affected the prescribing patterns
  • How the TIRF REMS can better promote safe prescribing
  • Reliability of current trend information, and how to collect even more accurate data

READFDA Briefing Document


FDA issues policy to facilitate the use of electronic health record data in clinical investigations

Publication of Guidance entitled, “Use of Electronic Health Record Data in Clinical Investigations; Guidance for Industry.”

  • Recommendations for sponsors, clinical investigators, contract research organizations (CROs), institutional review boards (IRBs), and other interested parties on the use of electronic health record (EHR) data in FDA-regulated clinical investigations
  • Goal to modernize and streamline clinical investigations through the use of EHR data
  • Inclusion of real world data in clinical investigations
  • Advance  interoperability and integration of EHR and Electronic Data Capture systems.



FDA supports critical research to spur innovation for continuous manufacturing technology to support and advance drug and biologics development

Under Emerging Technology Program, FDA awarded three grants, to study and recommend improvements for continuous manufacturing of drugs and biological products, innovative monitoring and control techniques

  • Rutgers University: Implementation in Continuous Pharmaceutical Manufacturing
  • Massachusetts Institute of Technology: Smart Data Analytics for Risk Based Regulatory Science and Bioprocessing Decisions
  • Georgia Institute of Technology: Continuous Synthesis, Crystallization, and Isolation (CSCI) of an API: Process Model-Controlled Enzymatic Synthesis of Beta-Lactam Antibiotics



New steps the agency is taking to support the development of novel nicotine replacement drug therapies to help smokers quit cigarettes

Aim to significantly reduce the rate of tobacco-related disease and death

  • Nicotine replacement therapy (NRT) products regulated as new drugs, is a critical part of overall strategy on nicotine
  •  New kinds of NRTs – with different characteristics or routes of delivery – can offer additional opportunities for smokers to quit combustible tobacco
  • Nicotine Steering Committee has been evaluating new, evidence-based opportunities to advance therapeutic nicotine products for combustible tobacco product cessation

Two draft guidances aimed at supporting the development of novel, inhaled nicotine replacement therapies that could be submitted to the FDA for approval as new drugs

  1. Nonclinical testing of orally inhaled nicotine-containing drug products
  2. Framework for new potential clinically relevant outcomes for smoking cessation products


Image credits: FDA, CDC

Authorizations: ORILISSA, MULPLETA, AZEDRA, FREESTYLE LIBRE Glucose Monitoring System


ORILISSA (elogolix) Tablets


INDICATION: Management of moderate to severe pain associated with endometriosis

ADDRESSING UNMET NEED:  First FDA-approved oral treatment for management of moderate to severe pain associated with endometriosis in over a decade

MECHANISM OF ACTION:  Nonpeptide small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist; causes  suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of ovarian sex hormones, estradiol and progesterone.


  • Two multinational double-blind, placebo-controlled trials, n=1686 premenopausal women with moderate to severe pain associated with endometriosis
  • Co-primary efficacy endpoints: (1) dysmenorrhea response at Month 3 and (2) non-menstrual pelvic pain response at Month 3
  • Daily self-assessment of their endometriosis pain using numeric rating scale (NRS)
  •  Statistically significant greater responses (mean decreases from baseline) vs. placebo
  • Statistically (p <0.001) significant reduction from baseline in NRS scores vs. placebo


  • Most common side effects: hot flashes or night sweats, headache, nausea, difficulty sleeping, absence of periods, anxiety, joint pain, depression and mood changes
  • Warnings and Precautions: Bone loss, reduced ability to recognize pregnancy, suicidal ideation and mood disorder, reduced efficacy if contraceptives


  • Priority Review
  • Pediatric Assessments: Waived -product does not represent meaningful therapeutic benefit over existing therapies for pediatric patients and is not likely to be used in a substantial number of pediatric patient
  • Postmarketing Requirements:  Prospective pregnancy registry to evaluate effects  on pregnancy  and maternal and fetal/neonatal outcomes


Capture.JPGMULPLETA (lusutrombopag) Tablets

Shionogi Inc.

INDICATION: Treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) who are scheduled to undergo a procedure

ADDRESSING UNMET NEED: Offers physicians and patients another choice beyond platelet transfusions as adult patients with CLD often undergo procedures that could put them at increased risk for bleeding

MECHANISM OF ACTION:  Thrombopoietin (TPO) receptor agonist; induces proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells and megakaryocyte maturation


  • 2 randomized, double‐blind, placebo‐controlled trials; n=312 patients with chronic liver disease who were undergoing an invasive procedure
  • Major efficacy outcome was the proportion of patients who require no platelet transfusion prior to the primary invasive procedure
  • Statistically significant (p<0.0001) treatment difference vs, placebo


  • Most common adverse reaction: Headache
  • Warning and Precautions: Thrombotic/Thromboembolic Complications


  • Priority Review
  • Pediatric assessments: Waived as necessary studies are impossible or highly impracticable



AZEDRA (iobenguane I 131) injection

Progenics Pharmaceuticals

INDICATION: Treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy


  • First FDA-approved drug for this use in ultra-rare cancer
  • Has been shown to decrease the need for blood pressure medication and reduce tumor size in some patients

MECHANISM OF ACTION: I 131 labeled iobenguane; taken up and accumulates within pheochromocytoma and paraganglioma cells, and radiation resulting from radioactive decay of I 131 causes cell death and tumor necrosis


  • Single-arm, open-label, clinical trial, n=68 patients
  • Primary Endpoint: ≥ 50% reduction of all antihypertensive medications lasting for at least six months
  • Secondary Endpoint: Overall tumor response measured by traditional imaging criteria
  • 25%  experienced ≥ 50% reduction of all antihypertensive medication
  • 22% with overall tumor response


  • Most common severe side effects:  Lymphopenia, neutropenia, thrombocytopenia, fatigue, anemia, increased INR, nausea, dizziness, hypertension and vomiting
  • Warning about radiation exposure to patients and family members
  • Other warnings and precautions:  Myelosuppression, underactive thyroid, elevations in blood pressure, renal failure or kidney injury and inflammation of lung tissue (pneumonitis)


  • Priority review, orphan product, fast track status, and breakthrough therapy designation



FREESTYLE LIBRE Libre 14 Day Flash Glucose Monitoring System


INDICATION FOR USE:  Continuous glucose monitoring (CGM) device indicated for the management of diabetes in persons age 18 and older. It is designed to replace blood glucose testing for diabetes treatment decisions

The System detects trends and tracks patterns aiding in the detection of episodes of hyperglycemia and hypoglycemia, facilitating both acute and long-term therapy adjustments

Interpretation of the System readings should be based on the glucose trends and several sequential readings over time. The System is intended for single patient use and requires a prescription

Expanding indication to:

  • extend the sensor wear period to 14 days
  • reduce the sensor warm up time to 1 hour

ADDRESSING UNMET NEED: Longest-lasting self-applied personal blood sugar sensor on the market


  • Externally-worn glucose sensor that continuously measures glucose levels and displays values to the user in response to a user-initiated action (scan)
  • Provide on-demand glucose information to user for up to fourteen days (the life of each sensor)
  • Does not passively monitor glucose levels or provide messages, alarms or alerts in the absence of user-intiated action


  • Non-randomized, single arm, multi-center, prospective, pivotal, nonsignificant risk study, without controls
  • Primary endpoint: Accuracy performance evaluation vs. laboratory glucose analyzer during in-clinic sessions that spanned the wear period of the device (days 1, 4, 7 and 10)
  • Comparable to performance of current generation CGM systems; established accuracy across the claimed measuring range (40 to 500 mg/dL glucose), precision, 14 day wear period (following the 1 hour warm-up period) for the sensor, notifications (Glucose Messages), and number of readings displayed during the wear period
  • Possible adverse effects of inserting sensor and wearing adhesive patch: local erythema, local infection, inflammation, pain or discomfort, bleeding at the glucose sensor insertion site, bruising, itching, scarring or skin discoloration, hematoma, and adhesive irritation
  • Potential adverse effects associated with making diabetes treatment decisions when glucose values and rates of change provided by the device are inaccurate


  • Previous version marketed in the US since October 2017 under P160030


Image credits: AbbVie, Shionogi, Progenics, Abbott



FDA News and Views: Essure Sales Halt, Biomarkers and Surrogate Markers, Mobile Medical Apps Listing


Manufacturer announcement to halt Essure sales in the U.S- 

Statement from FDA Commissioner

FDA notified by Bayer that Essure permanent birth control device will no longer be sold or distributed after December 31, 2018

Steps taken by FDA based on increased reporting to MAUDE database

  • September 2015: Input from expert panel on abdominal pain, abnormal uterine bleeding, device migration
  • February 2016: Ordered Bayer to conduct a postmarket study on safety profile
  • October 2016: FDA final Guidance on device and updated labeling with boxed warning and Patient Decision Checklist
  • February 2018: FDA meeting with women implanted with Essure and patient advocates
  • March 2018:FDA report on rise in safety reporitng with >90%  on device removal
  • April 2018: FDA restriction on sale and distribution

FDA will remain vigilant in protecting patients with implanted device

  • Restriction on sale and distribution will remain in place
  • Postmarket study, will continue to enroll new participants
  • Each study participant will be followed for a total of three years
  • Bayer will continue to submit reports on study’s progress and results


WATCH: The Bleeding Edge


Biomarkers and Surrogate Markers

Biomarker is objective measure of normal biological processes, pathologic processes, responses to exposure or therapeutic intervention

  • May be used for identifying patients for clinical trial enrollment, monitoring safety and effectiveness

Surrogate endpoints (SEs) are  small subclass of biomarkers

  • Clearly predicts beneficial effect through appropriate studies
  • More efficient drug development programs

FDA steps to enhance SE use in drug development



Examples of Pre-Market Submissions that Include Mobile Medical Apps (MMAs)  Cleared or Approved by FDA

Mobile apps are software programs run on smartphones and other mobile communication devices

  • Are medical devices if meet definition of medical device or accessory to regulated medical device or transform mobile platform into regulated medical device
  • Consumers can use both mobile medical apps and mobile apps to manage health and wellness

FDA providing listing of MMAs cleared or approved since 1997


Image credits: Bayer, FDA



TIBSOVO (ivosidenib) tablets

Agios Pharmaceuticals

 RealTime IDH1 Assay  

Abbott Laboratories

INDICATION:  Treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test


  • AML is rapidly progressing cancer;  ~19,520 people will be diagnosed with ~10,670 deaths in 2018
  • Targeted therapy  for patients with relapsed or refractory AML who have an IDH1 mutation

MECHANISM OF ACTION: Targets mutant isocitrate dehydrogenase 1 (IDH1) enzyme;  decreases abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells.


  • Open-label, single-arm, multicenter clinical trial, n=174 adult patients with relapsed or refractory AML with IDH1 mutation  confirmed using Abbott RealTime TM IDH1 Assay
  • Endpoints:  Rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, rate of conversion from transfusion dependence to transfusion independence
  • 32.8 % experienced a CR orCRh lasting median 8.2 months
  • 37% went at least 56 days without requiring transfusion


  • Common side effects: Fatigue, increase in white blood cells, joint pain, diarrhea, shortness of breath, swelling in the arms or legs, nausea, pain or sores in the mouth or throat, irregular heartbeat (QT prolongation), rash, fever, cough and constipation
  • Boxed warning: Differentiation syndrome can occur and can be fatal if not treated
  • Other serious warnings: QT prolongation, Guillain-Barré syndrome


  • Fast Track and Priority Review designations, Orphan Drug designation
  • Exempt from pediatric requirements
  • Postmarketing requirements:  long-term safety, PK/PD assessments



KISQALI (ribociclib) tablets


EXPANDED INDICATION:  KISQALI in combination with:

  • an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy


  • fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy


  • First cancer drug approval through new oncology review pilot that enables greater development efficiency
  • Aim to make development and review of cancer drugs more efficient, while improving FDA’s rigorous standard for evaluating efficacy and safety
  • FDA start evaluating clinical data as soon as trial results become available, enabling FDA to be ready to approve the new indication upon filing of a formal application


  • In combination with an AI for pre/perimenopausal women:  Clinical trial, n=495, Progression Free Survival (PFS) was longer for patients taking Kisqali plus an AI (median PFS of 27.5 months) compared to placebo plus an AI (median PFS of 13.8 months)
  • In combination with fulvestrant:  Clinical trial, n=726, PFS longer for patients taking Kisqali plus fulvestrant (median PFS of 20.5 months) compared to placebo plus fulvestrant (median PFS of 12.8 months)
  • Common side effects: Infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss and rash
  • Warnings: QT prolongation, serious liver problems, low white blood cell counts that may result in infections that may be severe, and fetal harm

REGULATORY PATHWAY: Prior Approval Supplement utilizing two new pilot programs

  • Real-Time Oncology Review (RTOR): Early submission of data that are the most relevant to assessing safety and effectiveness of the product. Then, when the sponsor submits the application with the FDA, the review team will already be familiar with the data and in a better position to conduct a more efficient, timely, and thorough review.
  • Assessment Aid to organize submission into structured format to facilitate review
  • Priority Review and Breakthrough Therapy designation

Updated LABEL not available at this time


TPOXX (tecovirimat) capsules

Siga Technologies 

Developed in conjunction with U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA)

INDICATION:  Treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 13 kg


  • First drug with an indication for treatment of smallpox
  • Addressing the risk of bioterrorism

MECHANISM OF ACTION:  Antiviral drug against variola (smallpox) virus


  • Has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical
  • Effectiveness based on results of adequate and well-controlled animal efficacy studies of non-human primates and rabbits infected with non-variola orthopoxviruses
  • Primary efficacy endpoint: Survival
  • Statistically significant improvement in survival relative to placebo


  • Evaluated in 359 healthy human volunteers without smallpox infection
  • Most frequently reported side effects: Headache, nausea and abdominal pain

REGULATORY PATHWAY: NDA, approved under the FDA’s Animal Rule

  • Fast Track and Priority Review designations, Orphan Drug designation
  • Awarded Material Threat Medical Countermeasure priority review voucher



XTANDI (enzalutamide) capsules


SUPPLEMENTAL INDICATION:  Treatment of patients with castration-resistant prostate cancer (CRPC)

ADDRESSING UNMET NEED:   Broadens indicated patient population to include patients with non-metastatic CRPC (NM-CRPC) in addition to previously approved metastatic CRPC


  • Randomized, multicenter clinical trial, n= 1,401 patients. XTANDI vs. placebo; patients continued on gonadotropin-releasing hormone (GnRH) therapy or had prior bilateral orchiectomy
  • Major efficacy outcome: Metastasis-free survival (MFS)
  • Statistically significant improvement:  Median MFS of 36.6 vs. 14.7 months (HR 0.29; 95% CI: 0.24, 0.35; p<0.0001).


  • Most common adverse reactions:  Asthenia/fatigue, hot flush, hypertension, dizziness, nausea, and fall


  • Postmarket requirements: Collect and analyze all cases of new (non-prostate) malignancies identified in treated patients on an annual basis


Capture.JPGCentre de Transfusion Sanguine des Armées Freeze Dried Plasma (French FDP)

U.S. Department of Defense (DoD)

USE: Treatment of hemorrhage or coagulopathy during an emergency involving agents of military combat when plasma is not available or when use of plasma is not practical


  • Importance of access to freeze-dried plasma in initial efforts to control hemorrhage from battlefield trauma
  • Collaborative program with DoD to expedite development and availability of safe and effective, priority medical products for military service members


  • Lyophilized, leukocyte-depleted, pathogen-reduced (Intercept-treated), pooled
    apheresis Fresh Frozen Plasma product collected from volunteer donors and manufactured by the Centre de Transfusion Sanguine des Armées
  • Following reconstitution with water for injection, it can be administered intravenously

DATA COLLECTION: Intended to support the safety of the use of French FDP in combat settings

  • Patient survival until transfer of care
  • Patient survival at Day 30 following treatment with French FDP
  • Adverse events related to French FDP administration until transfer of care

REGULATORY PATHWAY: Emergency Use Authorization

  • DoD request and declaration by Secretary of the Department of Health and Human Services



Image credits: Agios, Novartis, Siga, Astellas, FDA

News and Views: Biosimilars Action Plan, Treatment of Opioid Use Disorder, Medical Countermeasures Mission, Nonprescription Drugs Access, Generic Opioids with Abuse-Deterrent Formulations


Biosimilars Action Plan (BAP)

Focus on four key areas

  • Improving efficiency of biosimilar and interchangeable product development and approval process
  • Maximizing scientific and regulatory clarity for biosimilar product development community;
  • Developing effective communications to improve understanding of biosimilars among patients, clinicians, and payors
  • Supporting market competition by reducing gaming of FDA requirements or other attempts to unfairly delay competition

Actions will help create competitive market, provide incentives for sponsors

Commissioner Gottlieb’s remarksDynamic Regulation: Key to Maintaining Balance Between Biosimilars Innovation and Competition” at Brookings Institution about BAP



CDER Conversation: Treatment for Opioid Use Disorder

Medication assisted treatment (MAT) is key to combating opioid use disorder (OUD)

  • Evidence-based, FDA approved medication (methadone, buprenorphine,  naltrexone) combined with counseling and psychosocial support
  • Decrease cravings,  relieve withdrawal symptoms; none cause euphoria or “high”

Use Information

  • Can be administered through different routes depending on specific drug; however,  many clinicians are not assessing and treating patients with OUD
  • Potential for drug-drug interactions
  • Recommended for pregnant women with substance use disorder
  • SAMHSA’s treatment locator service can be helpful in finding a nearby treatment program


CaptureProtecting and Promoting Public Health: Advancing the FDA’s Medical Countermeasures Mission 

Role in national security by facilitating development and availability of safe and effective medical countermeasures

  • Animal Rule: Efficacy data obtained solely from animals when studies in humans are not ethical or feasible
  • New guidances: eg smallpox
  • Emergency Use Authorizations: Facilitating availability and use of MCMs needed during public health emergencies
  • FDA and DoD joint program for development of medical oroducts intended to save  American military personnel
  • FDA’s Medical Countermeasures Initiative (MCMi) established in 2010



New efforts to empower consumers by advancing access to nonprescription drugs

Increase access to broader selection of nonprescription drug products  empowering consumers to self-treat common conditions and potentially some chronic conditions

  • lower costs for health care system overall
  • provide greater efficiency and empowerment for consumers
  •  access to resources to help patients determine if medicine is right for them

Use of innovative technologies

  • Mobile Medical App with a set of questions to help someone determine (self-select) appropriateness of drug for them
  • Sponsors could develop approaches for self-selection and accurate use of their prescription product in the nonprescription setting


CaptureAgency’s efforts to encourage the development of and broaden access to generic versions of opioid analgesics that are formulated to deter abuse

Encouraging development of opioids with abuse-deterrent formulations (ADFs) intended to make certain types of abuse, e.g. crushing, dissolving, more difficult or less rewarding

  • New 43 product-specific guidances related to the development of generic drug products
  • In vivo and in vitro study considerations for abuse deterrence evaluations
  • Final guidance  on development of generic versions of approved ADF opioids


Image credits: FDA

News and Views: Budget and Real World Evidence, Inclusion/Exclusion in Clinical Trials, Gene Therapies, Balancing Opioid Access, Information and Usage Labeling, Mobile Medical Apps Regulation, Drug Shortages Task Force

CaptureFDA Budget Matters: A Cross-Cutting Data Enterprise for Real World Evidence 

FDA committed to new tools to collect data from routine medical care and develop valid scientific evidence  appropriate for regulatory decision making

  • Leverage “real world data” relating to patient health status and/or the delivery of health care obtained at the point of care
  • Enable more efficient medical product development by integrating safety and benefit information from clinical care
  • Can overcome limitations of traditional randomized clinical trials with defined inclusion and exclusion criteria

FDA’s Sentinel System and the National Evaluation System for health Technology (NEST) analyzes real world data for ‘real world evidence’

  • Need to govern responsible use of data and provide timely access through creation of national resource
  • Maintain strict data security and privacy of personal information
  • $100M medical data enterprise proposal budget for modern system for electronic health records from about 10 million lives

Current initiatives

  • Post-Market Data Sources: Claims Data vs. EHRs and access to clinical medical information in de-identified electronic health records and real-time information
  • Establishing a System that can Leverage All Data Sources by full interoperability
  • Improving Clinical Trials by using real world data for efficient recruitment, integration across clinical care settings, innovative statistical approaches to reduce  size and duration
  • Investing in Tools to More Wisely Use Data to Improve Health for data standards and data quality



Evaluating Inclusion and Exclusion Criteria in Clinical Trials

Eligibility criteria define patient population under investigation

  • Inclusion criteria identify population in which it is expected that the effect of the drug can be shown
  • Exclusion criteria specify characteristics that disqualify patients from participation
  • Both exclude patient subgroups who may eventually receive drug once approved

Strategies to Support Better Development of Eligibility Criteria and Increase Enrollment

  • Improving transparency and increasing patient involvement in clinical trial design
  • Re-examining exclusion and inclusion Practices
  • Increasing the use of innovative and alternative trial designs and methods to support inclusion



FDA’s Efforts to Advance Development of Gene Therapies

For novel technologies like gene therapy, FDA tailoring regulatory path for assuring safety and efficacy

  • Six scientific guidance documents for modern, comprehensive framework
  • Clear recommendations to support innovation

Disease Specific Gene Therapy Guidances

Human Gene Therapy for Rare Diseases

Guidances on Manufacturing Gene Therapies



Balancing access to appropriate treatment for patients with chronic and end-of-life pain with need to take steps to stem misuse and abuse of opioids

New policy to strike right balance between

  • reducing new addiction rate by decreasing exposure to opioids prescribing  – and –
  • make sure that patients with pain have access to appropriate, evidence-based care
  • Mostly, opioid treatment for acute pain and prescribed for short durations
  • Patient-Focused Drug Development meeting  for additional patient viewpoints

New steps to aggressively confront the addiction epidemic

  • Revised Blueprint for opioid drug manufacturers required to make available to prescribers
  • Required training on non-opioid alternatives
  • Develop evidence-based guidelines on appropriate prescribing
  • lnnovation challenge to spur development of medical devices ‒ including digital health and diagnostics – to provide novel solutions to treating pain
  • New series of guidance documents on development of new drugs targeted to the treatment of various types of pain
  • Collaboration with NIH public-private partnership to advance pharmacological treatments for pain and addiction




Steps to encourage more informative labeling on prescription drug and biological products’ indications and usage

General Principle: To enable health care practitioners to readily identify appropriate therapies for patients by clearly communicating drug’s approved indication(s)

  • Scope of an Indication Relative to Population Studied
  • Age Groups in Indication
  • Distribution of Information Among Labeling Sections

Content and Format

  • Indication: Disease, Condition, or Manifestation Being Treated, Prevented, Mitigated, Cured, or Diagnosed
  • Other Information Necessary To Describe the Approved Indication
  • Limitations of Use : Appropriate and Inappropriate situations

Other considerations

  • Identification of Outcomes, Endpoints, and Benefit(s)
  • Accelerated Approval
  • Required or Recommended Language
  • Preferred Wording and Wording Generally To avoid



FDA Regulation of Mobile Medical Apps

Efficient regulation of mobile medical apps – Software as Medical Device (SaMD) – tailored to potential benefits and risks

  • Traditional FDA regulatory framework can stifle the development/access
  • New framework being developed to  recognize distinctive aspects of digital health technology, clinical benefit, unique user interface, and compressed commercial cycles

FDA initiatives

  • Working with International Medical Device Regulators Forum (IMDRF) on internationally harmonized regulatory framework
  • Digital Health Innovation Action Plan to implement the software provisions of the Cures Act
  • Precertification program to qualify for a more streamlined premarket review process
  • New guidance on Mobile Medical Apps

Firm-based approach based on culture of excellence and leveraging

  • Postmarket data collection
  • Clinical data from device registries, EHRs
  • Other electronic health information sources through the National Evaluation System for health Technology (NEST)



Formation of a new drug shortages task force and FDA’s efforts to advance long-term solutions to prevent shortages

New Drug Shortages Task Force – including CMS and VA

  • Understand root causes – e.g. low margins with low incentives, reimbursement issues, limited manufacturing capacity
  • Consider regulations coupled with financial incentives to market critical access drugs
  • Conduct a risk assessment and mitigation plans  to proactively address shortage
  • Emerging technology program  to prevent shortages and new quality metrics initiatives


Image credits: FDA, HHS

Market Authorizations: EPIDIOLEX, ZEPHYR Endobronchial Valve, ELLIPSYS System, EVERLINQ System, DreaMed decision-support software, EVERSENSE CGM system


EPIDIOLEX  (cannabidiol) oral solution

GW Pharmaceuticals

INDICATION:  Treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients 2 years of age and older


  • Treatment of rare genetic conditions in pediatric population
  • First botanical marijuana product to be FDA approved

MECHANISM OF ACTION: Precise mechanisms of anticonvulsant effect unknown; does not appear to exert its anticonvulsant effects through interaction with cannabinoid receptors


  • Three randomized, double-blind, placebo-controlled clinical trials, n=516 patients with either Lennox-Gastaut syndrome or Dravet syndrome, Epidiolex + other medications vs. placebo, 14-week treatment period
  • Primary efficacy measure: %change from baseline in the frequency (per 28
    days) of drop seizures (atonic, tonic, or tonic-clonic seizures)
  • Significant decrease in seizures vs placebo; p≤0.01


  • Most serious risks: Thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks
  • Also caused liver injury, generally mild, but raising the possibility of rare, but more severe injury
  • Most common side effects:  Sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections
  • Must be dispensed with a patient Medication Guide



  • Orphan designation, Fast Track, Priority Review, Priority Review Voucher
  • Postmarketing requirements: Embryofetal development study, juvenile toxicology, carcinogenicity,  potential for chronic liver injury, pregnancy outcomes study, risk of drug-drug interactions or QT interval prolongation.


  • Currently controlled in Schedule I under the Controlled Substances Act
  • FDA scheduling recommendation has been transmitted to DEA
  • Final DEA scheduling decision pending



ZEPHYR Endobronchial Valve (Zephyr Valve)


INTENDED USE: Treat breathing difficulty associated with severe emphysema

ADDRESSING UNMET NEED:  Less invasive treatment that expands the options available to emphysema patients


  • Flexible bronchoscope to place Zephyr Valves, similar in size to pencil erasers, into diseased areas of lung airways
  • Device design intended to prevent air from entering damaged parts of lung and allow trapped air and fluids to escape
  • During inhalation, valves close, preventing air from entering damaged part of lung
  • During exhalation, valves open, letting out trapped air, which is intended to relieve pressure


  • Study, n=190 emphysema patients, Zephyr Valves + medical management (medications and pulmonary rehabilitation) vs. Control group received medical management only, one year treatment
  • Primary endpoint: % with at least a 15% improvement in pulmonary function scores (the volume of air that can forcibly be blown out in one second after full inhalation)
  • 47.7 % with Zephyr Valves  vs. 16.8% in control group


  • Adverse events: Death, air leak (pneumothorax), pneumonia, worsening of emphysema, coughing up blood, shortness of breath and chest pain
  • Contraindication: Active lung infections; those who are allergic to nitinol, nickel, titanium or silicone; active smokers and those who are not able to tolerate the bronchoscopic procedure


  • Breakthrough designation


Ellipsys Vascular Access System 

Avenu Medical

INDICATION FOR USE:  Creation of a proximal radial artery to perforating vein  anastomosis via a retrograde venous access approach in patients with a minimum vessel diameter of 2.0mm and less than 1.5mm of separation between the artery and vein at the fistula creation site who have chronic kidney disease requiring dialysis


EVERLINQ endoAVF System 

TVA Medical

INDICATION OF USE: Creation of an arteriovenous fistula (AVF) using the ulnar artery and ulnar vein in patients with minimum artery and vein diameters of 2.0 mm and less than 2.0 mm separation between the artery and vein at the fistula creation site who have chronic kidney disease and need hemodialysis


ADDRESSING UNMET NEED: Additional, less-invasive vascular access options for patients who will require hemodialysis

DEVICE TYPE: Percutaneous catheter for creation of an arteriovenous fistula for hemodialysis access

  • Single use percutaneous catheter system that creates an arteriovenous fistula (AVF) in the arm of patients with chronic kidney disease who need hemodialysis


  • Safely deliver, deploy, and remove the device
  • Create an arteriovenous fistula
  • Attain blood flow rate and diameter suitable for hemodialysis
  • Use fistula for vascular access for hemodialysis
  • Patency of the fistula


  • Unintended vascular or tissue injury
  • Adverse hemodynamic effects
  • Failure to create a durable fistula that is usable for hemodialysis
  • Use of the device adversely impacts future vascular access sites
  • Adverse tissue reaction
  • Infection
  • Electrical malfunction or interference leading to electrical shock, device failure, or inappropriate activation
  • Software malfunction leading to device failure or inappropriate activation


  • Regulation Number: 21 CFR 870.1252
  • Regulation Name: Percutaneous catheter for creation of an arteriovenous fistula for hemodialysis access
  • Regulatory Class: Class II
  • Product Code: PQK




DreaMed Advisor Pro decision-support software

DreaMed Diabetes, Ltd

INDICATION FOR USE:  Decision-support software intended for assisting healthcare professionals in the management of patients with Type 1 diabetes who:

  • use insulin pumps as their insulin delivery therapy
  • monitor their glucose levels using either of the following: CGM, or o CGM and self-management blood glucose meter
  • Are above the age of 6 and under 65 years old
  • Use rapid acting U-100 insulin analogs in their pump

Use by healthcare professionals when analyzing continuous glucose monitoring (CGM), self-monitoring blood glucose (SMBG) and pump data to generate recommendations for optimizing a patient’s insulin pump settings for basal rate, carbohydrate ratio (CR), and correction factor (CF); without considering the full clinical status of a particular patient.

DreaMed Advisor Pro does not replace clinical judgment

DEVICE TYPE: Insulin Therapy Adjustment Device

  • Incorporate biological inputs, including glucose measurement data from a CGM to recommend insulin therapy adjustments as an aid in optimizing insulin therapy regimens for patients with diabetes mellitus


  • Required data inputs, including timeframe over which data inputs must be collected and number of data points required
  • Types of device outputs and insulin therapy adjustment recommendations, including how the recommendations are generated
  • Clinical validity of the device outputs and insulin therapy recommendations
  • Input data specifications, including accuracy requirements for CGM  and other devices generating data inputs
  • Clinical justification for each specification
  • Ensure secure and reliable means of data transmission to and from device, data integrity checks, accuracy checks, reliability checks, security measures
  • Users can understand and appropriately interpret recommendations
  • Mitigation strategy to minimize dosing recommendation errors


  • Erroneous or extreme changes in insulin dosing recommendations may cause hypoglycemia or hyperglycemia
  • Incorrect interpretation of results may lead to inappropriate clinical decision making
  • Incorrect understanding of appropriate device use may lead to inappropriate treatment decisions
  • Patient harm due to insecure transmission of data
  • Data corruption may lead to inappropriate treatment recommendations


  • 21 CFR 862.1358
  • Regulation Name: Insulin Therapy Adjustment Device
  • Regulatory Class: Class II
  • Product Code: QCC



EVERSENSE Continuous Glucose Monitoring (CGM) system


INDICATION FOR USE: For continually measuring glucose levels in adults (18 years and older) with diabetes for up to 90 days.The system is intended to:

  1. Provide real-time glucose readings
  2. Provide glucose trend information
  3. Provide alerts for the detection and prediction of episodes of low blood glucose (hypoglycemia) and high blood glucose (hyperglycemia)

The system is a prescription device. Historical data from the system can be interpreted to aid in providing therapy adjustments. These adjustments should be based on patterns seen over time.The system is indicated for use as an adjunctive device to complement, not replace, information obtained from standard home blood glucose monitoring devices.


  • More seamless digital system giving patients ability to effectively manage diabetes
  • Modern regulatory approach for products that’s carefully adapted to the unique characteristics of these opportunities

DESCRIPTION: Continuous Glucose Monitor, Implanted, Adjunctive Use


  • Clinical study, n=1254 diabetes patients, comparing readings by Eversense CGM vs.  laboratory-based glucose analyzer
  • Safety based on procedure used to implant; <1% experiences serious adverse event
  • Potential adverse effects: Related to insertion, removal and wear of the sensor include allergic reaction to adhesives, bleeding, bruising, infection, pain or discomfort, scarring or skin discoloration, sensor fracture during removal, skin inflammation, thinning, discoloration or redness
  • Other risks: Hypoglycemia or hyperglycemia in cases where information provided by the device is inaccurate or where alerts are missed


  • Advisory Committee meeting:  8 to 0 vote, committee recommended that benefits outweigh the risks for patients with diabetes

PMA Listing

Image credit: GW, Pulmonx, Avenu, TVA, DreaMed, Senseonics

FDA News: Marijuana Research, Inhaled Antibiotics, Quality Metrics for Drugs, Compounded Drugs Enforcement


Importance of conducting proper research to prove safe and effective medical uses for the active chemicals in marijuana and its components

Marijuana is a Schedule I compound with known risks

  • Safety and effectiveness in treatment of medical disorders held to the same standard as other drug compounds
  • FDA approved purified form of drug cannabidiol (CBD) to treat seizures with rare, severe forms of epilepsy
  • Approval based on well-controlled clinical trials, reliable  dosage form, through  reproducible route of delivery to ensure anticipated benefits

Path for other marijuana-derived products 

  • Robust clinical development program, purity and  manufacturing controls
  • FDA Botanicals Team with expertise on botanical issues
  • Involvement of other federal agencies- National Institute on Drug Abuse, Drug Enforcement Administration
  • Continued vigilance of illegal marketing of unapproved CBD-containing products with unproven medical claims



Development of Inhaled Antibacterial Drugs for Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis


Public workshop held on “Development of Inhaled Antibacterial Drugs for Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis.”


Discuss the clinical trial design challenges and future considerations for inhaled antibacterial products to treat cystic fibrosis (CF) and non-CF bronchiectasis.



Quality Metrics for Drug Manufacturing

Quality metrics

  • Used throughout drugs and biologics industry to monitor quality control
  • Foundation for continual improvement of product and process quality
  • Element of companies’ commitment to quality culture

Two new programs on use of quality metrics to modernize pharmaceutical quality systems and advance innovation

  1. Quality Metrics Feedback Program: New drugs, generics, pharmaceutical ingredients (API) establishments, contract manufacturing organizations (CMOs), OTC products
  2. Quality Metrics Site Visit Program:  Experiential and firsthand learning opportunities to FDA staff i

Provide an opportunity for FDA to continue learning about the advantages and challenges companies have experienced in implementing Quality Systems



Continued efforts relating to compounded drugs for patients who cannot use an FDA-approved drug

Compounded drugs are not FDA-approved

  • Quality of products important
  • Developing policies and conducting oversight to minimize risks to patients
  • Taking actions to protect patients and enforce existing laws

Fraud enforcement actions 

  • Billing reimbursors for medically unnecessary compounded drugs
  • Examples: topical pain creams comprised of multiple ingredients to increase billing amount, include non-topical products such as antidepressants, anticonvulsants, antivirals, narcotics
  • Clinicians and patients not aware of potential safety risks, lack of effectiveness

FDA Actions:

  • Draft guidance on evaluation of  clinical need
  • Inspection of compounding facilities
  • Prescription requirement


Image credit: FDA

Authorizations: SYNOJOYNT, TRUETEAR Tear Neurostimulator, CURVE Positive Airway Pressure System




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


  • Sterile, non‐pyrogenic, clear, viscoelastic solution of hyaluronan contained in a single‐use prefilled syringe
  • Viscous solution of sodium hyaluronate in buffered physiological sodium chloride
  • Sodium hyaluronate is a high molecular weight fraction (approximately 2.5×106 daltons) of a natural complex sugar polymer consisting of repeating disaccharide units of Na‐glucuronate‐N acetylglucosamine


  • Double-blind, prospective, multi-site, randomized, threearm, parallel group, n=599,  injected into the target knee of  subjects with OA, vs. placebo, 26 weeks
  •  Adaptive investigation, two interim analyses (after approximately 50% and 75% of the planned sample size), sample size reassessment as needed
  • WOMAC pain scores : -167.73 (9.32) vs.  -131.64 (9.35) in placebo group, p=0.0033
  • Statistically significant differences in the WOMAC Pain score, WOMAC Stiffness score, WOMAC Physical Function score
  • Incidence of TEAEs  similar to that of saline placebo treatment


  • Classification: III
  • Product Code: MOZ



TRUETEAR Intranasal Tear Neurostimulator


INDICATION FOR USE:  Provides a temporary increase in tear production during neurostimulation to improve dry eye symptoms in adult patients with severe dry eye symptoms

GENERIC DEVICE TYPE:  Intranasal electrostimulation device for dry eye symptoms

  • Prescription non-implantable, electrostimulation device intended to increase tear production for improvement in dry eye symptoms


  • Tissue damage due to overstimulation/understimulation or mechanical injury (ex: tips too long), device breakage: Non-clinical performance testing, Software verification, validation, and hazard analysis, Electrical, thermal, and mechanical safety testing, Labeling
  • Adverse tissue reaction:Biocompatibility evaluation, Labeling
  • Infection:Labeling
  • Electrical shock or burn:Electrical, thermal, and mechanical safety testing, Software verification, validation, and hazard analysis, Labeling
  • Interference with other devices:Electromagnetic compatibility (EMC) testing
    Software verification, validation, and hazard analysis, Labeling
  • Pain, headache, or discomfort: Clinical performance testing, Non-clinical performance testing, Electrical, thermal, and mechanical safety testing, 
  • Failure to mitigate dry eye symptoms: Clinical performance testing, Training


  • Regulation Number: 21 CFR 886.5310
  • Regulation Name: Intranasal electrostimulation device for dry eye symptoms
  • Regulatory Class: Class II
  • Product Code: QBR

CLassification Order


CURVE Positive Airway Pressure System

Fresca Medical

INDICATION FOR USE:  To treat Obstructive Sleep Apnea by delivering a therapeutic breathing pressure to a patient. It provides positive airway pressure during expiration and also during an incipient apnea. The system includes a dedicated flow generator and a patient interface, and is intended for use in the home environment. This system is to be used by adult patients weighing more than 66 lbs (30 kg)

GENERIC DEVICE TYPE: Positive airway pressure delivery system

  • Prescription noninvasive ventilatory device that delivers expiratory positive airway pressure for patients suffering from obstructive sleep apnea. The system also provides positive airway pressure during incipient apnea. The system may include a dedicated flow generator and a patient interface


  • Adverse tissue reaction: Biocompatibility evaluation, Labeling
  • Electromagnetic interference: Electromagnetic compatibility testing
  • Infection:Reprocessing validation, Labeling
  • Device software failure: Software verification, validation, hazard analysis
  • Device hardware failure/malfunction leading to high airway pressure, carbon
    dioxide rebreathing or ineffective treatment: Non-clinical performance testing
  • Electrical shock injury or thermal injury: Electrical safety, thermal safety, and
    mechanical testing, Software verification, validation, and hazard analysis, Labeling
  • Use error leading to ineffective therapy or patient injury: Labeling


  • Regulation Number: 21 CFR 868.5273
  • Regulation Name: Positive airway pressure delivery system
  • Regulatory Class: Class II
  • Product Code: QBY

Classification Order

Image credit: Teva, Allergan, Fresca Medical




News: Software Precertification Working Model, Opioid Announcement


Software Precertification Model: A Working Model

Software Precertification Program

  • Voluntary pathway to provide more streamlined and efficient regulatory oversight of software as medical devices (SaMD)
  • From manufacturers who have demonstrated a robust culture of quality
    and organizational excellence (CQOE)
  • Committed to monitoring real-world performance


  • Tailored, pragmatic, least burdensome regulatory oversight
  • Assess – to establish trust of CQOE for high quality SaMD
  • Transparency –  across entire lifecycle of SaMD
  • Verify – continued safety, effectiveness, and performance of SaMD in real world


  • Excellence Appraisal and Precertification (Component 1)
  • Review Pathway Determination (Component 2)
  • Streamlined Premarket Review Process (Component 3)
  • Real-World Performance (Component 4)



FDA Announcement related to opioids

FDA supports U.S. Department of Health and Human Services’ 5-Point Strategy To Combat the Opioid Crisis

  • decreasing exposure to opioids and preventing new addiction
  • supporting treatment of those with opioid use disorder
  • fostering development of novel pain treatment therapies
  • fostering development of opioids more resistant to abuse and misuse
  • taking action against illegal importation and sale of opioids
  • evaluate how marketed opioids are used in both medical and illicit settings and take regulatory action where needed

Action against 53 websites marketing unapproved opioids More information

Patient Focused Drug Development for chronic pain More information

Approval of first generic versions of Suboxone sublingual film More information

Image credit: FDA, DHHS

Briefs: Communications for value-based care, New reimbursement model to fight antibiotic resistance, Patient Voice in regulatory decision-making, CDER organizational improvements


New efforts to advance medical product communications to support drug competition and value-based health care

HHS blueprint proposes measures for access to underinsured or uninsured

  • Prices to reflect the value in how medicines are prescribed and the outcomes they deliver
  • Control rising spending and reduce the burden of drug costs for consumers
  • Models to tie price of drugs closely to usefulness of  clinical setting in which they are prescribed. We want to encourage competitive contracting based on measures of value that matter most to purchasers and patients, not get in the way of these competitive negotiations

FDA will provide clear guidance to pharmaceutical companies about open, responsible communication with payors, formulary committees and others

First  guidance document

  • Inform market participants developing value-based contracts
  • Communication of outcomes important to purchasers like a health plan or hospital
  • Endpoint may not be expressly described in drug’s approved labeling

Second guidance document

  • Manufacturers’ communication of information that is not contained in the FDA-required labeling for their products, but that is consistent with that labeling
  • Such as data from post-market studies and surveillance
  • Additional information from the pre-market studies that were used to support approval of the product



FDA’s efforts to foster discovery and development of new tools to fight antimicrobial-resistant infections

Increase in serious antimicrobial drug resistant infections is critical public health concern

  • At least 2 million people become infected with bacteria that are resistant to antibiotics and 23,000 people die each year as direct result
  • Need for good antibiotic stewardship and use in appropriate clinical scenarios

In discussions with CMS, idea to change reimbursement model

  • For certain new, anti-microbial drugs that meet critical, public health needs
  • Move to licensing model – instead of paying for drugs that meet a narrow set of criteria on a per use basis
  • Acute care institutions would pay a fixed licensing fee to use a certain number of annual doses



New agency efforts to advance the PATIENT VOICE in medical product development and FDA regulatory decision-making

Need for systematic, methodologically-sound approaches to collect patient input to  inform regulatory decision-making

New guidance on Patient-Focused Drug Development: Collecting Comprehensive and Representative Input

  • Sampling methods for collecting patient experience – throughout the medical product lifecycle
  • How to operationalize and standardize the collection, analysis and dissemination of patient experience data



Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making

FDA Patient-Focused Drug Development Guidance Series 

  • To address, in a stepwise manner, how stakeholders can collect and submit patient experience data
  • Intended to facilitate the advancement and use of systematic approaches to collect and use robust and meaningful patient and caregiver input



Proposed modernization of FDA’s drug review office

CDER undertaking steps to modernize the organization and functions of  Office of New Drugs

  • Elevate role of scientists and medical officers to take on even more thought leadership
  • More time, better tools and greater support to advance the clinical and regulatory principles
  • Develop hundreds of new clinical guidance documents and make sure they stay up-to-date to reflect latest science

Allow review staff to have more time for reviewing and providing feedback to sponsors

  • Engage sponsors earlier in the development process
  • Ensure trial designs are efficient and  effectively structured for benefit/risk assessment
  • Ability to engage external stakeholders, such as disease specialists, academic researchers and regulatory partners at other agencies
  • Ongoing relationships and interactions with patient groups
  • Creating many new therapeutic-specific divisions to engage in discrete areas of medicine

Improve FDA review process

  • Integration around a common review process, common review template
  • Integrated across  discrete areas of science and regulatory expertise
  • Better organization of review process and development of key review memos

New alignment and processes will improve efficiency by 20% at a minimum overall


Image credit: FDA


Authorizations: DOPTELET, OSTEODETECT AI for Fractures, CUSTOMFLEX Artificial Iris


DOPTELET (avatrombopag) 

 AkaRx Inc.

INDICATION:  Treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure


  • Patients with chronic liver disease who have low platelet counts and require a procedure are at increased risk of bleeding
  • Doptelet safely increases platelet count; may decrease or eliminate platelet transfusions

MECHANISM OF ACTION:  Thrombopoietin (TPO) receptor agonist stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets


  • Two multicenter, randomized, double-blind, placebo-controlled trials, n= 435, patients with chronic liver disease and severe thrombocytopenia
  • Major efficacy outcome: Proportion of patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure.
  • Higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy with Doptelet


  • Most common side effects: Fever, stomach (abdominal) pain, nausea, headache, fatigue and swelling in the hands or feet (edema);  increased risk of developing blood clots when taking Doptelet


  • Priority review
  • Postmarketing required pediatric assessmenrs





INDICATION FOR USE: OsteoDetect analyzes wrist radiographs using machine learning techniques to identify and highlight distal radius fractures during the review of posterior-anterior (PA) and lateral (LAT) radiographs of adult wrists


  • AI algorithms have tremendous potential to help health care providers diagnose and treat medical conditions
  • Software can help providers detect wrist fractures more quickly and aid in the diagnosis of fractures

GENERIC DEVICE TYPE: Radiological Computer Assisted Detection and Diagnosis Software

  • Image processing device intended to aid in the detection, localization, and characterization of fracture, lesions, or other disease specific findings on acquired medical images (e.g. radiography, MR, CT)
  • Detects, identifies and characterizes findings based on features or information extracted from images, and provides information about the presence, location, and characteristics of the findings to the user
  • Analysis is intended to inform the primary diagnostic and patient management decisions that are made by the clinical user
  • Not intended as a replacement for a complete clinician’s review or their clinical judgment that takes into account other relevant information from the image or patient history


  • Retrospective study of 1,000 radiograph images that assessed the independent performance of the image analysis algorithm for detecting wrist fractures and the accuracy of the fracture localization of OsteoDetect against the performance of three board certified orthopedic hand surgeons
  • Retrospective study of 24 providers who reviewed 200 patient cases
  • Readers’ performance in detecting wrist fractures was improved using the software, including increased sensitivity, specificity, positive and negative predictive values vs. standard clinical practice


  • Regulation Number: 21 CFR 892.2090
  • Regulation Name: Radiological Computer Assisted Detection and Diagnosis Software
  • Regulatory Class: Class II
  • Product Code: QBS


CUSTOMFLEX  Artificial Iris

HumanOptics AG

INDICATION FOR USE:  Iris prosthesis for the treatment of iris defects. The CustomFlex™ Artificial Iris is indicated for use in children and adults for the treatment of full or partial aniridia resulting from congenital aniridia, acquired defects, or other conditions associated with full or partial aniridia


  • Congenital aniridia is a rare genetic disorder in which the iris is completely or partially absent
  • Affects approximately 1 in 50,000 to 100,000 people in the U.S.
  • CustomFlex Artificial Iris is indicated to treat iris defects due aniridia, other reasons or conditions, such as albinism, traumatic injury or surgical removal due to melanoma


  • Foldable iris prosthesis custom-made for each individual patient
  • Manufactured from a commercially available ophthalmic silicone
  • Colorized silicone paste is applied by hand in a pattern to match the color of the natural iris using a photograph of the existing iris or, in the case of aniridia, the color of the photograph selected by the patient
  • Surgeon makes a small incision, inserts the device under the incision, unfolds it and smooths out the edges using surgical instruments
  • Prosthetic iris is held in place by the anatomical structures of the eye or, if needed, by sutures


  • Non-randomized clinical trial, n=389 adult and pediatric patients with aniridia or other iris defects
  • Primary Endpoint: Self-reported decrease in severe sensitivity to light and glare post-procedure, health-related quality of life, and satisfaction with the cosmetic improvement or appearance of the prosthesis
  • >70 % reported significant decreases in light sensitivity and glare as well as an improvement in health-related quality of life following the procedure
  • 94% satisfied with the artificial iris’ appearance
  • Low rates of adverse events: Device movement or dislocation, strands of device fiber in the eye, increased intraocular pressure, inflammation of the iris (iritis), adhesion of the iris to the cornea or lens (synechiae) and the need for secondary surgery to reposition, remove or replace the device


  • Breakthrough device designation


Image credits:  AkaRx Inc., Imagen, HumanOptics AG



FDA news: Right to Try Act, Shared System REMS, Innovation Challenge for Devices targeting Abuse, Software Functions excluded as Devices, Liver Toxicity Understanding, Sunscreen Effectiveness


Statement from FDA Commissioner Scott Gottlieb, M.D., on the signing of the Right to Try Act

May 30th: President signed into law the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017 (Right to Try Act)

  • FDA to implement legislation to promote access and protect patients
  • Patients facing terminal conditions have an additional avenue to access promising investigational medicines
  • Will build on FDA’s exisiting Expanded Access program that enhances access to promising investigational medicines for those unable to access products through clinical trials
  • Will recognize the important balance between making sure patients have the assurances Congress intends, while enabling timely access to promising treatments in these devastating circumstances



New policies to reduce the ability of brand drug makers to use REMS programs as a way to block timely generic drug entry

Risk Evaluation and Mitigation Strategy (REMS) requirements have been exploited to block timely generic entry

  • At the front end of the drug development process- Restrict availability of branded drugs needed to run bioequivalence studies for generic drugs
  • At the back end of the process for drug approval and marketing – Delayed agreements for generics to enter branded drug Shared System REMS

New policy to help generic drug makers maintain safety controls sought by REMS



As part of efforts to combat opioid crisis, FDA launches innovation challenge to spur development of medical devices ‒ including digital health and diagnostics ‒ that target pain, addiction and diversion

FDA working to address opioid crisis and support goals of  U.S. Department of Health and Human Services’ Five-Point Strategy to Combat the Opioid Crisis

  • Significant focus on decreasing exposure to opioids and preventing new addiction
  • Supporting treatment of those with opioid use disorder
  • Fostering development of novel pain treatment therapies and opioids more resistant to abuse and misuse
  • Taking action against those who contribute to the illegal importation and sale of opioid products

Innovation challenge to encourage medical product developers to submit proposals

  • Diagnostics to identify patients at increased risk for addiction
  • Treatments for pain that eliminate the need for opioid analgesics
  • Treatments for opioid use disorder or symptoms of opioid withdrawal
  • Devices or technologies that can prevent diversion of prescription opioids
  • Devices with improved benefit-risk profile vs.  opioids in pain management

Benefits for accepted proposals

  • Enhanced interactions with FDA review divisions during development and evaluation
  • Breakthrough Device designation granted

Deadline: June 1 – Sept. 30, 2018


Capture.JPGFDA seeking comments on risks and benefits to health associated with software functions excluded from the device definition by the Cures Act

Per the Cures Act, certain medical software functions are not medical devices

  • for administrative support of a health care facility
  • for maintaining or encouraging a healthy lifestyle
  • to serve as electronic patient records
  • for transferring, storing, converting formats, or displaying data
  • to provide limited clinical decision support

FDA requesting input on risks and benefits  with these non-device software functions

  • From all interested parties, including patients, consumers, healthcare providers, startup companies, health plans or other third-party payers, venture capital investors, information technology vendors, health information technology vendors, small business purchasers, employers, and other stakeholders
  • FDA will incorporate input to develop report on risks and benefits of these software functions

submit your comments

Capture.JPGNCTR… Improving Understanding of Liver Toxicity

  • Role of Cytochromes in Dronedarone-Induced Liver Toxicity
  • Therapeutic Bile Acids and the Risks for Liver Toxicity
  • Monograph Published on Drug-Induced Liver Toxicity
  • Early and Sensitive Biomarkers of Liver Toxicity Discovered



New FDA actions to keep consumers safe from the harmful effects of sun exposure, and ensure the long-term safety and benefits of sunscreens

Most cases of melanoma can be attributed to cumulative UV exposure

  • Policy efforts to promote innovation in sunscreen (Sunscreen Innovation Act)
  • Help promote product innovation when it comes to better sunscreens

New efforts to advance framework for sun protection products

  • Making sure that products deliver advertised benefits
  • Warning letters to companies illegally marketing pills and capsules labeled as dietary supplements with unproven claims about protection from sun exposure harm
  • Encouraging industry to conduct research on additional sunscreen active ingredients to enhance safety
  • New FDA process to review the safety and effectiveness of sunscreen active ingredients
  • New draft guidance regarding Maximal Usage Trials (MUsT) for topically-applied active ingredients



Image credits: Congress, FDA

Device Market Authorizations: ULTRA Contact Lens, THINPREP Integrated Imager, ILLUMINOSS Bone Stabilization System


ULTRA (samfilcon A) Contact Lenses

Bausch + Lomb


Single Vision Spherical (SVS) Vision Correction : For extended wear for up to 7 days;  correction of refractive ametropia (myopia and hyperopia) in aphakic and/or not-aphakic persons with non-diseased eyes, exhibiting astigmatism of 2.00 diopters or less, that does not interfere with visual acuity.
Presbyopia Vision Correction: For extended wear for up to 7 days;  correction of refractive ametropia (myopia, hyperopia and astigmatism) and presbyopia in aphakic and/or not-aphakic persons with non-diseased eyes, exhibiting astigmatism of 2.00 diopters or less, that does not interfere with visual acuity.
Astigmatism Vision Correction: For extended wear for up to 7 days;  correction of refractive ametropia (myopia, hyperopia and astigmatism) in aphakic and/or not-aphakic persons with non-diseased eyes, exhibiting astigmatism up to 5.00 diopters.


  • Contact Lenses are 46% water and 54% samfilcon A material
  • Samfilcon A material is a hydrophilic copolymer of siloxane methacrylate, a siloxane cross-linker, and N-vinyl pyrrolidone
  • Tinted blue for visibility with Reactive Blue Dye 246, a color additive that conforms to 21 CFR Part 73.3106
  • Utilizes MoistureSeal® technology
  • In its hydrated state, when placed on the cornea acts as a refracting medium to focus light rays on the retina


  • Prospective, multi-center, two-arm cohort study, randomized, double-blinded, 12-month clinical study, n= 816, B+L ULTRA vs. B+L PureVision control group
  • Primary effectiveness endpoint: High contrast, distance visual acuity with dispensed lenses at the 12-Month Follow-up Visit.  97% of subject eyes achieved at least 20/25 with ULTRA
  • Secondary effectiveness endpoint: Lens wear time reported as average extended lens wear time (days/week) since last visit. Average wearing time was 6.7 (±0.031) days for both groups
  • Line change in visual acuity from baseline:  3.0% eyes in Ultra group vs. 3.8% eyes in PureVision group experienced worsening of ≥ 2 lines (≥ 10 letters)
  • Unfavorable lens performance: Higher proportion for PureVision group


  • The primary safety endpoint: Rate of serious or significant non-serious adverse
    events during the 12-month follow-up: No serious AEs for either lens group
  • 3.0% of Ultra eyes experienced significant non-serious AEs vs. 2.4% of PureVision eyes – Noninferiority was met using a predetermined threshold of 5.0%.


  • Device Procode: LPM



ThinPrep Integrated Imager 

Hologic, Inc.

INDICATION FOR USE: Uses computer imaging technology to assist in primary cervical cancer screening of ThinPrep® Pap Test slides for the presence of atypical cells, cervical neoplasia, including its precursor lesions (Low Grade Squamous Intraepithelial Lesions, High Grade Squamous Intraepithelial Lesions), and carcinoma as well as all other  cytologic criteria as defined by the Bethesda System: Terminology for Reporting Results of Cervical Cytology


Three major subsystems

  1. Microscope: Imaging camera, slide ID reader, automated stage, hand controls and adjustable touch screen user interface
  2. Controller: Controls the electromechnical components of the Microscope
  3. Computer: Hosts system application software and system database

Two major functions

  1. Imaging: Takes high magnification frames at more than 500 x-y locations covering entire cell spot. z-locations (focal plane)  calculated based on x-y locations. Software
    analyzes images of cell spot, identifies objects of interest based on optical density
  2. Review: Retrieves locations of the objects of interest and sequentially positions  for evaluation and interpretation by the cytotechnologist (CT)

Two work modalities

  1.  Sequential: Slide is imaged and then reviewed immediately by the CT.
  2. Batched:  Slides can be imaged in succession, with the coordinates stored in the
    computer database, for review by the CT or pathologist at a later time.


  • Multi-center, two-armed clinical study, n= 1,260 patient cases that covered all cytologic diagnosis categories, similarity of ThinPrep Integrated Imager (TI) to ThinPrep Imaging System (TIS)
  • Significantly higher sensitivity  and slight decrease in specificity, with TI
  • Workload assessment:  The number of slides that a CT can scan and review in one day is less on I2 than TIS although not significant


  • Incorrect diagnosis leading either to unnecessary care or delayed follow up care
  • Worst case scenario of false negative test result mitigated by multiple factors (aspects of the standard of care in the context of cervical precancer screening e.g. repeat testing,)


  • Device Procode: MKQ, MNM


Capture.JPGIlluminOss Photodynamic Bone Stabilization System

IlluminOss Medical, Inc.

INDICATION FOR USE: Skeletally mature patients in the treatment of impending and actual pathological fractures of the humerus, radius, and ulna, from metastatic bone disease


  • Used in fixation and stabilization of actual and impending pathological fractures of the humerus, radius, and ulna through a minimally invasive procedure
  • Catheter to deploy an inflatable, noncompliant, thin wall PET balloon into the medullary canal of the bone across the fracture site
  • Balloon is infused using a standard 20cc syringe with a photodynamic (light cured) monomer
  • Activation of light system allows for visible spectrum light to be delivered through a radially emitting light pipe
  • Curing (and hardening) occurs only when the photo initiator within the monomer is exposed to a specific frequency of light causing rapid polymerization of the monomer
  • Timer Key determines time the light source is activated during the curing process to ensure the appropriate cure time is used for each balloon size


  • Prospective, multi-center, historically controlled, open label, noninferiority study, n=81 implanted with the PBSS for the treatment of impending and actual pathological fractures in the humerus from metastatic bone disease
  • Primary efficacy parameters (Day 90 follow-up): Pain measured by the Visual Analog Scale (VAS) pain score, Function assessed by Musculoskeletal Tumor
    Society Rating Scale for Upper Extremity (MSTS)
  • Primary safety parameters: Major device-related adverse events, additional surgical interventions, radiographic evaluations for device fracture, migrations, mal-alignment, or loss of reduction or fixation
  • Average VAS pain reduction: 53 points from baseline to Day 90; large reduction of pain using other characteristics
  • Substantial increase in function: 40-point baseline to Day 90; other functional outcomes showed similar result
  • Low Device and Procedure Related Adverse Events,  second surgeries.  No bone infections with only one wound site infection


  • Product Code: QAD
  • Device Type: In vivo cured intramedullary fixation rod
  • Class: II
  • Regulation: 21 CFR 888.3023

Image credits:  Bausch+Lomb, Hologic, IllumiNoss





 PALYNZIQ (pegvaliase-pqpz) 


INDICATION:  Reduce blood phenylalanine concentrations in adult patients with  phenylketonuria (PKU) who have uncontrolled blood phenylalanine (Phe) concentrations greater than 600 micromol/L on existing management


  • PKU affects about 1 in 10,000 to 15,000 people in US
  • Can cause chronic intellectual, neurodevelopmental, psychiatric disabilitie
  • Novel enzyme substitution therapy for PKU patients unable to control blood Phe levels with current treatment options

MECHANISM OF ACTION: PEGylated phenylalanine ammonia lyase (PAL) enzyme that substitutes for deficient PAH enzyme activity in PKU patients


  • Two clinical trials, n>100 PKU patients, unrestricted diet prior to and during the trial
  • First trial- Randomized, open-label, increasing doses of subcutaneous Palynziq
  • Second trial – 8-week, placebo-controlled, randomized withdrawal trial in patients previously treated with Palynziq
  • Statistically significant reductions in blood phenylalanine concentrations from their pre-treatment baseline blood Phe concentrations


  • Most common adverse events:  Injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal pain, throat pain, fatigue, vomiting, cough and diarrhea\
  • Most serious adverse reaction: Anaphylaxis
  • Boxed Warning and restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Palynziq REMS Program


  • Orphan Drug Designation
  • Postmarketing Studies: Prospective, longitudinal, observational study to assess long-term risks of severe immune-mediated adverse reactions, Pre-/Postnatal development study in rats, Assay developments


Capture.JPGAIMOVIG (erenumab-aooe)


INDICATION: Preventive treatment of migraine in adults


  • Migraine is 3X more common in women than in men; affects > 10% worldwide
  • Novel option for reducing the number of days with migraine

MECHANISM OF ACTION:  Binds to calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function


  • Three clinical trials
  • First study, n= 955 participants with history of episodic migraine, Aimovig vs. placebo, 6 mo.- average one to two fewer monthly migraine days vs. placebo
  • Second study, n=577 patients with history of episodic migraine, Aimovig vs. placebo, 3 mo.,- average one fewer migraine day per month vs. placebo
  • Third study, n=667 patients with history of chronic migraine, Aimovig vs. placebo, 3 mo. – average, 2 ½ fewer monthly migraine days vs. placebo


  • Most common side effects: Injection site reactions and constipation


  • Deferred pediatric studies



LUCEMYRA (lofexidine hydrochloride) 

US WorldMeds LLC

INDICATION:  Mitigation of opioid withdrawal symptoms to facilitate abrupt
opioid discontinuation in adults


  • First FDA-approved non-opioid treatment for management of opioid withdrawal symptoms
  • New option for providers to work with patients to select the treatment best suited to an individual’s needs

MECHANISM OF ACTION:  Central alpha-2 adrenergic agonist binds to receptors on adrenergic neurons; reduces release of norepinephrine and decreases sympathetic tone


  • Two randomized, double-blind, placebo-controlled clinical trials, n=866 adults meeting DSM -IV criteria for opioid dependence, physically dependent on opioids, undergoing abrupt opioid discontinuation
  • Primary endpoint: Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) – Paient-reported outcome instrument for opioid withdrawal symptoms including feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes, insomnia
  • Patients rated symptom severity: Nnone, mild, moderate and severe; higher score indicates greater withdrawal symptom severity.
  • SOWS-Gossop scores lower with Lucemyra vs. placebo
  • More patients completed treatment period with Lucemyra vs. placebo


  • Most common side effects: Hypotension, bradycardia, somnolence, sedation and dizziness
  • Also associated: Syncope,  increase risk of abnormal heart rhythms


  • Fast Track Designation, Priority Review
  • 15 postmarketing studies, including both animal and human safety studies and to support longer term use, use in pediatrics


Capture.JPGRETACRIT(epoetin alfa-epbx) 



  • Anemia Due to Chronic Kidney Disease
  • Anemia Due to Zidovudine in Patients with HIV-infection\
  • Anemia Due to Chemotherapy in Patients with Cancer
  • Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery


  • First epoetin alfa biosimilar for the treatment of anemia
  • Biosimilars can provide greater access to treatment options, increasing competition and potentially lowering costs


  • Biosimilar approved based on data showing that it is highly similar to a marketed biological product
  • Has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product
  • Approval based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Retacrit is biosimilar to Epogen/Procrit


  • Most common side effects:  High blood pressure, joint pain, muscle spasm, fever, dizziness, medical device malfunction, blood vessel blockage, respiratory infection, cough, rash, injection site irritation, nausea, vomiting, muscle pain, inflammation of the mouth and lips, weight decrease, reduction in white blood cells, bone pain, high blood sugar, insomnia, headache, depression, difficulty swallowing, low blood potassium, blood clots, itching, headache, injection site pain and chills
  • Must be dispensed with patient Medication Guide that provides information about the drug’s uses and risks


Image credits: Biomarin, Amgen, US WorldMeds, Pfizer

FDA Alerts: Efficacy Issue with KEYTRUDA, TECENTRIQ, Potential Risk with Dolutegravir, Quality Problems with IQVIA


Capture.JPGEFFICACY ISSUE identified in clinical trials for some patients taking KEYTRUDA (pembrolizumab, Merck) or TECENTRIQ (atezolizumab, Genentech)

As monotherapy to treat urothelial cancer with low expression of PD-L1

Decreased survival associated with the use of Keytruda  or Tecentriq 

  • Results from 2 two ongoing clinical trials KEYNOTE-361 and IMVIGOR-130
  • Decreased survival vs. patients receiving cisplatin- or carboplatin-based chemotherapy
  • Trial enrollment stopped

Populations differ from those labeled for accelerated approvals of both drugs

  • FDA recommends patient selection per Section 14 of each label


Capture.JPGPOTENTIAL RISK  of neural tube birth defects with HIV medicine dolutegravir (JULUCA, TIVICAY, TRIUMEQ)

Serious cases of neural tube birth defects involving the brain, spine, and spinal cord d in babies born to women treated with dolutegravir

  • Used to treat human immunodeficiency virus (HIV)
  • Results from an ongoing observational study in Botswana
  • Seen in women taking  dolutegravir in first trimester
  • Neural tube defects occur because spinal cord, brain, related structures do not form properly
  • No reports in women taking drug later in pregnancy
  • Ongoing monitoring will continue

Dolutegravir marketed for 5 years as single ingredient product and fixed dose combination

  • Works by blocking integrase prevent virus from multiplying and reduce amount in body
  • Stopping dolutegravir can cause the HIV infection to become worse

Advice to patients and Health care professionals


Capture.JPGQUALITY PROBLEMS for data provided by IQVIA used to inform estimates for some controlled substances

Inaccuracy in data provided to FDA by IQVIA National Sales Perspectives database, including data on certain opioid drug products

  • FDA found discrepancy in data that showed a >20% drop in 5-yr fentanyl sales (expressed in kilograms,)  vs. previously reported
  • Past data overestimated because of error in IQVIA’s methods due to wrong weight-based conversion factors
  • Error could impact other federal agencies (eg DEA) using this data; can impact ongoing work to fight opioid epidemic
  • Additional data quality issues related to several other controlled substances  including oxymorphone and hydrocodone
  • Errors raise serious concerns about systemic issues with IQVIA’s data and quality control procedures

Data integrity and validity are critical to FDA and such deficiencies taken very seriously

  • FDA Commissioner has called upon IQVIA to immediately retain qualified independent, third party auditor
  • Conduct complete review of data quality and quality control procedures
  • Hire third party to conduct independent audit of data quality and quality control of all IQVIA products

FDA will brief members of Congress on IQVIA’s data quality issues and their potential public health implications


Image credit: Merck, Genentech, ViiV, IQVIA


Reference Listed Drugs (RLD)


Reference Listed Drugs (RLD) Access Inquiries

Prospective generic applicants are unable to obtain samples of the reference listed drug (RLD) necessary to support their ANDA 

  • RLD sponsor imposed limitations on distributions
  • Subject to Risk Evaluation and Mitigation Strategies (REMS) impacting distribution

FDA providing transparency regarding these inquiries

  • Published a list of all drug products with FDA inquiries on RLD access
  • Details on RLD sponsor
  • Update this list on a semi-annual basis.

Part of Drug Competition Action Plan, to expand access to safe, high quality, effective generic medicines and lower drug cost


RLD Website


FDA News: Drug Prices, Stem Cell clinic Injunctions, Opioid Crisis and Patient Needs, Drug Compounding, Medical Devices Servicing

Capture.JPGStatement from FDA Commissioner Scott Gottlieb, M.D., on the Trump Administration’s plan to lower drug prices 

Drug Competition Action Plan (DCAP) to address the rising cost of drugs

  • Strengthen and enhance the overall generic drug review process
  • Calling out abuses of the system that impede competition and fixing them
  • Adopting strong policies and taking action against anticompetitive strategies to delay development and approval of important generic drug

Biosimilar Action Plan to facilitate development and approval of biosimilars

  • Help address patient access to costly biological products
  • Address Risk Evaluation and Mitigation Strategies (REMS) “gaming” abuses that can delay the entry of generic drugs



CapturePermanent injunctions against two stem cell clinics

Permanent injunctions to stop two stem cell clinics from marketing stem cell products without FDA approval and for significant deviations from cGMP requirements

  • Unapproved treatments that put patients’ health at risk
  • US Stem Cell Clinic LLC of Sunrise, Florida
  • California Stem Cell Treatment Center Inc., with locations in Rancho Mirage and Beverly Hills, California


Capture.JPGAddressing Needs of Patients While Stemming the Tide of the Opioid Crisis

FDA goals to develop new policy solutions to

  • Reduce overall exposure to opioids
  • Prevent new addictions
  • Support development and use of medications to treat e with opioid use disorder

Need to address concerns of Americans living with chronic pain

  • Continued access to necessary pain medication
  • Fear of being stigmatized as an addict
  • Challenges in finding health care professionals willing to prescribe opioids
  • Increased thoughts of or actual suicide because crushing pain

Strike right balance between reducing new addiction while providing appropriate access

  • Upcoming public meeting focused on needs of those suffering from chronic pain
  • Allow appropriate prescribing for those in need
  • Encourage medical professional societies to develop evidence-based prescribing  guidelines
  • New guidances on efficient, modern pathway for development of pain drugs


Capture.JPGHuman Drug Compounding and Policies

Preserve access to appropriately compounded drugs for patients who have a medical need while protecting patients from poor quality compounded drugs causing harm

  • Risk-Based Approach to Manufacturing Standards for Outsourcing Facilities
  • Restricting Compounding of Drugs that are Essentially Copies of FDA-Approved Drugs
  • Regulating Compounding from Bulk Drug Substances
  • Solidifying FDA’s Partnership with State Regulatory Authorities
  • Finalization of Biological Products Guidance and Clarifying Other Policies on Activities that Compounders Undertake
  • Compliance


CaptureFDA Report on the Quality, Safety, and Effectiveness of Servicing of Medical Devices

FDA’s conclusions based on information related to quality, safety, and effectiveness of medical device servicing 

  • Evidence not sufficient to conclude whether or not there is a widespread public health concern
  • Indicates that many original equipment manufacturers (OEMs) and third party entities provide high quality, safe, and effective servicing of medical devices
  • Majority of comments, complaints, and adverse event reports alleging inadequate
    “servicing” actually pertain to “remanufacturing” and not “servicing”
  • Continued availability of third party entities to service and repair medical devices is critical

Formal regulatory action is not warranted; will pursue the following actions

  • Promote the Adoption of Quality Management Principles
  • Clarify the Difference Between Servicing and Remanufacturing
  • Strengthen Cybersecurity Practices
  • Foster Evidence Development to Assess the Quality, Safety and Effectiveness


Image credit: FDA

FDA Qualification, Market Authorization: MLHFQ Tool, ANDEXXA, KYMRIAH, AQUABEAM System



University of Minnesota

QUALIFIED CONTEXT OF USE: The paper self-administered version of the MLHFQ can be used to determine whether a device treatment is effective for improving patients’ quality of life by reducing the adverse impact of heart failure.

The instrument can be used as a secondary endpoint in feasibility and pivotal studies of outpatients with symptomatic (NYHA class II and III) heart failure. The 21-item instrument is completed by patients after they have been properly instructed by study staff. Study staff should be properly trained to instruct the patient and if needed, administer the questionnaire, according to pre-set administration instructions.

The MLHFQ instrument may be used by medical device companies and sponsor-investigators in controlled clinical trials designed to test superiority or non-inferiority of medical devices in support of regulatory submissions.


  • 21-item paper self-administered questionnaire as a measure of heart failure
  • Quantifies overall score as measure of impact of heart failure on patient’s life
    • Physical symptoms and signs of heart failure
    • Common physical/social functions
    • Psychosocial and cognitive function
    • Adverse impact on quality of life


  • Long history of use in medical device and pharmaceutical clinical studies
  • Additional publications evaluating the psychometric and statistical properties of the score
  • Publications support reliability and validity of the MLHFQ total score

REGULATORY PATHWAY: Medical Device Development Tool Qualification

  • Clinical Outcome Assessment

Decision Summary


ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) 

Lyophilized Powder for Solution For Intravenous Injection


INDICATION: For patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding

MECHANISM OF ACTION: Exerts procoagulant effect by binding and sequestering the FXa inhibitors, rivaroxaban and apixaban. Also binds and inhibits activity of Tissue Factor Pathway Inhibitor (TFPI)


Two prospective, randomized, placebo-controlled studies, healthy volunteers; examine percent change in anti-FXa activity, from baseline to nadir

  • Apixaban reversal: At 3 hours after the last apixaban dose (~ Cmax), ANDEXXA or placebo was administered, n=8
  • Rivaroxaban reversal: At 4 hours after the last rivaroxaban dose (~ Cmax), ANDEXXA or placebo was administered, n=13
  • Reduction in Anti-FXa Activity : Percent change from baseline in anti-FXa activity at its nadir was statistically significant (p < 0.0001) in favor of ANDEXXA

Ongoing multinational, prospective, single-arm, open-label study

  • ANDEXXA administered to patients taking FXa inhibitors who presented with acute major bleeding, n=185
  • Interim results : Median decrease from baseline to nadir was -93% for  apixaban and -90% for rivaroxaban


  • Boxed Warning: Arterial and venous thromboembolic events, ischemic events, including myocardial infarction and ischemic stroke, cardiac arrest, sudden deaths
  • Most common adverse reactions: Urinary tract infections, pneumonia, infusion-related reactions


  • Accelerated Approval based on change from baseline in anti-FXa activity in healthy volunteers; improvement in hemostasis has not been established
  • Continued approval may be contingent upon results of studies to demonstrate an improvement in hemostasis in patients



KYMRIAH (tisagenlecleucel)


SUPPLEMENTAL INDICATION: For adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma


  • Single-arm, open-label, multi-center, phase 2 trial, adults with relapsed or refractory DLBCL and DLBCL after transformation from follicular lymphoma
  • Treated with at least two prior lines of therapy, including an anthracycline and rituximab, or relapsed following autologous hematopoietic stem cell transplant
  • Single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy, n=68
  • Overall response rate (ORR):  50% (95% CI: 37.6, 62.4)
  • Complete response (CR) rate: 32% (95% CI: 21.5, 44.8)
  • Estimated median response duration among patients in PR: 3.4 months


  •  Most common adverse reactions: Cytokine release syndrome (CRS), infections-pathogen unspecified, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache. Because of the serious risks of CRS and neurologic toxicities
  • Has a Risk Evaluation and Mitigation Strategy (REMS)


  •  Priority review, Breakthrough Therapy designation, Orphan Product designation




Procept BioRobotics Corporation

INDICATION FOR USE: For the resection and removal of prostate tissue in males suffering from lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia


Personalized image-guided prostate tissue removal system that uses a high-velocity water jet to resect and remove a predetermined volume of tissue. Comprised of nine main components along with accessories

  • Conformal Planning Unit, Console, Motorpack, Roll Stand, Foot Pedal, Handpiece Articulating Arms, Articulating Arm, Handpiece, Scope

GENERIC DEVICE TYPE: Fluid jet system for prostate tissue removal.

Prescription device intended for the resection and removal of prostatic tissue for the treatment of benign prostatic hyperplasia (BPH). The device cuts tissue by using a pressurized jet of fluid delivered to the prostatic urethra. The device is able to image treatment area, or pairs with an imaging modality, to monitor treatment progress.


  • Prospective, multicenter, international double-blinded randomized clinical trial,   AQUABEAM vs. standard transurethral resection ofthe prostate (TURP)
  • Primary efficacy endpoint: Change in International Prostate Symptom Score (IPSS) at 6 months
  • Primary safety endpoint: Occunence of Clavien-Dindo persistent grade 1 or grade 2 or higher perioperative complications at 3 months
  • Mean IPSS scores: Decreased from 22.9 at baseline to 5.9 at 6 months with AQUABEAM vs. from 22.2 at baseline to 6.8 in TURP group
  • Clavien-Dindo grade 1 persistent or grade 2 or higher event: 25.0% in AQUABEAM vs, 40.0% in TURP


  • Injury from device operation: Clinical performance testing, Animal testing, Labeling, Training
  • Adverse tissue reaction: Biocompatibility evaluation
  • Infection: Sterilization validation, Reprocessing validation, Shelf life testing
  • Failure to remove target tissue or removal of nontarget tissue: Clinical performance testing, Animal testing, Software verification, validation, and hazard analysis, Non-clinical performance testing, Labeling
  • Electrical shock or electromagnetic interference: Electrical safety testing, Electromagnetic compatibility testing, Labeling


  • 21 CFR 876.4350
  • Regulation Name: Fluid jet system for prostate tissue removal
  • Regulatory Class: Class II
  • Product Code: PZP


Image credits: Unv. of Minnesota, Portola, Novartis, Procept


FDA News: Digital Health Approach, Advancing Health Equity, INFORMED,Treatments for Neurological Disorders, Science of Nanotechnology, Brain Injury Monitoring


Transforming FDA’s Approach to Digital Health

Remarks by Scott Gottlieb, M.D., Commissioner 
Academy Health’s 2018 Health Datapalooza
Washington, DC, April 26, 2018

Digital health tools have vast potential to

  • Improve ability to accurately diagnose and treat disease
  • Enhance delivery of health care for the individual
  • Make medical care truly patient centric — empowering the individual

Digital Health Innovation Action Plan

  •  New policy  to streamline path for digital health products with several functions
  • Draft of Working Model for precertification pilot program

Launch of Program to Apply Digital Health to Drugs

  • Expand opportunities to use digital health tools as part of drug development
  • Improve safety and effectiveness of drug delivery
  • Mobile devices and software linked to specific drugs for medication compliance
  • Advance policy framework and new guidance

Artificial Intelligence

  • New regulatory framework to support use of AI-based technologies
  • Understand connection between decision-making in traditional health care settings vs. use of advanced technologies
  • Appropriate guardrails for to deliver benefits  and meet safety /effectiveness stds
  • Make drug/device development more predictable, efficient, more reflective of patients’ real-world experience

Launch of a New Premarket Digital Safety Program

  • Launch of Premarket Digital Safety Program with unified data standard for electronic reporting requirements
  • New digital framework can significantly improve efficiency and accuracy of premarket safety submission and review process

Launch of FDA’s New Digital Health Incubator

  • Creation of an internal data science incubator – Information Exchange and Data Transformation (INFORMED)
  • Conduct of regulatory science research in health technology and cancer analytics
  • Collaboration with nonprofit open-access Project Data Sphere, to develop algorithms for classification of tumor dynamics
  •  Joint fellowship program with NCI to design and develop digital biomarkers as drug development tools


CaptureMission Possible: Moving the Needle Forward to Advance Health Equity

FDA’s Office of Minority Health (OMH) protects, promotes, advances public health of vulnerable and underrepresented populations

  • Conduct and fund research on diseases that disproportionately affect minorities
  • Diversify the public health workforce
  • Help minorities make better informed health decisions
  • Engage with minority-serving institutions of higher learning
  • Serve as a voice for those in need; rural health challenges, need for telemedicine

Partnering with private- and public-sector organizations (including VA, Yale University) to further equity on all fronts

  • Getting culturally sensitive messages out to minority communities
  • Ensuring minority representation in clinical trials

New Journal Article: Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs


CaptureInformation Exchange and Data Transformation (INFORMED)

Incubator for collaborative oncology regulatory science research

  • In collaboration with the U.S. Department of Health and Human Services’ Innovation, Design, Entrepreneurship and Action (IDEA) Lab
  • Focused on supporting innovations with expertise of a diverse group of oncologists, data scientists, statisticians, and entrepreneurs-in-residence
  • Big data analytics and modern approaches in evidence generation for regulatory decisions
  • Special emphasis on systems thinking in oncology regulatory science research t

Research portfolio

  • Use of real world data for clinical evidence generation. prospective pragmatic clinical trials
  • Utility of biosensors, IoT to quantify intrinsic and extrinsic factors influencing patient’s experience
  • Opportunities for machine learning and artificial intelligence to improve existing practices
  • Utility of open-access platforms and emerging technologies such as blockchain


CaptureAdvancing Development of Treatments for Neurological Disorders

Published five guidances for industry related to neurological conditions

Noteworthy aspects

  • Recent explosion of new scientific knowledge about nervous system.
  • Drug developers looking for clear paths to treatment solutions
  • Worked with patient advocacy organizations and scientists to ensure voices were heard
  • Streamlined internal review process  to encourage development of short, concise documents free of unnecessary background information

Stakeholder community engagement

  • Alzheimer’s disease (AD), Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), migraine, and epilepsy communities
  • Frequent conversations with multiple drug developers about their needs



Advancing Science of Nanotechnology in Drug Development

Steady increase in approved drug products containing nanomaterials

  • Including investigational new drugs, new drug applications, and abbreviated new drug applications (commonly known as generics)

Uniqueness of drug products containing nanomaterials

  • May take on different chemical, physical, or biological properties
  • May impact quality, safety, or efficacy
  • May follow a different pathway in the body compared to small molecule drug; reach areas typically difficult to reach for a small molecule

Research to Address Challenges Related to Nanotechnology

  • FDA’s Office of Testing and Research (OTR) conducting research on manufacturing and quality issues
  • Identifying critical processes and material properties that can impact quality within context of efficacy and safety
  • Evaluating drug’s performance and release from the nano carriers
  • Encourage use of advanced manufacturing techniques to reduce variations in product quality
  • Characterizing excipients in complex formulations

Draft guidance on Drug Products, including Biological Products, that Contain Nanomaterials



Biomarkers for Brain Injury Monitoring

FDA Center for Devices and Radiological Health (CDRH), Office of Science and Engineering Laboratories, Division of Physics

“We envision a day when soldiers or civilians who have experienced a blast or a head impact will be able to stick a small sensor to their forehead and know if they have sustained a brain injury. Although we may not be the ones who develop such a device, we want to contribute research that can help advance the field.” 

Recent  Scientific Advances

  • Fexible microelectronics that are wearable and conformable for portable electroencephalogram (EEG) technology
  • Use to detect brain injury in victims of traumatic events e.g. accidents, explosions
  • Need scientific knowledge base related to validated brain injury biomarkers and models

Research project on field-deployable devices to rapidly collect and evaluate EEG signals 

  • Detect Traumatic Brain Injury (TBI) rapidly and non-invasively
  • Create “smart sensors”  to for emergency responders to detect EEG signals rapidly
  • But lack of validated biomarkers and models of brain injury
  • This research focuses on developing useful brain injury models, identifying and validating brain injury biomarkers, and studying new EEG technologies


 Image credit: FDA



INDICATION FOR USE: Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy

  • Complementary diagnostic test, FoundationFocusTM CDx BRCA LOH, for tumor samples to determine  homologous recombination deficiency (HRD) status.


  • Randomized, double-blind, n=561, with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, RUCAPARIB  vs. placebo
  • Tumor tissue samples examined with next-generation sequencing assay for deleterious somatic or germline BRCA mutation (tBRCA); also percentage of genomic loss of heterozygosity (LOH); positive (HRD) status was tBRCA-positive and/or LOH high
  • Median progression-free survival (PFS):  10.8 vs. 5.4 months, p<0.0001, 13.6 vs. 5.4 months (HRD, p<0,0001), 16.6 vs 5.4 months (tBRCA, p<0.0001)


  • Most common adverse reactions: Nausea, fatigue (including asthenia), abdominal pain/distension, rash, dysgeusia, anemia, ALT/AST elevation, constipation, vomiting, diarrhea, thrombocytopenia, nasopharyngitis/URI, stomatitis, decreased appetite, and neutropenia
  • Myelodysplastic syndrome and/or acute myeloid leukemia


  • Priority Review, completes initial accelerated approval commitments
  • Initial approval for  deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer



TAFINLAR (dabrafenib) and MEKINIST (trametinib)


INDICATION: TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with  BRAF V600E mutation and with no satisfactory locoregional treatment options


  • Anaplastic thyroid cancer (ATC) is rare, aggressive; accounts for about 1 to 2 percent of all thyroid cancers
  • First FDA-approved treatment for patients with specific gene mutation
  • Targeting same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients


  • Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway; used in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive tumor xenografts compared with either drug alone.


  • Open-label clinical trial, n=23, patients with rare cancers with the BRAF V600E mutation including ATC
  • Partial reduction in tumore size: 57%
  • Complete response: 4%
  • No significant tumor growths for six months or longer: 64%


  • Side effects consistent with those seen in other cancers when the two drugs are used together
  • Common side effect: Pyrexia, rash, chills, headache, arthralgia, cough, fatigue, nausea, vomiting, diarrhea, myalgia, dry skin, decreased appetite, edema, hemorrhage, hypertension, dyspnea
  • Severe side effects of Tafinlar: Development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia.
  • Severe side effects of Mekinist: Development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes.


  • Priority review, breakthrough therapy designation and orphan drug designation
  • Both Tafinlar and Mekinist previously approved for use in BRAF V600 mutation-positive metastatic melanoma, BRAF V600E mutation-positive, metastatic non-small cell lung cancer

Tafinlar LABEL

Mekinist LABEL 



PartoSure test

Parsagen Diagnostics, Inc., Harvard Innovation Launch Lab

INDICATION FOR USE:  Rapid, qualitative test for detecting the presence of placental alpha microglobulin 1 (PAMG-1) in cervicovaginal secretions.

Indicated as an aid to rapidly assess the risk of spontaneous preterm delivery in ≤ 7 days from the time of cervicovaginal sample collection in pregnant women with signs and symptoms of early preterm labor, intact amniotic membranes and minimal cervical dilatation (<3 cm), sampled between 24 weeks, 0 days and 34 weeks, 6 days gestation in women with a singleton gestation


  • Spontaneous preterm delivery difficult to reliably predict
  • This test aids assessment of spontaneous preterm delivery; improves upon
    prediction of not undergoing preterm delivery


  • Sterile, Vaginal Swab: Taking vaginal secretion
  • Vial with Extraction Solvent: Saline solution with solubilizer and dispersant (Triton X100) and preservative (sodium azide); extracts vaginal secretions from swab
  • Lateral Flow Test Strip: Lateral flow, immunochromatographic assay to identify    presence PAMG-1; goat anti-mouse monoclonal antibodies at test region to detect PAMG-1 and goat anti-mouse anti-immunoglobulin antibodies at control region to detect IgG


  • For spontaneous preterm delivery in ≤ 7 days from the time of cervicovaginal sample collection in singleton pregnant women with signs and symptoms of early preterm labor, intact amniotic membranes and minimal cervical dilation (<3 cm)
  • US Study: 6 preterm deliveries within 7 days from sample collection – 3 predicted and 3 missed, Sensitivity of 50%, Specificity of  98.4% (CI: 97.1% – 99.2%)
  • Retrospective Spain study: 18 spontaneous preterm deliveries- 9 predicted, 9 were missed, Sensitivity of 50%, Specificity of 95.9%


  • False negative: Mother could progress unanticipated spontaneous preterm delivery without corticosteroids
  • Increased risk or increased severity of respiratory distress syndrome, intracranial hemorrhage, necrotizing enterocolitis, and death compared with neonates whose mothers do receive antenatal corticosteroids.


  • Product Code: QBB
  • Test results should always be considered in conjunction with other clinical evaluation and diagnostic procedures
  • Post-approval studies required for additional data to verify safety and effectiveness



Cala ONE

Cala Health Inc.

INDICATION FOR USE:  To aid in the transient relief of hand tremors in the treated hand following stimulation in adults with essential tremor


  • Delivers individualized therapy that is calibrated by a physician using on-board sensors to measure the individual’s tremor
  • Therapeutic device can be worn all day to provide on-demand
    relief at home, in social settings, at work, or whenever patients desire relief.

GENERIC TYPE OF DEVICE: External upper limb tremor stimulator

  • Prescription device which is placed externally on the upper limb and designed to aid in tremor symptom relief of the upper limb


  • Randomized, controlled, multi-center study
  • Improvements in the treatment group in both physician and patient-rated measures of tremor severity compared to the sham group


  • Tissue damage due to overstimulation: Non-clinical performance testing
    Software verification, validation, and hazard analysis, Electrical safety testing
    Shelf life testing, Labeling
  • Adverse tissue reaction: Biocompatibility evaluation, Labeling
  • Electrical shock or burn:  Electrical, thermal, and mechanical safety testing
    Software verification, validation, and hazard analysis , Labeling
  • Interference with other devices: Electromagnetic compatibility (EMC) testing
    Software verification, validation, and hazard analysis, Labeling


  • Regulation Number: 21 CFR 882.5897
  • Regulation Name: External upper limb tremor stimulator
  • Regulatory Class: Class II
  • Product Code: QBC


Image Credits: Clovis, Novartis, Parsagen, Cala


FDA Guidances: Multiple Function Device Products, Pregnant Women in Clinical Trials, Atopic Dermatitis Pediatric Studies, PRO Tool for COPD, BIMO Inspection Information


Multiple Function Device Products: Policy and Considerations

Products with at least one device function are referred to as “multiple function device products.”

  •  Function : Distinct purpose of the product, which could be intended use or subset
  • Examples: One function: analysis or three functions: storage, transfer, analysis
  • Product may contain multiple functions
    • – may / may not meet definition of ‘device’
    • -meet definition of device, but not subject to premarket review
    • -meet definition of device, but no enforcement of  compliance with applicable regulatory controls  (enforcement discretion policy)
  • Applies to device constituent of combination product


  • No regulation if does not meet ‘device’ definition
  • However, when assessing safety and effectiveness, FDA may assess the
    impact of the other function.
    235 compliance with applicable requirements. In accordance with existing policies, FDA intends not
    236 to review a device function subject to an enforcement discretion policy merely because it is part


  • Separation in design and implementation of device function
  • Impact of other function(s)
  • Assessing impact of other functions on device function-under-review
    • Impact on safety or effectiveness
    • Result in increased risk or adverse effect on performance
    • Impacts to safety and effectiveness

Content of premarket submission for Device Function-Under-Review

  • Indications for Use, Description of Functions, Architecture and Design, Risk Analysis, Requirements and Specifications, Submission Summary



Pregnant Women: Scientific and Ethical considerations for Inclusion in Clinical Trials

Inclusion of pregnant women in drug development clinical trials 

  • For safe and effective treatment during pregnancy
  • Establish dose/dosing regimen, safety, and efficacy of treatments during pregnancy
  • Enrollment of pregnant women may offer direct benefit to woman and/or fetus
  • For accessible treatment options for pregnant population

Ethical Considerations

  • FDA Regulations That Govern Research in Pregnant Women
  • Research-Related Risks
  • General Guidelines for Including Pregnant Women in Clinical Trials

Other Considerations

  • Disease Type and Availability of Therapeutic Options in Pregnant Population
  • Timing of Enrollment
  • Pharmacokinetic Data
  • Safety Data Collection and Monitoring
  • Stopping a Clinical Trial That Enrolls Pregnant Women



Atopic Dermatitis: Timing of Pediatric Studies During Development of Systemic Drugs

Relevant age groups to study and how early in a pediatric Atopic Dermatitis (AD) drug development

  • AD is chronic pruritic inflammatory skin disease primarily affecting pediatric patients
  • Based on input received Dermatologic and Ophthalmic Drug Advisory Committee


  • Base on labeling information on relevant pediatric populations and safe and effective use
  • Initiate early in development, typically after obtaining initial evidence of efficacy and safety from early phase adult studies
  • Discuss specifics as early as is feasible with FDA to submit pediatric study plans
  • Consider juvenile animal toxicity study with appropriate endpoints
  • Not generally necessary to have extensive adult safety database
  • Study all relevant age groups, including children < 2 yo



Chronic Obstructive Pulmonary Disease: Use of the St. George’s Respiratory Questionnaire (SGRQ) as a PRO Assessment Tool

Use of St. George’s Respiratory Questionnaire (SGRQ), a patient reported outcome measure (PRO) assessment tool for interventional clinical trials in COPD
  • COPD is chronic progressive disease caused by chronic inflammation and destruction of airways and lung parenchyma
  • Usually associated with tobacco smoking or prolonged exposure to other noxious particles and gases
  • SGRQ measures health status in patients with obstructive airway diseases
PRO assessment of efficacy
  • Use for stratification or enrichment purposes in protocol development phase.
  • Use as coprimary endpoint or as secondary endpoint
  • Clinically important and sponsor should report clinical trial data irrespective of  direction of results
Considerations for SGRQ
  • Use current version from St. George’s University of London Health Status Research website at
  • Administration
  • Scoring
  • Method of Analysis
  • Use of the SGRQ
Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions
To plan BIMO inspections for timely identification of inspection sites and provide information to FDA -ORA investigators 
  •  Clinical Study-Level Information
  • Comprehensive table listing all participating clinical sites
  • Table listing all entities with contracted clinical study-related activities
  • Protocol, protocol amendments, annotated Case Report Form(s)
  • Subject-level data line listings by clinical site
  • Summary-level clinical site dataset








Aug 13-14: Public Meeting – Pediatric Medical Device Development. Identify strategies that enhance medical device ecosystem toward development and innovation of devices that serve the complex needs of children. INFORMATION


Jul 9:  Public Meeting for Patient Focused Drug Development for Chronic Pain. Hearing patients’ perspectives on chronic pain, treatment approaches, challenges or barriers to accessing treatments and managed with opioids, acetaminophen, NSAIDs, antidepressants, non-pharmacologic interventions or therapies.INFORMATION


Jun 19-20: FDA/IMSN Summit with international drug regulators to discuss medication safety issues. Discussion among international drug regulators on medication safety issues with regulated pharmaceutical products and how to minimize medication errors with labeling and packaging. INFORMATION

Jun 22: Clinical Outcome Assessments (COAs) in Cancer Clinical Trials. Discussion between academia, industry, international regulatory, HTA bodies, and patient groups to advance measurement of the patient experience in cancer clinical trials; characteristics of PRO measurement tools, standardize PRO data analysis, FDA approaches to PRO data review. INFORMATION

Jun 25-26: 2018 Center for Biologics Evaluation and Research Science Symposium. Discuss scientific topics related to the regulation of biologics and highlight science conducted at CBER by showcasing how scientific research informs regulatory decision making and to provide a forum for developing collaborations within FDA and with external organizations.


May 2: Antimicrobial Drugs Advisory Committee Meeting. Discuss NDA for plazomicin, sponsored by Achaogen for proposed indications for treatment of complicated urinary tract infections & blood stream infections in adults  INFORMATION

May 3: Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Pediatric Advisory Committee Meeting. Discuss NDA for stannsoporfin injection, submitted by InfaCare, proposed for treatment of neonates with indicators of hemolysis who are at risk of developing severe hyperbilirubinemia INFORMATION

May 4: Annual Public Meeting; Reagan-Udall Foundation for the FDA. FDA Commissioner Scott Gottlieb as keynote speaker; discuss activities and how it supports FDA; panel discussion on “Evolution of FDA Science and Engagement.” INFORMATION

 ⊕ May 8: FDA Drug Topics: Protecting Patients – Pharmacists Requirements under the Drug Supply Chain Security Act. FDA’s Division of Drug Information in the Center for Drug Evaluation and Research (CDER) is presenting a series of continuing education webinars targeting the needs of all health care professionals. INFORMATION

May 8: CBER Update: Office of Vaccine Research and Review Data Submission. Update on best practices INFORMATION

May 9: Tissue Agnostic Therapies: Regulatory Considerations for Orphan Drug Designation; Public Workshop. Discuss factors when evaluating drugs for orphan designation that treat tissue agnostic disease or condition in oncology, additional factors related to orphan exclusivity when approving such a product INFORMATION

⊕ May 10: User Session – Digital Health Software Precertification (Pre-Cert) Pilot Program. Interactive session to discuss progress on Software Precertification Pilot Program, working model, key program areas, questions for public input.  INFORMATION

May 10: FDA Grand Rounds spotlights stakeholder opportunities in FDA predictive toxicology roadmap. Framework for integrating novel predictive toxicology methods into safety and risk assessments of its products. INFORMATION

May 10: Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Discuss NDA for volanesoren solution for subcutaneous injection, Akcea Therapeutics, Inc, for use as an adjunct to diet for the treatment of patients with familial chylomicronemia syndrome. INFORMATION

May 11: Medical Gas Workshop III. Provide opportunity for medical gas manufacturers and public to provide input on potential areas of Federal drug regulation that should be revised with respect to medical gases.  INFORMATION

May 15-16: FDA Regulatory Education for Industry (REdI). FDA-led forum that brings together the regulatory educators from FDA’s CDER and CDRH. Meeting Information

May 17:  Webinar: Pioneering Modeling Methodologies in Generic Drug Development. Discuss novel ways FDA is approaching the use of quantitative methods and modeling for development and demonstration of generic samenessINFORMATION 

May 18: MDIC workshop on Patient-Centered Clinical Trial Design. Method for incorporating patient preference information to set significance levels in clinical trial design. Focus on Parkinson’s disease; may be generalizable to other diseases.  In collaboratorion with FDA (CDRH), MIT, RTI Health Solutions and Michael J. Fox Foundation. INFORMATION

May 22: Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee.  Discuss NDA for buprenorphine sublingual spray, by INSYS, for the treatment of moderate-to-severe acute pain where the use of an opioid analgesic is appropriate INFORMATION

May 22-23: Accreditation Scheme for Conformity Assessment (ASCA) of Medical Devices to Food and Drug Administration-Recognized Standards; Public Workshop.  Discuss draft design of pilot program, including goals and scope, framework, requirements, and streamline standards. INFORMATION

May 24: FY 2018 Generic Drug Research Public Workshop.  Provide overview of regulatory science initiatives for generic drugs and public input on research priorities INFORMATION


Apr 3: Public workshop: CDER and You: Keys to Effective Engagement. Share information with stakeholders including patients, patient advocates, academic and medical researchers, health care professionals, drug developers. Share unique perspectives on drug development and safety. INFORMATION

Apr 6: US FDA and Health Canada: Joint Regional Consultation on the ICH. To provide information and receive comments on the current ICH activities as well as the upcoming meetings in Kobe, Japan INFORMATION

Apr 10: FDA Drug Topics: An Introduction to Drug Safety Surveillance and the FDA Adverse Event Reporting System. Introduce the many phases of drug safety surveillance from the earliest stages of drug development through post approval, and will focus on how FDA conducts pharmacovigilance, develops safety signals, and communicates our findings.INFORMATION

Apr 11-12: CDER Small Business and Industry Assistance Regulatory Education for Industry (REdI): Generic Drugs ForumInteract with FDA subject matter experts  on Generic Drug Review Program, program progress, current initiatives. INFORMATION

Apr 16: Evaluating Inclusion and Exclusion Criteria in Clinical Trials; Public Meeting. Discuss topics related to eligibility criteria in clinical trials and their potential impact on patient access to investigational drugs, and how to facilitate the enrollment of a diverse patient population. INFORMATION

Apr 16: Public Workshop: Study Design Considerations for Devices including Digital Health Technologies for Sleep Disordered Breathing (SDB). Appropriate design of clinical studies to evaluate devices including digital health technologies intended for the diagnosis, monitoring, or treatment of SDB INFORMATION

Apr 16-18: 2018 AAPS Workshop on Drug Transporters in ADME: From Bench to Bedside. Present next generation of transporters and transport mechanisms that may contribute to ADME properties of drugs in disease states considered in drug discovery and development. INFORMATION 

Apr 17: Public Meeting on Patient-Focused Drug Development for Opioid Use Disorder (OUD). To learn patients’ perspectives on OUD, effects on health and well-being, experience using prescription medical treatments and other treatments, challenges or barriers to accessing medical treatments for OUD. INFORMATION

Apr 19: Peripheral and Central Nervous System Drugs Advisory Committee Meeting Discuss NDA for cannabidiol oral solution, GW Pharmaceuticals, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older. INFORMATION

Apr 20: FDA/OCE Public Meeting on Relevant Molecular Targets in Pediatric Cancers: Applicability to Therapeutic Investigation FDARA 2017. Discuss provisional list of molecular targets for adult cancer indications but also relevant to cancer in children thereby providing a rationale for early pediatric evaluation. INFORMATION

Apr 21: Public Meeting on Electronic Submissions and Data Standards. Discuss current status of electronic submissions and data standards initiatives to improve predictability and consistency of electronic submissions process in support of human drug review program. INFORMATION

Apr 23: Arthritis Advisory Committee Meeting. Discuss NDA for baricitinib tablets, submitted by Eli Lilly and Company, for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. INFORMATION

Apr 23-25: 12th Annual FDA/DIA Biostatistics Industry and Regulator Forum. Discuss relevant statistical issues associated with the development and review of therapeutic drugs and biologics. INFORMATION

Apr 30Public Workshop – Orthopaedic Sensing, Measuring, and Advanced Reporting Technology (SMART) Devices. Enhance engagement with stakeholders to facilitate device development and to discuss scientific and regulatory challenges associated with Orthopaedic SMART Devices.   INFORMATION


Mar 1: Vaccines and Related Biological Products Advisory Committee Meeting. Hear  research program in the Laboratory of Mucosal Pathogens and Cellular Immunology (LMPCI), Division of Bacterial, Parasitic and Allergenic Products (DBPAP), Office of Vaccines Research and Review (OVRR), and discuss selection of strains to for vaccines for the 2018-2019 influenza season INFORMATION

Mar 1: 21st US-Japan Cellular and Gene Therapy Conference. Exchange ideas on cutting edge and diverse areas of biomedical research, and enhance opportunities for collaborations among scientists from the US and Japan.  INFORMATION

Mar 1: Neurological Devices Panel  Advisory Committee Meeting. Discuss safety and effectiveness of intracranial aneurysm treatment devices and factors affecting clinical outcomes such as aneurysm morphology, size, and location in the neurovasculature. INFORMATION

Mar 1-2: IASLC-FDA Lung Cancer Neoadjuvant Meeting.Discuss standardization and validation of endpoints in neoadjuvant lung cancer trials. INFORMATION

Mar 4-6: FDA-PhUSE Computational Science Symposium. Review progress on topics such as data standards, best-practices-driven analytical tool development, business processes for information systems, evaluation of current tools. INFORMATION

Mar 5: Risk Communication Advisory Committee Meeting. Committee will discuss  impact of pregnancy and lactation labeling information in prescription drug and biological products as modified under the Pregnancy and Lactation Labeling Rule.  INFORMATION

Mar 8: FDA Grand Rounds:  Stem cell-based cellular therapies. Use of stem cell-based products is new and characterizing the product still faces hurdles.  FDA conducting research into identifying cell therapy product characteristics that will predict the reliably of the performance of cell-based therapies in humans. INFORMATION

 Mar 8: Gastrointestinal Drugs Advisory Committee Meeting. Discuss sNDA for XELJANZ (tofacitinib) proposed for the treatment of adult patients with moderately to severely active ulcerative colitis. INFORMATION

Mar 8: Public Workshop: Safety Assessment for Investigational New Drug Safety Reporting. Engage external stakeholders in discussions related to finalizing the draft guidance entitled “Safety Assessment for IND Safety Reporting.” INFORMATION

Mar 15: Oncology Center of Excellence Listening Session; Solicit comments regarding what stakeholders desire of the OCE in terms of structure, function, regulatory purview, and activity. INFORMATION

Mar 20: Promoting the Use of Complex Innovative Designs (CID) in Clinical Trials. March 20, 2018. Discuss use of CID in drug development and regulatory decision making, CID pilot program. INFORMATION

Mar 21-22: Joint Meeting of the Blood Products Advisory Committee and the Microbiology Devices Panel. Discuss reclassification from Class III to Class II of nucleic acid and serology-based point-of-care and laboratory-based in vitro diagnostic devices indicated for use as aids in the diagnosis of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection.⊕ INFORMATION

Mar 22: Webinar – Duodenoscope Sampling and Culturing. FDA, CDC, ASM and other endoscope culturing experts will review the voluntary duodenoscope surveillance sampling and culturing protocols to monitor quality of reprocessing procedures.  INFORMATION

Mar 22:  Patient Engagement in the National Evaluation System for health Technology (NEST): Lessons Learned and Best Practices Workshop.  Gather lessons learned and best practices for patient engagement in evidence generation (planning, collection of data and information, analysis, and dissemination). INFORMATION

Mar 22: Pediatric Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee Meeting. To discuss major objectives of Phase 3 drug development program for treatment of children with achondroplasia (ACH) submitted by BioMarin Pharmaceutical Inc. INFORMATION

Mar 23: Advisory Committee Meeting: Pediatric. Discuss the following products for CDER – BANZEL, INTUNIV, LEXAPRO and CDRH – FLOURISH, ACTIVA, LIPOSORBER, IMPELLA RP SYSTEM. INFORMATION

Mar 26-28: Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics for Alcoholic Hepatitis and Alcohol Associated Liver Disease and Pediatric Irritable Bowel Syndrome and Pediatric Functional Constipation Workshop, Facilitate dialogue among industry, academia, and other stakeholders on common data elements needed to be included in clinical trials, clinical trial designs, potential surrogate and clinical benefit endpoints, and practical issues with managing clinical trials.  INFORMATION

Mar 27: Meeting of the Psychopharmacologic Drugs Advisory Committee. Discuss  NDA for  lofexidine hydrochloride, US WorldMeds, LLC, for mitigation of symptoms associated with opioid withdrawal and facilitation of completion of opioid discontinuation treatment. INFORMATION

Mar 28: Promoting the Use of Complex Innovative Designs in Clinical Trials
Inform development of guidance document and CID pilot program. INFORMATION


Feb 1: FDA-ISoP Public Workshop: Model Informed Drug Development (MIDD) for Oncology Products. Discuss integrating human pharmacokinetic, pharmacodynamic, efficacy, safety data into models, use of  novel imaging techniques, diagnostic, predictive biomarkers, shift from traditional endpoints,  regulatory implications.  INFORMATION

Feb 7-8: 10th Annual Sentinel Initiative Public Workshop.  Bring stakeholder community together to discuss a variety of topics on active medical product surveillance. INFORMATION

Feb 14-15:  Joint Drugs Advisory Committee Meeting: Anesthetic and Analgesic Products and Drug Safety and Risk Management. Discuss NDA for HYDEXOR, for the short-term management of acute pain severe enough to require an opioid analgesic while preventing and reducing opioid-induced nausea and vomiting. Also discuss sNDA  for EXPAREL (bupivacaine liposomal injectable suspension) to produce local analgesia and as a nerve block to produce regional analgesia. INFORMATION

Feb 22-23: FDA-AACR-ASTRO Regulatory Science and Policy Workshop – Clinical Development of Drug-radiotherapy Combinations. Address the lack of drug development for products intended specifically for use with radiation therapy.   INFORMATION

Feb 27:  Webinar – Custom Device Annual Reporting. Custom Device Exemption allows manufacturers to market medical devices designed to treat a unique pathology or physiological condition without premarket approval. Webinar to discuss custom device annual report requirement. INFORMATION

Feb 28: Public Meeting: Enhanced Drug Distribution Security under the Drug Supply Chain Security Act.Provide members of the drug distribution supply chain and other interested stakeholders an opportunity to discuss strategies and issues related to the enhanced drug distribution security provisions of the Act. INFORMATION


Jan 8: CLIA Waiver Applications Draft Guidance Documents. Discuss draft guidances on CLIA waiver applications and Dual 510(k) and CLIA waivers INFORMATION

Jan 9:  Webinar – Pediatric Information for X-ray Imaging Device Premarket Notifications:  Discuss final guidance on radiation safety of pediatric populations in the design of X-ray imaging devices. INFORMATION

Jan 10:  Webinar – Technical Considerations for Additive Manufactured Medical Devices. Technical aspects associated with AM processes, recommendations for device design, manufacturing, testing considerations. INFORMATION

Jan 11: Public Workshop – Self-Collection Devices for Pap Test. Obtain feedback on feasibility, benefits, risks for self-collection cervical sampling devices for cervical cancer screening by Pap testing INFORMATION

Jan 11:  Safety Assessment for IND Safety Reporting.Convened by the Duke-Robert J. Margolis Center for Health Policy at Duke University and FDA; to bring stakeholder community together to discuss IND safety topics INFORMATION

Jan 11: FDA Grand Rounds. Marker of brain injury increased in African Americans with Alzheimer’sBetter understanding of ethnicity and gender differences involved in the cause and progression of Alzheimer’s Disease could contribute to better drugs–and other types of interventions–to slow Alzheimer’s progression INFORMATION

Jan 16:  Webinar – FDA Categorization of Investigational Device Exemption (IDE) Devices to Assist the Centers for Medicare and Medicaid Services (CMS) with Coverage Decisions. Discuss final guidance on FDA categorization of IDE devices that is used by CMS to determine whether an IDE device, and certain related services, may be covered by CMS. INFORMATION

Jan 26: Evaluating Nicotine Replacement Therapies. Public comments on FDA’s approach to evaluating the safety and efficacy of nicotine replacement therapy (NRT) products, including how they should be used and labeled. INFORMATION

Jan 29: Weighing the Evidence: Variant Classification and Interpretation in Precision Oncology. To discuss how genetic sequencing data is best implemented in patient management to advance innovative regulatory strategies to support development of safe and effective precision-based drugs and devices. INFORMATION

Jan 30: Opioid Policy Steering CommitteePrescribing Information  Receive stakeholder input on how FDA REMS authority, might improve the safe use of opioid analgesics by curbing over-prescribing to decrease the occurrence of new addictions and limit misuse and abuse INFORMATION

Jan 30-31: Fostering Digital Health Innovation. Developing the Software Precertification Program. Discuss progress of pilot precertification program and seek input on ongoing development of the Software Precertification Program. INFORMATION

Image credit: FDA

FDA Market Authorization: CRYSVITA, TAVALISSE, MALDI Biotyper, CARDIOFORM Septal Occluder, GUARDIAN Connect System 


CRYSVITA (burosumab-twza) injection

Ultragenyx Pharmaceutical, Inc.

INDICATION:  Treatment of X-linked hypophosphatemia (XLH) in adult and pediatric
patients 1 year of age and older.


  • XLH, a rare, inherited form of rickets, affects ~ 3,000 children and 12,000 adults in US
  • XLH differs from other forms of rickets in that vitamin D therapy is not effective
  • First drug approved to treat adults and children ages 1 year and older with XLH 

MECHANISM OF ACTION: Binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.


  • 65 pediatric patients and 134 adults with XLH in 4 studies, CRYSVITA vs, placebo,
  • Achievement of normal phosphorus levels: Adults: 94% adults vs. 8%, Children: 94-100%
  • Improved radiographic evaluation of rickets vs.  natural history cohort: In both children and adults,


  • Most common adverse reactions: Back pain, headache, restless leg syndrome, decreased vitamin D, dizziness and constipation
  • Most common adverse reactions in children: Headache, injection site reaction, vomiting, decreased vitamin D and pyrexia


  • Orphan designation, Breakthrough therapy designation
  • Pediatric Priority Review Voucher granted
  • Exempt from required pediatric assessments
  • Postmarketing requirements: Post-approval surveillance program with safety objectives, lactation sub-study in lactating women ,  reanalyze banked immunogenicity serum samples

REIMBURSEMENT PATHWAY: For rare disease indication

  • Covered with limited issue in Medicaid and Medicare
  • However, increased scrutiny of rare disease therapies and evolution of
    precision medicine; need to articulate long-term benefit of early
    diagnosis and treatment to patient and the health care system



TAVALISSE (fostamatinib disodium hexahydrate) tablets

Rigel Pharmaceuticals, Inc.

INDICATION: Treatment of thrombocytopenia in adult patients with chronic immune
thrombocytopenia (ITP) who have had an insufficient response to a previous treatment


  • Two identical, double-blind, placebo-controlled trials, n=150,  patients with persistent or chronic ITP who had an insufficient response to previous treatment, TAVALISSE vs. placebo
  • Endpoint: Stable platelet response (at least 50 x109/L on at least 4 of the 6 visits between Weeks 14 to 24)
  • Study 1: 18% (n=9) vs, 0% (p=0.03)
  • Study 2: 16% (n=8) vs. 4% (n=1), (p=0.26)
  • Study 3: Stable response in 23% (n=10)
  • Durable platelet responses seen


  • Most common adverse reactions: Diarrhea, hypertension, nausea, dizziness, alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased, respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia
  • Serious adverse drug reactions: Febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis


  • Orphan desugnation
  • Postmarketing commitmenets: Quality assessments



MALDI Biotyper CA System

Bruker Daltonik GmbH

INDICATION FOR USE: Mass spectrometer system using matrix-assisted laser
desorption/ionization – time of flight (MALDI-TOF) for the identification and differentiation of microorganisms cultured from human specimens.

The MALDI Biotyper CA System is a qualitative in vitro diagnostic device indicated for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of bacterial and fungal infections – particularly  Candida auris (C. auris)


  • Emerging pathogen Candida auris (C. auris) can cause serious infections in hospitalized patients
  • Can cause serious infections in hospitalized patients (e.g., bloodstream infections) and is frequently resistant to multiple antifungal drugs used to treat Candida infections.

GENERIC DEVICE TYPE:  Clinical mass spectrometry microorganism identification and differentiation system

  • Qualitative in vitro diagnostic device intended for the identification and differentiation of microorganisms from processed human specimens. The system acquires, processes, and analyzes spectra to generate data specific to microorganism(s). The device is indicated for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of bacterial and fungal infection.


  • Evaluated use of a standard protocol for adding C. auris to system database in conjunction with the performance data of 28 C. auris isolates (samples)
  •  C.auris isolates obtained from various culture collections, including the U.S. Centers for Disease Control and Prevention’s and FDA’s Antibiotic Resistance Isolate Bank.
  • System can reliably identify C. auris 100% of the time


  • Incorrect identification or lack of identification of a pathogenic microorganism: Special Controls
  • Failure to correctly interpret test results: Special Controls
  • Failure to correctly operate the instrument: Special Controls


  • Add to cleared uses for identification of 333 species or species groups, covering 424 clinically relevant bacteria and yeast species
  • Regulation Number: 21 CFR 866.3378
  • Regulation Name: Clinical Mass Spectrometry Microorganism Identification and Differentiation System
  • Regulatory Class: Class II
  • Product Code: QBN



GORE® CARDIOFORM Septal Occluder

W. L. Gore and Associates, Inc.

SUPPLEMENTAL INDICATION FOR USE: Permanently implanted device indicated for the percutaneous, transcatheter closure of the following defects of the atrial septum:

  • ostium secundum atrial septal defects (ASDs)
  • patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke.


  • Implant (occluder) and delivery catheter (a small tube)
  • Occluder made of self-expanding, nickel-titanium (Nitinol) wires, covered in woven fabric
  • Occluder shaped as two discs connected in the cente
  • Occluder compressed to a small size to allow it to pass through the delivery catheter for implantation


  • Prospective, randomized (2:1), open-label, multi-center study, n=664, antiplatelet medical management and PFO closure with the GORE® CARDIOFORM Septal Occluder vs. antiplatelet medical management alone
  • Co-primary endpoints: Freedom from recurrent stroke and incidence of new brain infarction. PFO closure was associated with a statistically significant
    77% relative risk reduction in recurrent stroke
  • PFO closure was also associated with  a statistically significant 49% relative risk reduction in incidence of new brain infarction


  • No significant difference in overall rate of SAEs between the control (medical management) and device groups
  • Low rate of device- or procedure-related SAEs (3.6%)
  • Subjects had a higher incidence of atrial fibrillation or flutter (6.6%), but were non-serious
  • No device- or procedure related deaths.


  • For expanding the indications to include closure of the patent foramen
    ovale (PFO) to reduce the risk of recurrent ischemic stroke
  • Product Code: MLV
  • Postapproval studies: Safety through 5 years post-procedure, acute, subacute, and longterm safety and effectiveness


  • Approved CMS IDE study
  • Partnership with CODING STRATEGIES (an independent industry-leading resource in coding, coverage, and reimbursement education)



GUARDIAN Connect System 

Medtronic MiniMed, Inc.

INDICATION FOR USE: For continuous or periodic monitoring of glucose levels in the interstitial fluid under the skin, in patients (14 to 75 years of age) with diabetes mellitus.

Provides real-time glucose values and trends through a Guardian Connect app installed on a compatible consumer electronic mobile device. It allows users to detect trends and track patterns in glucose concentrations. The Guardian Connect app alerts if a Guardian Sensor (3) glucose level reaches, falls below, rises above, or is predicted to surpass set values.

The Guardian Sensor (3) glucose values are not intended to be used directly for making
therapy adjustments, but rather to provide an indication of when a finger stick may be
required. All therapy adjustments should be based on measurements obtained using a
home glucose monitor and not on values provided by the Guardian Sensor (3).


  • Provides real-time glucose values and trends through a Guardian Connect app installed on a compatible mobile device platform (e.g., iPhone or iPad)
  • Guardian Connect app is a mobile medical application that allows users to track patterns in glucose concentrations and to possibly identify episodes of low and high glucose
  • System is designed to provide continuous glucose monitoring for up to seven days
  • System consists primarily of a sensor, transmitter, and mobile medical app


  • Evaluate the performance of the Guardian Sensor (3) to support 7 days of use
  • Missed alerts and false negative hypoglycemia and hyperglycemic readings related to patients not being alerted to the need to perform a fingerstick to detect hypoglycemia or hyperglycemia


  • Device Procode: MDS
  • The Guardian Sensor (3) used with the Guardian Connect system is the same as the
    Guardian Sensor (3) used with the MiniMed 670G System (P160017) and the iniMed
    630G System (P150001/S008), which were previously approved


  • Continuous Glucose Monitors are reimbursed by CMS




FDA News: Predictive Toxicology Roadmap, 2019 FDA Budget, Medical Device Safety Action Plan, Opioid Use Disorder Treatments, Drug Safety Priorities


Predictive Toxicology Roadmap

Significant steps by FDA to upgrade toxicology toolboxes

  • Expand toxicology predictive capabilities
  • Potentially reduce the use of animal testing

Goals of roadmap for integrating predictive toxicology methods into safety and risk assessments

  • Develop and evaluate emerging toxicological methods and new technologies
  • Incorporate these methods and technologies into regulatory review



Remarks from FDA Commissioner Scott Gottlieb, M.D. on Fiscal Year 2019 budget request for FDA

President’s 2019 Budget request for $5.8 billion in total resources for FDA

  • Includes $190 million in user fees
  • Requests new FDA resources to advance science, domestic technology, public health
  • Advance new paradigm in regulation of digital health technology
  • Advanced manufacturing to bring more production back to US
  • Improve ability to respond to public health emergencies like flu
  • Modernize generic drug review
  • New approaches for treatments for rare pediatric diseases

Build knowledge management platform for drug and medical device review programs

  • Store and manage collected experience of review staff
  • Essential to modernizing medical product review and establish scientific precedents
  • Issue guidances documents focused on specific diseases using efficient approaches


CaptureMedical Device Safety Action Plan: Protecting Patients, Promoting Public Health

Outlines how Agency will encourage innovation to improve safety, detect safety risks earlier, and keep doctors and patients better informed

  • Robust medical device patient safety net
  • Regulatory options to streamline and modernize timely implementation of postmarket mitigations
  • Innovation towards safer medical devices
  • Advance medical device cybersecurity
  • Integrate premarket and postmarket offices and use of a Total Product Life Cycle (TPLC) approach to device safety


CaptureNew steps to encourage more widespread innovation and development of new treatments for opioid use disorder

Encouraging more widespread innovation and development of medication for use in medication-assisted treatments (MAT)

  • Three FDA-approved MAT drugs – methadone, buprenorphine and naltrexone
  • Facilitate development of new MAT products, and new formulations of existing drugs

FDA issued draft guidance: Opioid Dependence: Developing Buprenorphine Depot Products for Treatment

  • Drug development and trial design issues
  • Possible ways for innovations in buprenorphine products
  • Use of 505(b)(2) regulatory pathway for product development programs
  • Develop validated measurement of “craving” or “urge to use” illicit opioids



2017 Drug Safety Priorities

CDER’s efforts to enhance drug safety for the American public

  • Safety surveillance and oversight of marketed drug products 7,446 safety reviews
  • Importance of real-world evidence to help advance drug safety science: New scientific computing and data storage technologies to gain valuable information from “real world evidence.”
  • New tools and new approaches for fighting our Nation’s opioid crisis: To 1) decreasing exposure and preventing new addiction, 2) safely treating those with opioid addiction, 3) developing safe and effective novel alternative therapies to opioids, 4) improving enforcement of safety measures and assessing benefit-risk ratios.
  • Safety oversight for generic drugs: Flag early safety concerns
  • Efforts to reduce preventable harm from medications: Safe Use Initiative
  • Compounded drugs – continuing regulatory and oversight efforts: Conducted 140 inspections, sent 55 warning letters, and issued 40 recalls related to compounding.
  • Diverse strategies, tools, and services for communicating drug safety: Responded to 57,094 inquiries from the public


Image credit: FDA

Market Authorizations: ACUVUE OASYS Light Adaptive Contact Lens, IDx-DR retinal diagnostic software, OCS Lung System

Capture.JPGAcuvue Oasys Contact Lenses with Transitions Light Intelligent Technology 

Johnson & Johnson Vision care

USE: Soft Contact lenses that automatically darkens the lens when exposed to bright light. Indicated for daily use to correct the vision of people with non-diseased eyes who are nearsighted (myopia) or farsighted (hyperopia).

ADDRESSING UNMET NEED:  First contact lens to incorporate the same technology that is used in eyeglasses that automatically darken in the sun


  • Contains photochromic additive that adapts the amount of visible light filtered to the eye based on the amount of UV light to which they are exposed
  • Results in slightly darkened lenses in bright sunlight that automatically return to a regular tint when exposed to normal or dark lighting conditions. 


  • Clinical study of 24 patients that evaluated daytime and nighttime driving performance while wearing the contact lenses
  • No evidence of concerns with either driving performance or vision while wearing the lenses
  • May cause inflammation or infection in or around the eye or eyelids 


  • Classification: II
  • Regulation No. : 886.5925
  • Classification Product Code: LPL
  • Subsequent Product Code: MVN


  • Medicare provides limited coverage for contact lenses under Medicare Vision Services
  • Acuvue Brand covered by private payors


IDx-DR Retinal diagnostic software device


INDICATION FOR USE: For use by health care providers to automatically detect more than mild diabetic retinopathy (mtmDR) in adults diagnosed with diabetes who have not been previously diagnosed with diabetic retinopathy. IDx-DR is indicated for use with the Topcon NW400.


  • Diabetic retinopathy is the most common cause of vision loss among the more than 30 million Americans living with diabetes
  • Leading cause of vision impairment and blindness among working-age adults
  • First medical device to use Artificial Intelligence (AI) to detect greater than a mild level of the eye disease diabetic retinopathy in adults who have diabetes


  • Software program using AI to analyze eye images taken with retinal camera, Topcon NW400
  • Doctor uploads digital images of retinas to cloud server w