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

Bisimilars Learning Toolkit


Biosimilar Development Process

Biological products that are demonstrated to be biosimilar to or interchangeable with an FDA-approved biological product

  • Abbreviated pathway to provide more treatment options, increase access, lower costs
  • Rigorous approval standards for  safety and effectiveness
  • Ten biosmilars approved to date

Learning toolkit to help promote understanding of biosimilars and interchangeable products


Image credit: FDA

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