Market Authorizations: MASTERS heart valve for newborns, 23andMe PGS for BRCA1/BRCA2, TROGARZO, IMUGEN Fluorescent Immunoassay, SKINPEN



SJM Masters Series Mechanical Heart Valve with Hemodynamic Plus (HP) Sewing Cuff

St. Jude’s Medical (Abbott)

INDICATION FOR USE: Use as a replacement valve in newborn pediatric patients with a diseased, damaged, or malfunctioning mitral or aortic heart valve


  • Smallest mechanical valve size approved in the world
  • > 35,000 babies in U.S. born with congenital heart defects, requiring heart valve surgery, replacement heart valve surgery
  • Limited replacement heart valve options because of patients’ small size
  • Masters Series 15-mm HP valve represents important treatment option


  • Rotatable, bileaflet (two-leaflet) valve designed for implantation in the aortic or mitral position
  • Bileaflet design consists of two semi-circular discs
  • Open and close in response to blood pressure changes during the heartbeat
  • Similar to a patient’s own valve


  • Single-arm study (N=20) Age 1.5 weeks to 27 months, serious heart failure
  • Probability of survival post-implant:  69.3%
  • Probability of not experiencing a valve-related adverse event: 66.8%
  • Adverse events in 1 year followup: Blood clots in the device, bleeding in the brain
  • Anticoagulation therapy may be necessary after procedure, to prevent clotting on the device


  • PMA initially approved in 1995 for use in adult patients
  • Also approved for use in replacing previously implanted aortic or mitral prosthetic heart valves
  • New approval expands range of valve sizes available


  • Considerations: Hospital Coding And Reimbursement (ICD-9, ICD-10), Inpatient Reimbursement (MS-DRG), Hospital Billing (FDA approved indication, diagnosis, condition, procedure)
  • Sponsor Coding information

Fact Sheet


Capture.JPG23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 



Personal Genome Service (PGS) uses qualitative genotyping to detect select cxlinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years with the Oragene Dx model OGD500.001 for the purpose of reporting and interpreting genetic health risks, including 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants).

The 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) is indicated for reporting of the 185delAG and 5382insC variants in the BRCA1 gene and 6174delT variant in the BRCA2 gene.

The report describes if a woman is at increased risk of developing breast and ovarian cancer, and if a man is at increased risk of developing breast cancer or may be at  increased risk of developing prostate cancer. The three variants included in this report are most common in people of Ashkenazi Jewish descent and do not represent majority of BRCA1/BRCA2 variants in the general population.

The test report does not describe a person’s overall risk of developing any type of cancer, and the absence of a variant tested does not rule out the presence of other variants that may be cancer-related. This test is not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine
any treatments.


  • Provides information on increased breast, ovarian or prostate cancer risk to those who might not otherwise get genetic screening
  • Step forward in the availability of Direct-To-Consumer genetic tests

GENERIC DEVICE TYPE:  Cancer Predisposition Risk Assessment System for BRCA1/BRCA2 Select Variants

Qualitative in vitro molecular diagnostic system used for detecting variants in genomic deoxyribonucleic acid (DNA) isolated from human specimens that will allow users to access information about their genetic predisposition for some cancers.

The test could help to inform conversations with a healthcare professional. Assessment system is for over-the-counter use.


  • Sufficient data to show that the test is accurate (i.e., can correctly identify the three genetic variants in saliva samples), and can provide reproducible results
  • Accuracy> 99% concordance to Sanger sequencing
  • Precision> 99% reproducibility and repeatability
  • User comprehension studies, using representative GHR test reports
  • Instructions, reports easy to follow and understood by consumer
  • Test report provides information describing what results mean, interpret results and additional information


  • Incorrect understanding of the device and test system: General controls and special controls 
  • Incorrect test results (false positives, false negatives): General controls and special controls 
  • Incorrect interpretation of test results: General controls and special controls 


  • Regulation Number: 21 CFR 866.6090
  • Regulation Name: Cancer Predisposition Risk Assessment System for BRCA1/BRCA2 Select Variants
  • Regulatory Class: Class II
  • Product Code: QAZ


  • N/A. Non-prescription product


CaptureTROGARZO™ (ibalizumab-uiyk) injection

TaiMed Biologics USA Corp.

INDICATION:  In combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.


  • Multidrug resistant HIV patients have limited treatment options
  • High risk of HIV-related complications and progression to death
  • First drug in new class of antiretroviral medications to provide significant benefit to patients who have run out of treatment options; improve outcomes

DESCRIPTION: Recombinant humanized monoclonal antibody, blocks HIV-1 from infecting CD4+ T cells by binding to domain 2 of CD4 and interfering with post-attachment steps required for entry


  • Single arm, multicenter clinical trial, n=40 heavily treatment-experienced
    HIV-infected subjects with multidrug resistant HIV-1,  viral load >1,000 copies/mL
  • 3 discreet periods: Control, functional monotherapy period, maintenance period
  • Primary efficacy endpoint: Proportion of subjects achieving a ≥ 0.5 log10 decrease in viral load in functional monotherapy period vs control period
  • 83% (monotherapy period) vs. 3% (control period)
  • 55% had a ≥ 1 log10 reduction in viral load, 48% had a ≥ 2 log10 reduction
  • 43% achieved HIV RNA suppression


  • Seriousness of disease, need to individualize other drugs in treatment regimen, and safety data from other trials considered in evaluating Trogarzo development program
  • 292 patients with HIV-1 infection exposed to Trogarzo IV infusion
  • Most common adverse reactions: Diarrhea, dizziness, nausea and rash. Severe side effects included rash and changes in the immune system (immune reconstitution syndrome)


  • Fast Track, Priority Review and Breakthrough Therapy designations
  • Also received Orphan Drug
  • Several postmarketing requirements




Imugen Babesia microtiArrayed Fluorescent Immunoassay (AFIA)

Oxford Immunotec


Donor screening test to detect antibodies to Babesia microti in plasma samples from individual human donors, including volunteer donors of whole blood and blood components, as well as other living donors.

Also intended for use to screen organ and tissue donors when specimens are obtained while the donor’s heart is still beating


  • Babesiosis caused by Babesia parasites transmitted by Ixodes scapularis ticks (blacklegged or deer ticks)
  • 1,000 -2,000 cases reported each year
  • Babesia can also be transmitted by transfusion of blood
  • First approval of Babesia detection tests for use in screening donors


  • Priority review
  • Currently is no FDA guidance for the testing of donor samples for Babesia; planning to issue guidance

CBER Infectious disease tests


SkinPen Precision System

Bellus Medical, LLC

INDICATION FOR USE:  Microneedling device and accessories intended to be used as a treatment to improve the appearance of facial acne scars in adults aged 22 years or older

GENERIC DEVICE TYPE: Microneedling device for aesthetic use

Device using one or more needles to mechanically puncture and injure skin tissue for aesthetic use. This classification does not include devices intended for transdermal delivery of topical products such as cosmetics, drugs, or biologics.


  • Adverse tissue reaction: Biocompatibility evaluation, Labeling
  • Cross-contamination and infection: Sterilization validation, Reprocessing validation, Non-clinical performance testing, Shelf life testing, Labeling
  • Electrical shock or electromagnetic interference with other devices:  Electromagnetic compatibility testing, Electrical safety testing, Labeling
  • Damage to underlying tissue including nerves and blood vessels, scarring, and
    hyper/hypopigmentation due to (i) Exceeding safe penetration depth (ii) Mechanical failure (iii) Software malfunction: Non-clinical performance testing, Technological characteristics, Shelf life testing, Labeling, Software verification, validation, and hazard analysis


  • Regulation Number: 21 CFR 878.4430
  • Regulation Name: Microneedling device for aesthetic use
  • Regulatory Class: Class II
  • Product Code: QAI


  • CMS does not cover products for aesthetic use; not deemed to be medically necessary


Image Credits: Abbott, 23andMe, Taimed, Oxford Immunotec, Bellus Medical


FDA News: Predicting Stem Cell Activity, Essure Post-Market Review, CDER Regulatory Science Videos



 Predicting Stem Cell Activity to Ensure Safe and Effective Therapies

Human multipotent stromal cells (MSCs) being prepared for use as therapies to treat human diseases or medical conditions- but have serious limitations:

  • As of January 2018, no MSC-based clinical trials have resulted in FDA-approved treatments
  • Significant challenge in ensuring MSCs will work together to perform the same desired function when they are administered to patients

FDA scientists developing ways to improve predictability

  • FDA’s MSC Consortium  trying to develop methods to predict with more certainty how manufactured or isolated MSCs will behave in patients
  • Predict MSC behavior stimulated by growth factors
  • Powerful imaging technologies to monitor and analyze changes in size and shape of many thousands of cells in a matter of hours
  • Applicable to development and FDA approval of potential stem-cell based products


Capture.JPGFDA activities related to the ongoing post-market review of Essure and FDA’s commitment to keep women informed

Active role in providing Essure consumers with up-to-date, evidence-based information to help  informed medical decisions

  • Met with consumers affected by Essure, a method of permanent birth control
  •  >750,000 women worldwide have received implant
  • Some developed significant medical problems e.g.  abdominal pain, abnormal uterine bleeding, device migration

FDA Steps

  • Monitor product safety and effectiveness since approval in 2002
  • Convened medical experts panel n the fall of 2015 to provide advice on understanding concerns
  • Ordered manufacturer, Bayer, to conduct postmarketing study to better evaluate safety profile
  • Boxed Warning and Patient Decision Checklist added to labeling
  • Ongoing activities posted on  Essure website

FDA continues to believe that Essure may be appropriate for some women

  • Based on current information
  • Recognize serious problems associated with use
  • Consider regulatory options that appropriately balance benefits and risks based on new information
  • Continue to communicate publicly, share learnings, help women make informed decisions

Patient Decision Checklist



 CDER: Regulatory Science

CDER has launched new video series on major challenges in drug evaluation and development and how to address

Image credit: FDA

FDA News: Brain Implants, Rare Disease Day, Flu Vaccine Effectiveness, Duodenoscope Surveillance

FDA BRIEF: Week of February 26, 2018

Capture.JPGBrain Implant for Some Blind People Shows Benefits of FDA’s Breakthrough Device Program

FDA’s Breakthrough Devices Program is beginning to show important results

  • Second Sight Medical Products Inc.’s Orion Cortical Visual Prosthesis System
  • Early FDA interactions for flexible study design, review team support, and senior management engagement
  • Involved specialists across disciplines such as ophthalmology and neurology
  • Solved any potential stumbling blocks – e.g. measuring benefits/risks

Novel technology with novel way to evaluate benefits/risks of device

  • Mimics perception of light through miniature video camera worn by patient
  • Transmits signals to implant in their visual cortex
  • CDRH approved clinical trial involves five patients at two sites;  first patient received the implant on Jan. 30, 2018


Capture.JPGTaking new steps to  meet the challenges of rare diseases – FDA markets 11th Rare Disease Day

One out of every 10 Americans lives with at least one of more than 7,000 rare diseases

  • U.S. observes last day of February as Rare Disease Day
  • Raise awareness about rare diseases and their impact on patient’s lives
  • What more FDA can do to advance needs of patients and families

FDA incentives, approvals, trends

  • Orphan Drug Act financial and other incentives (1983)
  • Humanitarian Device Exemption regulatory path for devices (1990)
  • >650 therapies, 72 devices approved
  • Increasing emphasis on personalized medicine, including genetically targeted drug development

Modernization and new initiatives

  • Orphan Drug Designation Modernization Plan for more efficient process
  • Orphan Products Council to further address scientific and regulatory challenges
  • New Memorandum of Understanding with National Organization for Rare Disorders (NORD) to conduct outreach
  • Public meeting om changing landscape of orphan drug development

New Website



FDA’s ongoing efforts to help improve effectiveness of influenza vaccines

Working to determine the root causes

  • Collaborating with CMS to use large database with details of flu vaccine administered to four million individuals
  • Better understand less than optimal effectiveness with both cell-based and egg-based vaccines
  • Potential differences in outcomes between high-dose vs. normal dose

Looking ahead to 2018-2019 flu season

  • FDA advisory committee meeting March 1, 2018. to select strains, WHO recommendations
  • Apply learnings from this flu season


Capture.JPGDuodenoscope surveillance sampling and culturing

Duodenoscopes used to treat patients undergoing endoscopic retrograde cholangiopancreatography (ECRP)

  • Life-saving, least invasive way treating cancerous tumors, gallstones
  • > 500,000 ERCPs performed each year in US
  • Scopes are reused; if not thoroughly cleaned and disinfected, high risk of patient-to-patient infection.

FDA, CDC and ASM announced availability of voluntary, standardized duodenoscope surveillance sampling, culturing protocols

  • For hospitals and health care facilities
  • To further reduce risk of infection and increase safety of these medical devices


Image credit: FDA, CDC


Market Authorizations: IMFINZI, VERZENIO


 IMFINZI (durvalumab) injection


EXPANDED INDICATION: Treatment of patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy


  • Lung cancer is the leading cause of cancer death in the United States, with an estimated 222,500 new diagnoses and 155,870 deaths in 2017
  • First treatment approved for stage III unresectable NSCLC
  • An approved therapy to keep the cancer from progressing for a longer time after chemoradiation


  • Randomized trial, n=713 patients whose cancer had not progressed after completing chemotherapy and radiation, IMFINZI vs. placebo
  • Major efficacy outcome: Progression-free survival (PFS) assessed by a BICR RECIST 1.1 and overall survival (OS)
  • PFS: 45% vs. 66%, p<0.0001



  • Common side effects:  Cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, rash
  • Serious risks: Immune-mediated side effects, such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis


  • Priority Review, Breakthrough status
  • Postmarketing commitments: Overall Survival data, efficacy outcomes in subgroups defined by ADA binding and neutralizing status vs. control
  • Granted accelerated approval in 2017 for the treatment of locally advanced or metastatic bladder cancer


  • HCPCS Code: C9492, special coverage
  • CPT codes for infusion administration and home infusion


Capture.JPGVERZENIO (abemaciclib) tablets

Eli Lilly

EXPANDED INDICATION:  In combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative  advanced or metastatic breast cancer

ADDRESSING UNMET NEED: Initial therapy for HR-positive, HER2-negative metastatic breast cancer


  • Randomized (2:1), double-blinded, placebo-controlled, multicenter clinical trial in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, n=493, VERZENIO vs placebo on top of physician’s choice of letrozole or anastrozole
  • Primary endpoint: Progression-free survival (PFS) (RECIST 1.1): 28.2 mo. vs. 4.8 mo.,  p<0.0001


  • Most common adverse reactions:  Diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, leukopenia



  • No Medicare coverage
  • Obtained through specialty pharmacies


Image credit: AstraZeneca, Eli Lilly 

FDA News: CDER Warning Letters, Information Technology Progress

FDA BRIEF: Week of Feb 19, 2018

CaptureCDER Warning Letters

Provided by CDER Freedom of Information Office (FOI)

  • Some have been redacted or edited to remove confidential information
  • Matters may have been subject to subsequent interaction between FDA and the recipient that may have changed the regulatory status

Types of Letters



PDUFA VI Information Technology Goals and Progress

Goal of improving predictability and consistency of electronic submission process

  • Electronic Submission Documentation
  • Electronic Submission and System Status
  • Electronic Submission Gateway (ESG) Target Timeframes, Milestones and Notifications

Enhance transprency and accountability of electronic submission and data standards activities

  • IT Public Meetings
  • Electronic Submissions Performance Metrics
  • Data Standards


Image credit: FDA

Market Authorization: ContaCT, ERLEADA, BANYAN Brain Trauma Indicator, APTIMA HBV Quant Assay





Notification-only, parallel workflow tool for use by hospital networks, trained clinicians to identify and communicate images of specific patients to a specialist, independent of standard of care workflow.

Uses an artificial intelligence (AI) algorithm to analyze images for findings suggestive of a prespecified clinical condition and to notify an appropriate medical specialist of these findings in parallel to standard of care image interpretation. Identification of suspected findings is not for diagnostic use beyond notification. Specifically, the device analyzes CT angiogram images of the brain acquired in the acute setting, and sends notifications to a neurovascular specialist that a suspected large vessel occlusion has been identified and recommends review of those images. Images can be previewed through mobile application.

Images that are previewed through the mobile application are compressed and are for informational purposes only and not intended for diagnostic use beyond notification. Notified clinicians are responsible for viewing non-compressed images on a diagnostic viewer and engaging in appropriate patient evaluation and relevant discussion with a treating physician before making care-related decisions or requests. ContaCT is limited to analysis of imaging data and should not be used in-lieu of full patient evaluation or relied upon to make or confirm diagnosis.


  • First approved Clinical Decision Software to analyze computed tomography (CT) results that may notify providers of stroke potential
  • 795,000 in U.S. have stroke each year; causes serious and irreversible damage
  • Software device notifies specialist earlier thereby decreasing the time to treatment


  • Computer-aided triage software using AI algorithm to analyze images for stroke indicators
  • Designed to analyze brain CT images
  • Send text notification to neurovascular specialist if suspected large vessel blockage
  • Involve specialist sooner with algorithm automatically notifying specialist concurrently with first-line provider who is conducting standard review of images
  • Specialist still needs to review images on clinical workstation


  • Retrospective study of 300 CT images
  • Brain large vessel blockage detection: Algorithm image analysis and notification vs.  performance of two trained neuro-radiologists
  • Real-world evidence used with clinical study to demonstrate neurovascular specialist notification sooner in cases of suspected blockage


  • 21 CFR 892.2080
  • Regulation Name: Radiological Computer Aided Triage and Notification Software
  • Class II, Product Code: QAS

GENERIC DEVICE TYPE:  Radiological computer aided triage and notification software

  • Image processing device intended to aid in prioritization and triage of radiological medical image
  • Notifies designated list of clinicians of the availability of time sensitive radiological medical images for review based on computer aided image analysis of those images performed by the device
  • Does not mark, highlight, or direct users’ attention to a specific location in original image
  • Does not remove cases from a reading queue
  • Operates in parallel with standard of care, which remains default option for all cases


  • Detailed description of notification and triage algorithms
  • Detailed description of pre-specified performance testing protocols and dataset(s) used to assess whether the device will provide effective triage
  • Performance testing
  • Appropriate software documentation
  • Labeling


  • Failure to prioritize images for review with positive findings may result in incorrect and/or delayed patient management
  • Positive notifications may result in deprioritization of review of images from other patients
  • Misuse to analyze images (unintended patient population, incompatible imaging
    hardware and image acquisition)
  • Device failure leading to absence, delay, incorrect results
  • Inappropriate use of triage and notification outputs
  • Mitigated by general and special controls


  • Precedence for CMS qualification of Clinical Decision Support Mechanisms


Capture.JPGERLEADA (apalutamide) tablets


INDICATION: Treatment of patients with non-metastatic, castration-resistant prostate cancer (NM-CRPC)


  • Prostate cancer is second most common form of cancer in men;  161,360 men diagnosed-26,730 expected to die of disease
  • 10 to 20 % cases are castration-resistant; up to 16% show no evidence of metastasis  at the time of castration-resistant diagnosis
  • First approval based on endpoint of metastasis-free survival

MECHANISM OF ACTION: Androgen Receptor (AR) inhibitor,  inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription


  • Single multicenter, double-blind, clinical trial, n= 1,207 patients with NM-CRPC,  ERLEADA vs placebo
  • Major efficacy outcome: Metastasis-free survival (MFS), time to metastasis (TTM), progression-free survival (PFS) and overall survival (OS)


  • Significant improvement in MFS: 40.5 months vs 16. 2 months, HR=0.28, CI: 0.23, 0.35;p<0.0001


  • Most common adverse reactions : Fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema


  • Pediatric requirements waived


  • CMS covers prostate CA drugs
  • Novel and clinically meaningful endpoint could secure favorable coverage and pricing


CaptureBANYAN Brain Trauma Indicator

Banyan Biomarkers, Inc.


In vitro diagnostic chemiluminescent enzyme-linked immunosorbent assay (ELISA). Assay provides semi-quantitative measurement of the concentrations of ubiquitin Cterminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in human serum, and is used with the Synergy 2 Multi-mode Reader.

The assay results obtained from serum collected within 12 hours of suspected head injury are used, along with other available clinical information, to aid in the evaluation of patients 18 years of age and older with suspected traumatic brain injury (TBI, Glasgow Coma Scale score 13-15). A negative assay result is associated with the absence of acute intracranial lesions visualized on a head CT (computed tomography) scan.

The Banyan BTI is for prescription use only.


  • 2.8 million TBI-related emergency department visits, hospitalizations, deaths in US
  • Need for innovative testing technologies that minimize health impacts
  • Supports FDA Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging
  • Blood-testing option for TBI/concussion is a new tool, modernizing standard of and  likely reduce CT scans performed

GENERIC DEVICE TYPE: Brain trauma assessment test

  • Consists of reagents used to detect and measure brain injury biomarkers in human specimens
  • Measurements aid in evaluation of patients with suspected mild traumatic brain injury in conjunction with other clinical information to assist in determining the need for head imaging per current standard of care


  • Multi-center, prospective clinical study, n=1,947 individual blood samples from adults with suspected TBI/concussion
  • Comparison TBI/concussion blood tests results vs CT scan results
  • Prediction: 97.5% accuracy (presence of lesions),  99.6% accuracy (absence of lesions


  • Approval in <6 months as part of its Breakthrough Devices Program
  • 21 CFR 866.5830
  • Regulation Name: Brain trauma assessment test
  • Class II, Product Code: QAT


  • Performance testing including clinical testing
  • Labeling


  • Inaccurate test results that provide false positive or false negative results
  • Failure to correctly interpret test results can lead to false positive or false negative results
  • Mitigated by general and special controls


Capture.JPGAPTIMA HBV Quant Assay

Hologic, Inc


In vitro nucleic acid amplification test for the quantitation of hepatitis B virus (HBV) DNA in human plasma and serum on the fully automated Panther® system.

Plasma may be prepared in ethylenediaminetetraacetic acid (EDTA), anticoagulant citrate dextrose (ACD) solution, and plasma preparation tubes (PPTs). Serum may be prepared in serum tubes and serum separator tubes (SSTs). Specimens are tested using the fully automated Panther system for sample processing, amplification, and quantitation. Specimens containing HBV genotypes A, B, C, D, E, F, G, and H are validated for quantitation in the assay.

The Aptima HBV Quant assay is intended for use as an aid in the management of patients with chronic HBV infections undergoing HBV antiviral drug therapy. The assay can be used to measure HBV DNA levels at baseline and during treatment to aid in assessing viral response to treatment. The results from the Aptima HBV Quant assay must be interpreted within the context of all relevant clinical and laboratory findings. Assay performance for determining the clinical stage of HBV infection has not been established. Clinical performance characteristics have been established for individuals treated with tenofovir disoproxil fumarate or entecavir.

The Aptima HBV Quant assay is not approved for use as a screening test for the presence of HBV DNA in blood or blood products or as a diagnostic test to confirm the presence of HBV infection


  • Hepatitis B is a liver infection caused by HBV; transmitted through infected blood, semen, or other body fluid
  • Risk for chronic infection is related to age at infection: ~ 90% of infected infants become chronically infected, vs. 2%–6% of adults
  • Chronic Hepatitis B infection can lead to cirrhosis or liver cancer


  • In vitro nucleic acid amplification test with real time transcription-mediated amplification (TMA) technology on Panther system
  • Standardized to the 3rd WHO International Standard for Hepatitis B Virus
  • Three main steps which all take place in a single tube on the Panther system: (1) target capture, (2) target amplification by TMA, (3) detection of amplification products (amplicon) by fluorescent labeled probes


  •  Effectiveness demonstrated when used for the quantitation of HBV DNA in human plasma and serum and serum separation tubes for management of patients undergoing treatment.
  • Clinical performance evaluated in ethnically diverse population representative of intended use population
  • Accurately measures viral load in patient at baseline and at intervals during antiviral therapy
  • Should benefit physician and patients in management of chronic HBV infected individuals undergoing antiviral therapy when used according to the directions for use in labeling


  • Product Code: MKT


  • CMS has determined that screening for HBV infection  is reasonable and necessary for the prevention or early detection
  • Will cover screening for HBV infection with FDA approved/cleared laboratory tests, used consistent with FDA approved labeling and in compliance with CLIA regulations Decision memo


Image credit: Viz.AI, Banyan, Janssen, Hologic


FDA News: 2017-2018 Flu Vaccine, Rapid Flu Tests, Warfarin INR Test Meters, Funding for Innovation, Advancing Neurological Treatments, External Stakeholder Meeting Requests

Week of February 12, 2018

CaptureEfficacy of the 2017-2018 influenza vaccine

2017-2018 Seasonal flu has been widespread with high rates of hospitalization 

  • Caused by one strain of influenza A called H3N2, with another strain of influenza A called H1N1 and strains of influenza B contributing to lesser extents
  • Viruses can change genetic make-up rapidly during course of single year
  • Questions raised about how flu vaccine efficacy; initial report of 36%

Select strains for next season’s flu vaccines

  • Convene Vaccines and Related Biological Products Advisory Committee
  • Collaboration with WHO, CDC, NIH, other federal partners to address full spectrum of measures for optimal protection
  • Select most appropriate flu strains, provide seed viruses and quality control reagents to manufacturers, ensure quality of manufacturing process
  • Analyze CMS databases covering millions of individuals for signals
    • Better effectiveness with cell-based vs egg-based vaccine



CLIA-Waived Rapid Flu Test Facts

Available Rapid flu tests have demonstrated acceptable clinical performance

  • Antigen-based rapid flu tests (rapid influenza diagnostic tests or RIDTs)
  • Nucleic acid-based rapid molecular flu tests

Performance Levels for antigen-based RIDTs

  • Reclassified  into class II to improve overall quality of flu testing
  • Prompted  by poor sensitivity resulting in misdiagnosed cases, even death.
  • Established special controls for assuring accuracy, reliability and clinical relevance

2017-2018 Flu Season

  • Earlier than usual flu season with high incidence of flu cases
  • Manufacturers’ marketing forecasts may have underestimated needs
  • Some manufacturers have ramped up production



Capture.JPGWarfarin INR test meters 

INR test meter is portable, battery-operated meter, to monitor patient response to warfarin (brand names Coumadin and Jantoven)

  • Medical Device Reporting (MDRs) of adverse events of inaccurate results
  • Need to update information provided to patients, caregivers, and health care providers to safe and effective use

Updates include

  • Correct use: how to take blood from a fingerstick, how to make sure meter working properly
  • Information for health care providers: Medical conditions that could affect test results, recommendations for confirming test results
  • How to report problems with INR test meters



New FDA funding to promote innovation and broaden patient access through competition

  • Foster development of therapeutics and diagnostics for unmet medical needs
  • Advance drug and device competition
  • New domestic industries – pharmacy outsourcing facilities
  • Create modern, domestically-based manufacturing

I. Promote Domestic Manufacturing

  • Development of efficient regulatory pathways for personalized medicines and novel technologies – such as cell- and gene-based therapies, vaccines
  • Continuous manufacturing platforms to ramp up on short notice
  • Return product manufacturing to domestic sites, foster job creation

II. Robust and Reliable Source of Compounded Products

  • Create “Center of Excellence on Compounding for Outsourcing Facilities”
  • Wider availability of reliable compounded drugs meeting GMP

III. Advance Medical Device Manufacturing and Quality

  • Voluntary program for certification of manufacturers
  • Facilitate manufacturing innovation, investment in new production methods/ materials, lead to better medical products
  • Work collaboratively with industry, patients, providers and payers to develop parameters

IV. New Medical Data Enterprise

  • Advance use of Real-World Evidence to better inform patient care, provide more efficient, robust lower-cost ways to develop clinical data
  • Expanded use of natural language processing to speed recognition and remediation of emerging safety concerns
  • Cover data gaps in the Sentinel and NEST systems

V. Digital Health Technology Industry and Framework for Reliable Post-Market Oversight

  • New paradigm to market lower-risk products without FDA premarket review and market higher-risk products with streamlined FDA review
  • Validate quality of a firm’s software design and firm’s methods for certifying the quality and reliability of its underlying software performance
  • Create Center of Excellence on Digital Health to recognize third-party certifiers,  support cybersecurity unit

VI. Modern Science-Based Principles for New Drug Development 

  • Build knowledge management system and portal
  • Build on evolving information, decisions, gaps in policies and pathways, consistent responses to regulatory questions, prevent delays in response to innovations

VII. Medical Products Targeted to Rare Diseases

  • Develop clinical trial networks to understand natural history and clinical outcomes
  • Initial focus would be on rare and ultra-rare diseases to address challenges in clinical trial recruitment

VIII. Modernize Generic Drug Development 

  • Create new review platform for data-based assessment
  • Improve clarity for generic sponsors, reviews more efficient, increasing first-cycle approvals



Advancing development of novel treatments for neurological conditions

Symptoms and progression of neurological diseases vary significantly across patients, within patients, across organ systems

  • Urgent need for new medical treatments
  • Need to modernize multiple aspects of regulatory programs

CDER team-based modern approach

  • Integrate expert knowledge across different fields,  different stages of product life cycle toward a common public health goal
  • Piloting streamlined process for writing science-based, disease-based guidance documents

Duchenne Muscular Dystrophy and Related Dystrophinopathies

  • Support from Parent Project Muscular Dystrophy with scientific and patient input from DMD community

Amyotrophic Lateral Sclerosis

  • Support from ALS Association guidance funded by “ice bucket challenge”

Early Alzheimer’s Disease

  • Innovative approaches to studying very early disease before onset of dementia, use of sensitive cognitive screening, imaging tests, or biomarkers


  • Innovative approaches to clinical trial design for acute migraine

Partial Onset Seizures

  • Rigorous approach based on extrapolation of effectiveness adult patients to pediatric patients

External Stakeholder Meeting Request (ESMR) system

Meetings between stakeholders and CDER promote effective two-way communication to improve drug development and safety

  • To help external, non-industry stakeholders more easily request meetings with CDER
  • Mechanism for communicating, sharing ideas to improve efficiency and advance medical product development
  • ESMR system to improve value and efficiency of stakeholder meetings
  • Professional Affairs and Stakeholder Engagement (PASE) Staff facilitate meeting

 Image credit: FDA

Market Authorizations: BIKTARVY, ZYTIGA, RADIOGENIX system


BIKTARVY (bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF)) tablet


INDICATION: Complete regimen for the treatment of HIV-1 infection in adults who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of

MECHANISM OF ACTION: Fixed dose tablet of antiretroviral drugs:

  • bictegravir (BIC) : Integrase strand transfer inhibitor
  • emtricitabine (FTC): HIV nucleoside analog reverse transcriptase inhibitor
  • tenofovir alafenamide : Acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate


  • 2 trials each in (a) adults with no antiretroviral treatment history and (b) virologically suppressed adults, n=2,415
  • Met primary objective of non-inferiority at 48 weeks across all four studies
  • No partients  failed Biktarvy with treatment-emergent virologic resistance
  • No patients discontinued Biktarvy due to renal adverse events, no cases of proximal renal tubulopathy or Fanconi syndrome
  • Most common adverse reactions: Diarrhea, nausea and headache.


  • Required postmarketing studies in pediatrics


  • Patient Assistance programs: Gilead’s U.S. Advancing Access® program
  • Working closely with the AIDS Drug Assistance Programs (ADAP) Crisis Task Force to provide discounts to state ADAPs



ZYTIGA (abiraterone acetate) in combination with prednisone


INDICATION:  For metastatic high-risk castration-sensitive prostate cancer (CSPC)


  • Placebo controlled international clinical trial, n=1,199 patients, placebo controlled
  • Patients in both arms received gonadotropin releasing hormone or had bilateral orchiectomy
  • Major efficacy endpoint: Overall Survival. Median OS not estimable in ZYTIGA arm vs. 34.7 months in placebo arm, p<0.0001
  • Median time-to-initiation of chemotherapy: Not reached in ZYTIGA arm vs. 38.9 in  placebo arm, p<0.0001


  • Adverse reactions:  Hypertension, hot flush, hypokalemia, increased alanine aminotransferase or aspartate aminotransferase, headache, urinary tract infection, upper respiratory tract infection, and cough


  • Priority Review; approved more than a month ahead of due date
  • Postmarketing commitment: Overall survival analysis
  • Initial approval in 2011 for patients with metastatic castration-resistant prostate cancer (CRPC)
  • Expanded indication in 2012 for patients with metastatic CRPC


  • 100% of Medicare Part D and Medicare Advantage plans coverage; quantity limits and prior authorization
  • Tier 5- Non-preferred brand-name drug



RADIOGENIX System (technetium Tc-99m generator )

NorthStar Medical

INDICATION FOR USE: Technetium Tc-99m generator used to produce sterile, non-pyrogenic Sodium Pertechnetate Tc-99m injection. Sodium Pertechnetate Tc-99m injection is indicated for use in the preparation of FDA approved diagnostic radiopharmaceuticals

Sodium Pertechnetate Tc-99m injection is also indicated:

In Adults for:

  • Thyroid Imaging
  • Salivary Gland Imaging
  • Urinary Bladder Imaging (direct isotopic cystography) for detection of vesicoureteralreflux
  • Nasolacrimal Drainage System Imaging (dacryoscintigraphy)

In Pediatric Patients for:

  • Thyroid Imaging
  • Urinary Bladder Imaging (direct isotopic cystography) for the detection of vesicoureteralreflux


  • Broad collaboration across FDA, Nuclear Regulatory Commission (NRC) and  industry
  • Tc-99m plays vital role in nuclear imaging studies for wide range of uses, including cancer and cardiology
  • Used > 80 percent of routine medical imaging procedures
  • Stable supply chain is critical due to limited shelf life
  • Approval restores U.S. ability to domestically supply a critical medical diagnostic tool for the first time in 30 years

MECHANISM OF ACTION: Pertechnetate ion distributes in the body similarly to iodide ion, but is not organified. In contrast to the iodide ion, the pertechnetate is released unchanged from the thyroid gland.


  • Did not require new clinical studies because it relied on safety and efficacy information and data from an already FDA-approved Tc-99m generator
  • Common side effects: Allergic reactions, including anaphylaxis


  • Complete response to FDA’s November 4, 2013, action letter
  • Exempt from pediatric requirements
  • Postmarking requirements: Evaluation of fluid path bioburden and final product endotoxins and sterility


 Image credits: Gilead, Janssen, NorthStar Medical


FDA News: NTP report on Radiofrequency Energy Exposure, CDER/CBER Data Standards, GAIN Report, Complete ANDA submissions, Kratom Abuse

FDA BRIEF: Week of February 5, 2018


Statement from Jeffrey Shuren, director CDRH: National Toxicology Program draft report on radiofrequency energy exposure

FDA ensures safety of electronic products that emit radiation (e.g. cell phones, TV)

  • Federal Communications Commission (FCC) standards +  other health agencies for scientific expertise

Recently released National Toxicology Program research on radiofrequency energy exposure in rodents

  • Male rats showed carcinogenic activity with radiofrequency energy exposure rate much higher than current safety standard
  • Equivocal/ambiguous evidence that whole body radiofrequency energy exposures in rats/mice actually caused cancer; additional unusual findings
  • FDA to participate in peer review of study
  • Public comment welcome Federal Register notice

FDA has reviewed many sources of scientific and medical evidence on possibility of adverse health effects from radiofrequency energy exposure

  • Not found sufficient evidence of adverse health effects or increase in events like brain tumors
  • Current safety limits for cell phones acceptable for protecting public health



CDER/CBER Data Standards Strategy FY2018-FY2022

Development, implementation, maintenance of comprehensive data standards program for pre- and postmarket regulatory review

  • With Stakeholder collaboration
  • Other Regulatory Authorities, Other Federal Agencies, Clinical Data Interchange Consortium (CDISC), Critical Path Institute, Health Level 7 (HL7), International Council on Harmonisation, International Organization for Standards, TransCelerate BioPharma, World Health Organization

Strategic Goals

  • More efficient, science-based pre-market review
  • Improve postmarket risk management strategies and pharmacovigilance
  • Improve quality and integrity of marketed products
  • Promote innovation in development and use of data standards
  • Effective communication and collaboration with stakeholders
  • Improve management and usability of  information



Generating Antibiotic Incentives Now (GAIN)  FY2012-FY2017

GAIN passed in 2012 to address public health threat of antibacterial drug resistance by stimulating new antibacterial and antifungal drug development

  • Qualified Infectious Disease Products (QIDP): Designation (147), Approval with Priority Review (12)
  • Review and revision of guidance documents for streamlined development, limited population pathway for antibacterial and antifungal drugs (LPAD)
  • Engagement to support development by public workshops and advisory committee meetings, collaborative partnerships, funding regulatory science research
  • Development and implementation of stewardship programs to slow and control spread of resistant infections



FDA Helping Generic Industry Submit Complete Applications

Improve Abbreviated New Drug Application (ANDA) submission and assessment process;~ 50% ANDAs required at least 3 review cycles

  • Guidance to industry
  • Establishing internal practices to help reduce review cycles

Good ANDA Submission Practices to address

  • Patent and Exclusivity Deficiencies
  • Labeling Deficiencies
  • Product Quality Deficiencies
  • Bioequivalence Deficiencies



Statement from FDA Commissioner Scott Gottlieb: Scientific evidence on presence of opioid compounds in kratom, underscoring its potential for abuse

Scientific tools, data, research on FDA’s concerns about kratom’s potential for abuse, addiction, and serious health consequences; including death

  • Public Health Assessment via Structural Evaluation (PHASE) methodology to use molecular structure to predict biological function
    • Analyzed chemical structures of 25 most prevalent compounds in kratom
    • All had structural similarities with controlled opioid analgesics, e.g. morphine derivatives
  • Analyzed chemical structure against software to determine biologic targets
    • 22 (including mitragynine) of 25 compounds bind to mu-opioid receptors
    • Top five most prevalent compounds (including mitragynine) activate opioid receptors (“opioid agonists”)
    • Some may bind to brain receptors and impact neurologic and cardiovascular functions – seizures and respiratory depression
  • 3-D image on how strongly they bind to biological targets
    • Comparable to scheduled opioid drugs

Learnings from reports of death associated with kratom

  • Monitoring the use of kratom for several years, with import alerts
  • Releasing reports of 36 deaths  underscoring serious and deadly risks
  • One new report of death with no known opioid use, except for kratom

Kratom should not be used to treat medical conditions, or as an alternative to prescription opioids

  • No evidence of safety and effectiveness


Image credit: FDA








FDA News and Views: OTC Loperamide Limitations, REMS Education Blueprint, Research Subjects Reimbursement

FDA BRIEF: Week of January 29, 2018


New steps to help prevent new addiction, curb abuse and overdose related to opioid products: OTC LOPERAMIDE

Unprecedented and novel action regarding OTC Loperamide (Brand Name Imodium A-D)

  • Approved to help control short-term symptoms of diarrhea, including Travelers’ Diarrhea
  • However, intentional misuse and abuse of loperamide has been increasing;  used as potential alternative to manage opioid withdrawal symptoms or to achieve euphoric effects of opioid use
  • Reports of serious heart problems and deaths

Loperamide packaging limitations and unit-of-dose packaging

  • Limited amount appropriate for use for short-term diarrhea per product label
  • Manufactures to implement changes in a timely fashion
  • Online retail web sites advised to take voluntary steps to limit distribution



Opioid REMS Education Blueprint

Blueprint for Extended-Release and Long-Acting Opioid Analgesic Risk Evaluation and Mitigation Strategy (ER/LA REMS) to ensure benefits outweigh risks

  • Core educational messages for health care providers for pain
  • Information on acute and chronic pain management, non-pharmacologic and pharmacologic treatments (non-opioid and opioid analgesic)
  • Education for safe and effective use

Revised FDA Blueprint contains

  • Core educational messages  to be included in educational programs developed under Opioid Analgesic REMS
  • Focus on fundamentals of acute and chronic pain management and contextual framework for safe prescribing
  • Directed to prescribers, pharmacists, and nurses, but also relevant for other HCPs who participate in pain management of pain


Capture.JPGPayment and Reimbursement to Research Subjects

Updates to the Payment for Research Subjects: Information Sheet

  • Reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging are acceptable

Image credit: SAMHSA, FDA

FDA Marketing Authorizations: LUTATHERA, REMODULIN Impant

FDA BRIEF: Week of January 22, 2018


LUTATHERA (lutetium Lu 177 dotatate) injection

 Advanced Accelerator Applications

INDICATION: Treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults


  •  First FDA Approval for a Peptide Receptor Radionuclide Therapy (PRRT) –  targeting molecule that carries radioactive component
  • Approved indication is a rare disease and unmet need in NET community

MECHANISM OF ACTION:  Binds to somatostatin receptors including malignant somatostatin receptor-positive tumors, and is internalized; beta emission from Lu 177 induces cellular damage


  • Randomized, multicenter, open-label, active-controlled trial, n=229, patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumor, LUTATHERA vs. high-dose long-acting octreotides
  • Major efficacy outcome measure: Progression free survival (PFS); additional efficacy outcome measures were overall response rate (ORR), duration of response, overall survival (OS), RECIST criteria


  • Median PFS was not reached for LUTATHERA vs. 8.5 mo. in octreotide (p<0.0001)
  • Efficacy in subset (n=360) of 1214 patients with GEP-NET tumors;  16% ORR  including 3 complete responses


  • Adverse Reactions:  Lymphopenia, increased GGT, vomiting, nausea, elevated AST,  increased ALT, hyperglycemia, hypokalemia
  • Myelodysplastic syndrome reported


  • Priority review, Orphan Drug Designation
  • Postmarketing Requirements: Safety analyses based on 5 and 10 yr followups, Overall Survival data
  • Complete Response Letter and Discipline Review Letter issued previously requesting additional data


  • Expanded Access Program
  • NETSPOT, another FDA-approved Molecular Nuclear Medicine from Advanced Accelerator,  granted Transitional Pass-Through status under “A-code” (A9587) for drug reimbursement
    • HCPCS “A Code” will be used on claims to private payers
  • However, UK medicines cost-effectiveness group, NICE, has published draft guidance not recommending LUTATHERA




INDICATIONS FOR USE:  For adult patients with Class I, II and III pulmonary arterial hypertension (PAH) receiving intravenous delivery of Remodulin.

Physicians prescribing this system for use with Remodulin must be familiar with the indications, contraindications, warnings, precautions, adverse events, and dosage and administration information described in the Remodulin drug labeling.

The Model 8551 Refill Kit is intended for use in refilling the Medtronic implantable  programmable infusion pumps with the exception of Medtronic MiniMed infusion pumps.


Consists of the following components:

  • Medtronic SynchroMed II 8637P Programmable Pump (the “pump”)
  • Medtronic 8201 Implantable Intravascular Catheter (the “catheter”)
  • Medtronic N’Vision 8840 Clinician Programmer with 8870 Application Card (the  “programmer”)
  • Remodulin (treprostinil) Injection stored in pump reservoir and, per a programmed prescription, moves through pump tubing, catheter port, and catheter to  intravascular delivery site
  • Programmer is handheld device for healthcare provider use only that is used to review and program pump parameters using telemetry, a radio frequency communication


  • Multi-center, prospective, single arm, non-randomized open label Investigational Device Exemption (IDE) clinical study, n=64, met the approved Remodulin indication, using approved concentrations, and approved intravenous route
  • Primary endpoint: Demonstrate safety when used with the Medtronic SynchroMed II Implantable Infusion System to deliver Remodulin
  • No effectiveness endpoint – effectiveness based on ability to provide accurate drug delivery
  • Clinical data, mathematical modeling, bench testing indicate that over the expected longevity of the pump, the accuracy ratio will decrease and plateau at ~ 0.8
  •  Primary safety objective met (p<0.0001); catheter revisions, early pump  replacement rates significantly less than literature reports


  • Device Generic Names: Pump, Infusion, Implanted, Programmable
    Implantable Intravascular Catheter, Clinician Programmer
  • Device Procode: LKK
  • Postmarketing requirements: Report on  pump failure analysis, validate the initial training program utilizing the to-be-marketed user interface, PAS reports


  • Existing codes and coverage for infusion pumps and associated parts
  • Information specific to this device not available


Image credit:  Advanced Accelerator Applications, Medtronic

FDA news and Views: Quality Overall Summary, Third Party Review Metrics, Rogue Online Pharmacies, State of CDER, Warning for illegal, unapproved opioid cessation products

FDA BRIEF: Week of January 22, 2018

Quality Overall Summary (QOS) of all quality-related information provided in NDA, ANDA, BLA

  • Considering adjustments to QOS format to improve efficiency

CDER new white paper describes key considerations for QOS preparation:

  • Explaining product and process development in a patient-focused context
  • Effectively summarizing the overall control strategy
  • Guiding the regulator through the submission


510(k) Third Party Review Metrics

510 (k) Accredited Persons Program created to improve efficiency and timeliness

  • FDA accredits Third Parties to conduct 510(k) primary review
  • Third Party 510(k) submission goes through four different stages
    • Stage A – Reviews sponsor submission and sends recommendation to FDA
    • Stage B – FDA reviews submission to ensure Third Party has submitted
      all information needed to make final decision
    • Stage C (Optional) – Third Party reviews FDA’s request for additional
      information and notifies 510(k) submitter
    • Stage D – FDA reviews additional information and makes final decision.

Accredited Organizations: AABB, CMSI: Center for Measurement Standards of Industria, NYSDOH: New York State Department of Health, NIOM: Nordic Institute of Dental Materials, RTS: Regulatory Technology Services, LLC, TPRG: Third Party Review Group, LLC, TUV: TUV SUD America Inc

Review Metrics:
Capture.JPG READ

Buying from Online Pharmacies

Rogue online pharmacies

  • No valid prescription required
  • Do not have U.S. state-licensed pharmacist to answer questions
  • Low prices seem too good to be true
  • Send spam or unsolicited email offering cheap medicine
  • Located outside of US or ship worldwide.

Sell dangerous products with compromised safety and effectiveness

  • Under dosage or over dosage
  • Incorrect active ingredient
  • Addition of unsafe ingredients
  • Incorrect storage

Shop Safely Online


Capture.JPGPodcast: State of CDER 

Podcast: State of CDER 2018Transcript


FDA, FTC warn companies for selling illegal, unapproved opioid cessation products using deceptive claims

FDA +  FTC joint warning letters to marketers and distributors of 12 opioid cessation products

  • Health fraud for illegally marketing unapproved products with claims about treatment of opioid addiction and withdrawal
  • Products have not been demonstrated to be safe or effective
  • May keep patients from seeking appropriate, FDA-approved therapies
  • Making unsubstantiated therapeutic claims is violation of the Federal Trade Commission Act

 Have requested responses from each of the companies within 15 working days

  • Specific actions taken to address each concern
  • Failure to correct violations may result in law enforcement action such as seizure or injunction


Image credit: FDA







How can you tell if an online pharmacy is operating legally? The U.S. Food and Drug Administration’s BeSafeRx web page can help you identify and avoid rogue online pharmacies.

The FDA has several tips for buying medicines online safely. Read more here.


FDA News & Views: CDRH Accomplishments and Priorities, Clinical Trial Information Transparency, Expediting Military Products, Supervisory Review of CDRH Decisions, Complex Generic Drugs, Enforcement Reports, Compounding Priorities, Orally Inhaled and Nasal Drug products

FDA BRIEF: Week of January 15, 2018


Capture.JPGCDRH 2016-2017 Accomplishments and 2018-2020 Strategic Priorities 

Achievement of strategic priorities for 2016-2017

  • National Evaluation System for Medical Devices (NEST): Framework for the incorporation of real-world evidence into regulatory decision making
  • Partner with Patients: Established Patient Engagement Advisory Committee, increased use of patient reported outcomes in clinical studies, patient preference  patient preference studies in decision making
  • Promote Culture of Quality and Organizational Excellence CDRH staff formal quality training and certifications, PMA Critical-to-Quality Pilot Program to streamline the pre-market approval process

Foster innovation to spur the development of safer, more effective technologies, assure timely patient access

  • Annual number of approved devices has steadily

Three strategic priorities for 2018-2020: Holistic approaches to improvement

  • Employee Engagement, Opportunity, and Success. Recognize connection between taking care of FDA employees and achieving FDA vision
  • Simplicity. Streamline policies, processes, programs, approaches e.g. Total Product Life Cycle approach to integrates our pre-market, post-market surveillance, Least Burdensome principle
  • Collaborative Communities. Foster public and private sector Collaborative Communities,  advancement of smart regulation and rise of ‘Patient Scientists’

2016-2017 Accomplishments

2018-2020 Strategic Priorities

business person

Capture.JPGNew steps to enhance transparency of clinical trial information to support innovation and scientific inquiry related to new drugs 

Enhance transparency around FDA drug approval decisions by better informing of  clinical study reports (CSRs) to scientists, providers, and patients

  • Current approach- Summaries in Drugs@FDA database
  • New pilot program –  Post portions of clinical trial-related summaries from the pivotal trials that were submitted to the FDA by drug’s sponsor on Drugs@FDA
  • Include study report body, protocol and amendments, and statistical analysis plan for pivotal studies
  • New website

Add identifier number (NCT #) to FDA summaries

  • Easier to associate clinical trial listings on to FDA communications about specific drugs, including product labeling and advisory committee meeting materials


Image result for DoD logoFDA and DoD launch program to expedite availability of medical products for the emergency care of American military personnel

Joint program with Health Affairs to prioritize efficient development of safe and effective medical products intended to save lives of American military personnel

  • Better understand military’s medical needs for deployed personnel
  • Give highest level of attention to and expedite its review of priority DoD medical products
  • Provide ongoing technical advice for rapid development and manufacturing
  • Take closer look at products currently under development to determine opportunities to expedite availability

FDA and Health Affairs to hold workshops to discuss scientific and clinical development


Capture.JPGInternal Agency Review of Decisions; Requests for Supervisory Review of Certain Decisions Made by CDRH

Implement regulations regarding internal agency supervisory review of certain CDRH decisions related to conform to FDASIA and the Cures Act

  • Provide transparency for internal and external stakeholders on supervisory review of decisions
  • Give requesters new predictability through binding deadlines on “significant decisions”
  • Codify types of decisions that are considered “significant decisions”

Following decisions being proposed as significant decisions – “517A decisions”

  • 510(k): Not substantially equivalent; Substantially equivalent
  • PMA/HDE: Not approvable; Approvable; Approval; Denial
  • Breakthrough Devices: Expedited access pathway, Grant, Denial
  • IDE: Disapproval, Approval
  • Failure to reach agreement on protocol
  • “Clinical Hold” determinations


Capture.JPGStatement from FDA Commissioner Scott Gottlieb, M.D. responding to GAO report and updating FDA’s ongoing efforts to increase access to complex generic drugs

U.S. Government Accountability Office (GAO) published report titled “Generic Drugs: FDA Should Make Public Its Plans to Issue and Revise Guidance on Nonbiological Complex Drugs.

  • GAO studied issues related to FDA’s review and approval of “nonbiological complex drugs”
  • Recommendation for FDA — announce plans to issue or revise related guidances

FDA Actions

  • Drug Competition Action Plan: Promoting competition and access, to generics
  • Focus GDUFA resources to aid generic drug developers of complex products
  • Issued four general guidance documents covering complex generics

Looking forward

  • Develop additional guidance for clarifying “sameness” requirements for ANDAs
  • Specific guidance on drug-device combination products


Capture.JPGNew policy steps for strengthening public warning and notification of recalls

FDA to improve recall processes to help ensure product safety

  • Recalls remove potentially unsafe products quickly and efficiently
  • Draft guidance describes public warning and notification of recalled products
  • Gives industry clear direction on communication of recalls and empower consumers by providing timely and accurate information

FDA Enforcement Report

  •  Listing of all recalls monitored by  FDA. You can read more about the changes the FDA made to its Enforcement Report in today’s blog


Capture.JPG2018 Compounding Policy Priorities Plan

2018 Compounding Policy Priorities Plan to implement federal compounding laws and advance public health mission

  • In accordance with Drug Quality and Security Act (DQSA)
  • Recognizes  importance of compounders’ role in access to quality drugs
  • Tailor policies for traditional compounding pharmacies and outsourcing facilities

2018 Priorities

  • 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


Capture.JPGLocally-Acting Orally Inhaled and Nasal Drug Products 


Demonstration of Bioequivalence (BE) for locally-acting orally inhaled and nasal drug products  presents a unique challenge

  • FDA guidance to measure bioavailability under NDA and BE under ANDA
  • Increased understanding of complex interactions between formulation, manufacturing, and device

Better characterization, tools/methods to investigate  BE and product specific outcomes

  • Orally Inhaled Drug Products
  • Locally Acting Nasal Products


Image credits: FDA, DoD


FDA Guidances: IND communications, PDUFA Formal Meetings, Medical Device Accessories, Class I Unique Device Identification


Best Practices For Communication between IND Sponsors and FDA During Drug Development


  • Describe best practices and procedures for timely, transparent, effective communications between IND sponsors and FDA
    • May facilitate earlier availability of safe and effective drugs


  • Philosophy regarding timely interactive communication
  • Scope of appropriate interactions
  • Types of advice
  • General expectations FDA response timing
  • Best Practices and Communication Methods
    • Formal Meetings
    • Written Correspondence from FDA
    • Sponsor Submissions
    • Acknowledging Receipt of Communications
    • Email Between FDA and Sponsors
    • General Telephone Calls Between FDA and Sponsors
    • Faxes Between FDA and Sponsors
    • Use of Out-of-Office Messages by FDA and Sponsors

Resources for Sponsors

  • Guidances, Policy and Procedures, Basics for Industry, Interactive Media, Presentations, Labeling and Approvals, Rules and Regulations, Scientific Research Results, Code of Federal Regulations

Additional Contacts

  • CDER : Biomarker Qualification Program, Controlled Substance Staff , Division of Drug Information, Division of Pediatric and Maternal Health, Emerging Technology Team, Enhanced Communication Team, Import/Export, Office of Pharmaceutical Quality, Ombudsman, Rare Diseases Program, Small Business and Industry Assistance Program, Therapeutic Biologics and Biosimilars Staff
  • CBER : Manufacturers Assistance and Technical Training,  Ombudsman
  • Office of Special Medical Programs: Advisory Committee Oversight and Management Staff, Office of Combination Products, Office of Good Clinical Practice,  Office of Orphan Products Development, Office of Pediatric Therapeutics



Formal Meetings Between FDA ad Sponsors or Applicants of PDUFA Products


  • Discuss principles of good meeting management practices (GMMPs)
  • Describe standardized procedures for requesting, preparing, scheduling, conducting, documenting formal meetings


  • Meeting Types : Type A, Type B Meeting, Type B (EOP),  Type C
  • Meeting Formats
  • Meeting Requests
  • Assessing and Responding to meeting requests: Denied, Granted
  • Meeting Package: Submission timing, Copies, Content
  • Preliminary Responses
  • Rescheduling and Canceling
  • Meeting Conduct
  • Meeting Minutes



Medical Device Accessories – Describing Accessories and Classification Pathways


  • Describe policy concerning classification of accessories
  • Application of policy to devices that are commonly used as accessorie
  • Explain what devices considered an “accessory”
  • Describes processes to allow requests for risk- and regulatory control-based classification


  • Accessory: Finished device intended to support, supplement, and/or augment the
    performance of one or more parent devices
  • Component: [A]ny raw material, substance, piece, part, software, firmware, labeling, or assembly which is intended to be included as part of finished,
    packaged, and labeled device
  • Finished Device: [A]ny device or accessory to any device that is suitable for
    use or capable of functioning, whether or not it is packaged, labeled, or sterilized
  • Parent Device: Finished device whose performance is supported, supplemented, and/or augmented by one or more accessories

Accessory Classification Policy

  • Is the article an accessory?
    • Supports : Performance of parent device by enabling or facilitating performance according to its intended use
    • Supplements: Performance of parent device if it adds new function or new way of using the parent device, without changing intended use
    • Augments: Performance of parent device by enabling more safe or effective use
  • What are risks of accessory when used as intended with the parent device(s)
  • What regulatory controls necessary to provide reasonable assurance of safety
    and effectiveness

Accessory Classification Process

  • Accessory Requests
  • Classification of New Accessory Types through the De Novo Process




  • Describe enforcement of  Unique Device Identification (UDI) System
  • For Class I and unclassified devices  other than implantable, life-supporting or life-sustaining (I/LS/LS) devices
  • Does not intend to enforce standard date formatting, labeling, and GUDID data submission requirements
  • Does not intend to enforce direct mark requirements

Compliance Dates




FDA News and Views: 2017 Medical Product Innovation, Many “Firsts” for 2017 Drug Approvals, Opioid Cough and Cold medicines Safety Labeling

FDA BRIEF: Week of January 8, 2018

Dr. Scott Gottlieb

Reflections on a Landmark Year for Medical Product Innovation and Public Health Advances and Looking Ahead to Policy in 2018

Inspiring year of advances in both medicine and public health

  • A Record Year for New Innovation
  • Modernizing FDA’s Regulatory Programs
  • Promoting Drug Competition
  • New Steps to Combat Addiction
  • New Steps to Combat Addiction
  • Improving our Stewardship of Vital Drugs
  • Protecting and Empowering Consumers

pie chart of approvals

Chart of device approvals

2017 generics approvalsREAD


Many “Firsts” for CDER’s 2017 Drug Approvals Reflect Innovation and Enhanced Patient Care

Approved new treatments for patients with rare diseases

  • Batten disease
  • Chagas disease
  • Hemophilia A with inhibitors

Novel “Firsts” in treating

  • Liver cancer in almost a decade
  • Sickle cell diseasein almost 20 years
  • Giant cell arteritis
  • Cytokine release syndrome
  • Chronic graft versus host disease after a bone marrow transplant
  • Marginal zone lymphoma
  • Eosinophilic granulomatosis with polyangiitis
  • Erdheim-Chester Disease

Other firsts that are not novel drug approvals 

  • Biosimilars to treat certain cancers
  • Immediate-release opioid product with properties intended to deter abuse
  • Once-monthly injectable buprenorphine product for opioid addiction
  • Cancer treatment based on a genetic feature rather than location
  • Treatment to help prevent recurrence of renal cell carcinoma
  • Complete regimen to treat HIV-1 that contains only two drugs, neither a nucleoside reverse transcriptase inhibitor, which can be detrimental to a patient’s kidneys, bones, and heart;
  • Drug with a sensor embedded in pill to track medication compliance
  • Short-acting “follow-on” insulin product




FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older

Safety labeling changes to limit the use of prescription opioid cough and cold medicines containing codeine or hydrocodone in children younger than 18 years old

  • Serious risks of these medicines outweigh potential benefits in population
  • Products will no longer be indicated for use to treat cough in pediatric population
  • Additional safety information for adult use – risks of misuse, abuse, addiction, overdose and death, and slowed or difficult breathing

Addressing epidemic of opioid addiction

  • Limit unnecessary exposure to opioids, especially in young children
  • Taking steps to help reassure parents that treating the common cough and cold is possible without using opioid-containing products
  • Guidances for Health care professionals and Parents and caregivers

List of Prescription Cough and Cold Medicines Containing Codeine

Active Ingredient(s)

Brand Name(s)

codeine, chlorpheniramine

Tuxarin ER, Tuzistra XR

codeine, phenylephrine, promethazine

Only generics available

codeine, promethazine

Only generics available

codeine, pseudoephedrine, tripolidine

Triacin C

List of Prescription Cough and Cold Medicines Containing Hydrocodone

Active Ingredient(s)

Brand Name(s)

hydrocodone, guaifenesin

FlowTuss, Obredon

hydrocodone, pseudoephedrine, guaifenesin

Hycofenix, Rezira

hydrocodone, chlorpheniramine

Tussionex Pennkinetic, Vituz

hydrocodone, chlorpheniramine, pseudoephedrine


hydrocodone, homatropine

Only generics available


Image credits: FDA


FDA News and Views: CDER standards program, Anti-aging Products, Enhancing Generic Drug Review and Availability, Smoking Cessation Products

FDA BRIEF: Week of Jan 1, 2018


CDER Data Standards Program Action Plan

Governing body for drug data standards

  • Provides quarterly updates on  current initiatives

Program Initiatives

  • Drug Development and Pre-Market Review
  • Drug Safety Performance and Promotion
  • Pharmaceutical Quality
  • Policy


Examples of claims cosmetics are allowed to make: Cleanses skin, Enhances beauty, Promotes attractiveness, Alters appearance. Examples of claims cosmetics may NOT make: Treats a disease, such as acne, eczema, or rosacea; Increases collagen; Revives cells.

Wrinkle Treatments and Other Anti-aging Products

Cosmetics – if:

  • Intended to make people more attractive e.g. moisturizing
  • Intended to make lines and wrinkles less noticeableby moisturizing the skin
  • Makeup or “primers” intended hide signs of aging
  • Must be safe when used according to product labeling
  • Does not require cosmetics to be approved by FDA

Drugs or Medical Devices – if:

  • Intended to affect the structure or function of the body, such as the skin
  • To remove wrinkles or increase the skin’s production of collagen
  • Will require marketing authorization by FDA based on effectiveness and safety

FDA concern: Product claims, marketed as cosmetics (skin care, anti-wrinkle, anti-aging) that involve supposed effects on the structure or function of the skin



Statement from FDA Commissioner Scott Gottlieb, M.D. on new steps to facilitate efficient generic drug review to enhance competition, promote access and lower drug prices

Continued implementation of the “Drug Competition Action Plan”

  • Reducing gaming by branded companies that can delay generic drug entry
  • Resolving scientific and regulatory obstacles to generics approval
  • Improving efficiency and predictability of  FDA’s generic review process

Releasing 2 documents:

Additional Steps:

  • Improve FDA practices and efficiency
  • Accelerate generic entry of complex generics e.g. metered dose inhalers
  • Take steps to minimize brand companies tactics to deter generics

Potential abuses of the citizen petition process

Restricting access to testing samples of branded drugs

Abuses of the single, shared system REMS negotiation process



FDA-approved smoking cessation products

Nicotine Replacement Therapy (NRT)

  • Nicotine primarily responsible for causing addiction
  • NRTproducts designed to wean smokers by supplying nicotine in controlled amounts while sparing from other chemicals found in tobacco products
  • Short time use to manage nicotine cravings and withdrawal
  • Available over the counter and by prescription

Over-the-counter NRTs 

  • Skin patches (also called “transdermal nicotine patches”)
  • Chewing gum (also called “nicotine gum”)
  • Lozenges (also called “nicotine lozenges”)
  • Important to follow the instructions on the Drug Facts Label (DFL) and User’s Guide

Prescription nicotine replacement therapy (prescription): Nicotrol

Smoking cessation products that do not contain nicotine (prescription): Chantix (varenicline tartrate) and Zyban (buproprion hydrochloride)


Image credit: FDA


FDA Device Market Authorizations: DERMAPACE System, VERSICE Deep Brain Stimulation, HEMOBLAST Bellows



Sanuwave, Inc.

INDICATION FOR USE: To provide acoustic pressure shockwaves in the treatment of chronic, full-thickness diabetic foot ulcers with wound areas measuring no larger than 16 cm2 , which extend through the epidermis, dermis, tendon, or capsule, but without bone exposure.

The dermaPACE System is indicated for adult (22 years and older), diabetic patients presenting with diabetic foot ulcers greater than 30 days in duration and is indicated for use in conjunction with standard diabetic ulcer care.


  • About 25 percent of people with diabetes will experience a foot ulcer in their lifetime; leading cause of lower limb amputations
  • Additional option for successfully treating and healing ulcer wounds may help prevent lower limb amputations


  • Extracorporeal shockwave device for treatment of chronic wounds is a prescription device that focuses acoustic shock waves onto the dermal tissue. The shock waves are generated inside the device and transferred to thevbody using an acoustic interface.


  • Two multi-center, randomized, double-blind studies, n= 336 diabetic patients receiving either usual care plus Dermapace System shock wave therapy vs. usual care plus non-working (sham) shock wave therapy
  • Both patient groups included those with poorly controlled and well-controlled blood glucose levels
  • Increase in wound healing at 24 weeks, 44% vs. 30% wound closure rate
  • Most common side effects: Pain, local bruising and numbness, migraines, nausea, fainting, wound infection, infection beyond the wound (cellulitis, osteomyelitis) and fever


  • Initial PMA submission not approved
  • Resubmission as De Novo
  • Regulation Number: 21 CFR 878.4685
  • Regulation Name: Extracorporeal shock wave device for treatment of chronic wounds
  • Regulatory Class: Class II
  • Product Code: PZL


  • Adverse tissue reaction – Biocompatibility evaluation
  • Infection – Reprocessing validation, Labeling
  • Inadequate healing – Labeling
  • Device failure / malfunction – Non-clinical performance testing, Electrical safety testing, Electromagnetic compatibility (EMC) testing, Use life testing, Software verification, validation, and hazard analysis, Labeling
  • Hearing loss – Non-clinical performance testing, Labeling



Capture.JPGVERCISE Deep Brain Stimulation (DBS) System

Boston Scientific Corporation

INDICATION FOR USE: In bilateral stimulation of the subthalamic nucleus (STN) as an adjunctive therapy in reducing some of the symptoms of moderate to advanced levodopa-responsive Parkinson’s disease (PD) that are not adequately controlled with medication.


  • At present there is no cure for PD
  • Additional surgical treatment option focused on management of symptoms that  best meets expectations and lifestyle
  • Adjunct to therapy towards reducing the motor complications of subjects with PD


  • Includes a Stimulator with DBS Leads for stimulation of selected targets (i.e., the subthalamic nucleus) in the brain.
  • DBS Extensions are used to connect the DBS Leads to the Stimulator implanted near the clavicle.
  • The Vercise DBS System utilizes current steering across eight contacts per DBS Lead,
    which is intended to provide precise positioning of stimulation.
  • The Stimulator is controlled by a handheld Remote Control, and can be programmed by a Clinician Programmer using the Bionic Navigator™ Software.
  • Periodically, the rechargeable Stimulator battery must be replenished with a radiofrequency (RF) charging device provided in the Charging Kit.


  • Study on bilateral DBS of the STN, n=160 pre-specified interim analysis; active vs control, 12 weeks
  • Primary endpoint: Mean change from baseline in mean number of waking hours per day with good symptom control and no troublesome dyskinesia as measured on the PD diary, with no increase in antiparkinsonian medications – mean difference of  3.03 ± 4.2 hours, p < 0.001
  • Secondary endpoints: UPDRS III scores in the stim on/meds off condition, PDQ-39, Modified Schwab and England, Global Impression of Change as assessed by clinician and Treatment Satisfaction
  • UPDRS III score: Mean 30% improvement (12.02 ± 11.42 points) was noted in UDPRS III scores (stim on/meds off)
  • Statistically significant improvement in quality of life: Based on PDQ-39 and modified Schwab and England scales


  • Infection: Most commonly reported serious adverse event associated with device-hardware/procedure


  • Device Generic Name: Stimulator, Electrical, Implanted, for Parkinsonian Tremor
  • Device Procode: NHL


  • DBS Devices assigned ICD-10 daignosis and procedure codes
  • HCPCS II Device Codes
  • Device C-Codes and Device Edits
  • CPT Procedure Codes
  • MS-DRG Assignments




Biom’Up SA

INDICATION FOR USE: In surgical procedures as an adjunct to hemostasis when control of minimal, mild, and moderate bleeding by conventional procedures is ineffective or impractical, except in neurosurgical, ophthalmic and urological procedures.


  • Consists of hemostatic powder (HEMOBLAST™ Bellows Hemostatic Powder) supplied in an applicator system incorporating a bellows design
  • Powder is dry, sterilized, biocompatible, and non-pyrogenic. No intraoperative preparation, mixing, or heating is required. absorbs in vivo over a 4-week period
  • Powder composed predominantly of highly purified porcine collagen (with glucose) with smaller amounts of bovine chondroitin sulfate (CS) and human pooled plasma derived thrombin.
  • Bellows Applicator contains the Powder and is sterilized using gamma-sterilization
  • Nozzle Extension serves to assist in the delivery of the Powder, during surgery


  • Prospective, multicenter, single-arm pilot clinical investigation, to evaluate  Surface Bleeding Severity Scale (“SBSS”), n=31 undergoing orthopedic and abdominal surgeries with associated bleeding sites
  • Statistical superiority in achieving hemostasis at 3 and 6 minutes vs. standard of care
  • Safety  profile similar to standard of care

REGULATORY PATHWAY: Combination product, PMA

  • Regulation number: 878.4490
  • Product Code: PMX
  • Generic name: Absorbable Collagen Hemostatic Agent With Thrombin


  • Pending
  • Precedents for reimbursement for absorbable collagen hemostatic


Image credits: Sanuwave, Boston Scientific, Biom’Up


FDA approved


BOSULIF (bosutinib) tablets


SUPPLEMENTAL INDICATION:  Newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML).


  • Open-label, randomized, multicenter trial, n=487 patients with Ph+ newly-diagnosed CP CML, bosutinib 400 mg once daily vs. imatinib 400 mg once daily
  • Major efficacy outcome: Major molecular response (MMR) at 12 months, defined as ≤0.1% BCR ABL ratio on international scale (corresponding to ≥3 log reduction from standardized baseline) with a minimum of 3000 ABL transcripts as assessed by the central laboratory.
  • 47.2% (95% CI: 40.9, 53.4) vs. 36.9% (95% CI: 30.8, 43.0), p=0.0200


  • Most common adverse reactions: Diarrhea, nausea, thrombocytopenia, rash, increased alanine aminotransferase, abdominal pain, and increased aspartate aminotransferase


  • Priority Review, and Orphan Drug designation, Accelerated approval for supplemental application
  • Approval based on molecular and cytogenetic response rates;  continued approval may be contingent upon verification and confirmation of clinical benefit in an ongoing long-term follow up trial
  • First approval in 2012 for treatment of patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.


  • 100% of Medicare Part D and Medicare Advantage plans coverage
  • Tier 5 (specialty); Co-pay based on coverage stage
  • Patient Assistance programs



GIAPREZA (angiotensin II) injection

La Jolla Pharmaceutical Company

FIRST INDICATION: Increases blood pressure in adults with septic or other distributive shock


  • Shock can result in organ failure and death
  • Need for treatment options for critically ill hypotensive patients who do not adequately respond to available therapies

MECHANISM OF ACTION: Angiotensin II raises blood pressure by vasoconstriction and increased aldosterone release


  • Single double-blind study, n=321 adults with septic or other distributive shock, GIAPREZA vs.placebo
  • Primary endpoint: % of subjects with Mean Arterial Pressure (MAP) ≥ 75 mmHg or a ≥ 10 mmHg increase in MAP without an increase in baseline vasopressor therapy at 3 hours
  • 70% vs. 23%, p < 0.0001 (treatment effect of 47%)


  • Can cause dangerous blood clots with serious consequences (clots in arteries and veins, including deep venous thrombosis)
  • Prophylactic treatment for blood clots should be used


  • Priority Review
  • Required pediatric assessments


  • Available March 2018



CABOMETYX (cabozantinib) tablets


SUPPLEMENTAL INDICATION:  Treatment of patients with advanced renal cell carcinoma (RCC)


  • Single, randomized, open-label phase 2 multicenter study, n=157 patients with intermediate and poor-risk previously untreated RCC, Cabometyx vs. sunitinib
  • Endpoint: Estimated median progression-free survival (assessed by blinded independent radiology review committee)
  • 8.6 months (95% CI: 6.8, 14.0) vs. 5.3 months (95% CI: 3.0, 8.2),  p=0.0008


  • Most commonly reported adverse reactions: Diarrhea, fatigue, nausea, decreased appetite, hypertension, palmar-plantar erythrodysesthesia, weight decreased, vomiting, dysgeusia, and stomatitis
  • Most frequent grade 3-4 adverse reactions:  Hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE, fatigue, ALT increased, decreased appetite, stomatitis, pain, hypotension, and syncope



  • Approval provides for treatment in first-line setting
  • Previous approval in 2016 for treatment of patients with advanced RCC who have received prior anti-angiogenic therapy


  • 100% of Medicare Part D and Medicare Advantage plans coverage
  • Tier 5 (specialty); Co-pay based on coverage stage
  • Patient Assistance programs



PERJETA (pertuzumab)


SUPPLEMENTAL INDICATION:  In combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease


  • Single multicenter, randomized, double-blind, n= 4804 patients with HER2-positive early breast cancer with primary tumor excised prior to randomization, PERJETA vs placebo
  • Efficacy outcome: Invasive disease-free survival (IDFS), defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause
  • Intent to Treat population: 7.1% (n=171) vs. 8.7%, p=0.047
    • In patients with hormone receptor negative disease:  8.2% vs. 10.6%
    • In patients with node positive disease: 9.2% vs. 12.1%
  • Overall survival data are not yet mature


  • Adverse reactions:  Diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting
  • Most common grade 3-4 adverse reactions: Neutropenia, febrile neutropenia, diarrhea, neutrophil count decreased, anemia, white blood cell count decreased, leukopenia, fatigue, nausea, and stomatitis


  • Fulfills post-marketing requirement for 2013 accelerated approval
  • First approval in 2012 for use in combination with trastuzumab and docetaxel for  HER2-positive metastatic breast cancer with no prior therapy
  • Accelerated approval in 2013 as neoadjuvant treatment


  • 70% of Medicare Part D and Medicare Advantage plan coverage
  • Tier 5 (specialty); Co-pay based on coverage stage
  • Patient Assistance programs


Image credit: DailyMed, La Jolla

FDA News and Views: Patient Engagement Collaborative, Case for Quality Pilots, Medical Device Accessories, Malfunction Reporting

FDA BRIEF: Weeks of Dec 22 and 29

FDA Voice

You Spoke, FDA Listened: New Patient Engagement Collaborative, Call for Nominations 

Patient Engagement Collaborative (PEC)

  • Patients who have personal disease experience
  • Caregivers who support patients
  • Representatives from patient groups who have direct or indirect disease experience
  • Joint endeavor between the CTTI and FDA

PEC forum to discuss

  • More meaningful patient engagement in medical product development
  • Incorporating various perspectives into regulatory decision-making processes
  • Builds on existing  Patient Focused Drug Development (drugs, biologics)  and the Patient Preference Initiative (medical devices)
  • Modeled after the European Medicines Agency’s Patients’ and Consumers’ Working Party

Nomination ProcessREAD


Case for Quality Pilot Activities

Case for Quality

  • Allows FDA identify device manufacturers consistently producing high-quality devices
  • Focus FDA resources helping other manufacturers raise quality level
  • Identify and promote practices supporting consistent quality manufacturing, and align regulatory, enforcement, compliance approaches

1. Premarket Approval (PMA) Critical-to-Quality Pilot Program

  • PMA device manufacturers meeting participation criteria to engage with FDA early in review process of new applications
  • Proactive engagement to develop critical-to-quality characteristics and controls  and a focused inspectional approach
  • Streamline the premarket approval process while assuring quality system
  • FDA to forego pre-approval inspection, instead conduct post-approval inspection

2. Voluntary Medical Device Manufacturing and Product Quality Pilot Program

  • Third-party teams certified by Capability Maturity Model Integration (CMMI) Institute to conduct quality system maturity appraisals of device manufacturers
  • Drive continuous improvement and organizational excellence
  • Engage early with CDRH and submit baseline metrics before and during appraisal to monitor progress
  • FDA to forego conducting surveillance and preapproval inspections

3. Digital Health Software Precertification (Pre-Cert) Program

  • Modern and tailored approach for software iterations and changes
  • Enable companies demonstrate their embedded culture of quality and organization excellence (CQOE)
  • FDA to learn, adapt, adjust key elements based on program effectiveness

4. Digital Health Entrepreneurs-in-Residence Program

  • Entrepreneurs work intensively with FDA Digital Health Unit staff to iteratively develop and test key conceptual elements of  software precertification program

5. Medical Device Single Audit Program (MDSAP)

  • Global approach to auditing and monitoring manufacture of medical devices
  • MDSAP recognized Auditing Organization to conduct single regulatory audit of manufacturer to satisfy requirements of multiple regulatory authorities : US, Australia, Brazil, Canada, Japan, WHO, EU



Medical Device Accessories

Intended Use : Finished device intended to support, supplement, and/or augment performance of one or more parent devices

Accessory Classification Request: Written request for appropriate classification

Classification of New Accessory Type: Submitted together with the parent device submission or submitted separately as De Novo Classification Request

  • Submit necessary information, based on Least Burdensome principles, to establish  risk profile of accessory when used as intended with parent device
  • Class II must include an initial draft proposal for special controls,

FDA Consulation: Prior to Accessory Classification Request – through Pre-Submission



Voluntary Medical Device and Combination Products Malfunction Summary Reporting

Manufacturer reporting of certain device malfunction medical device reports (MDRs) in summary form

  • Streamlining malfunction reporting
  • Permitting manufacturers of devices in certain product codes to report malfunctions on a quarterly basis and in a summary format
  • Reflecting FDA’s findings from pilot program to study summary reporting formats for malfunction MDRs.


Image credits: FDA


FDA Guidances: Least Burdensome Principles, Refusal to File, Nanomaterials


Capture.JPGThe Least Burdensome Provisions: Concept and Principles

Definition:  “Least burdensome” is the minimum amount of information necessary to adequately address a regulatory question or issue through the most efficient manner at the right time

  • Applies to devices throughout the total product lifecycle (premarket and postmarket)

Guiding Principles

  • FDA:  intends to request minimum necessary information
    • streamline processes and policies, timeliness, interactive and tailored approaches, just-in-time data collection, data from other countries
  • Industry: submissions that are least burdensome for FDA review
    • well-organized, clear, and concise information

Applications of Least Burdensome Principles

  • The minimum information necessary
    (1) Less burdensome sources of clinical data: Leveraging existing data, Real-World Evidence
    (2) Use of nonclinical data: Bench performance testing, computer modeling and simulation 
    (3) Acceptance of alternative approaches: Resolution of scientific issues, alternative labeling, 
  • The most efficient means
    (1) Reducing burden of traditional clinical studies: Historical control groups, non-comparative studies, subject as own control, adaptive design, sample collection alternatives
    (2) Use of benefit-risk assessments in marketing submissions
    (3) Streamlining processes and reducing administrative burden: Bundled submissions, MDDT, MDR burden reduction
    (4) Smart regulation: 510(k) exemption
    (5) Global harmonization:  Voluntary consensus standards, IMDRF, MDSAP
  • The right time: Balancing premarket and postmarket information needs
  • Compliance Policies that Support the Goals of the Least Burdensome Concept


Capture.JPGRefuse to File: NDA and BLA Submissions to CDER

FDA will file an NDA/BLA within 60 days of receipt or inform the applicant of the Refusal to File (RTF)

  • Filing an application means that FDA has made threshold determination that application is sufficiently complete to permit a substantive review
  • To efficiently and effectively review applications, it is critical to have applications that are not deficient and are complete
  • FDA exercises RTF authority for incomplete applications to optimize the use of both the applicant’s and the FDA’s resources

Filing Review and Assessment

Filing issues grouped into two categories:

  • Potentially easily correctable deficiencies: Corrected before filling
  • Complex significant deficiencies that cannot be corrected before filing:  Materially lacking or inadequately organized applications, inadequate information, single study when more than one trial needed, lack of abuse potential studies for CNS drugs,  content not submitted electronically

FDA Decision-Making and Notification to the Applicant

  • FDA internal filing meeting with Division director making final filing decision
  • If  application cannot be filed, communicate RTF action to by day 60



Drug Products, Including Biological Products, that Contain Nanomaterials


Guidance on the development of human drug products, including biological products, in which a nanomaterial  is present in the finished dosage form

  • nanomaterials serve a variety of functions, for example as active ingredients,  carriers loaded with an active ingredient, or inactive ingredients
  • material or end product engineered to have at least one external dimension, or an internal or surface structure, in the nanoscale range (approximately 1 nm to 100 nm)
  • material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to one micrometer (1,000 nm)


  • Adequacy of characterization, complexity of material structure and function
  • Mechanism of impact of physicochemical properties on biological effects, release
  • In Vitro-In vivo correlation
  • Physical and chemical stability, maturity, impact of manufacturing changes
  • Physical state upon administration, route of administration
  • Predictability of dissolution, bioavailability, distribution, biodegradation, accumulation


  • Description of the Nanomaterial(s) in the Drug Product
  • Nanomaterial Quality Attributes and Structural Characterization
  • Nanomaterial Physicochemical Characterization Methods
  • Dissolution/In Vitro Drug Release Methods for Quality Testing
  • Manufacturing Process and In-Process Controls
  • Excipients
  • Stability
  • Postmarket CMC Changes


  • General Applicability of Existing Guidance
  • Absorption, Distribution, Metabolism, and Excretion Considerations..
  • Routes of Administration: Topical, Subcutaneous, Inhalation, Intravenous, Oral
  • Testing of Representative Nanomaterial
  • Bridging Toxicology


  • Submission type: 505(b)(2), 505(j) (ANDA), 351(k) (Biosimilar)
  • Bioanalytical Methods
  • In Vitro Tests With Human Biomaterials
  • Immunogenicity




Market Authorizations: Boston Scientific Spinal Cord Stimulation System, ADMELOG, IXIFI, NUCALA, LUXTURNA

Diagram of the device, indicating External Trial Stimulator (ETS), Clinical Programmer (CP), Remote Control, Charger, Implantable Pulse Generator (IPG), Percutaneous Leads, and Surgical Paddle Leads.

Boston Scientific Spinal Cord Stimulation System

Boston Scientific 

Aid in the management of chronic intractable pain of the trunk and/or limbs including unilateral or bilateral pain associated with the following: failed back surgery syndrome, Complex Regional Pain Syndrome (CRPS) Types I and II, intractable low back pain and leg pain. Associated conditions and etiologies may be

  • radicular pain syndrome
  • radiculopathies resulting in pain secondary to failed back syndrome, herniated disc
  • epidural fibrosis
  • degenerative disc disease
  • arachnoiditis
  • multiple back surgeries



  • Implanted spinal cord stimulation system that was previously indicated as an aid in the management of chronic intractable pain of the trunk and/or limbs
  • Two main components include:
    • stimulator device (signal generator) implanted under the skin that sends electrical signals to the spinal cord through an insulated lead wire
    • hand-held remote control that allows the patient to control the implanted stimulator device in order to achieve the best pain control


  • Based on published clinical studies (22 publications, 633 implanted patients) relevant to Spinal Cord Stimulation System features and indications
  • Improvement in pain ranged from 29.2%-100% for CRPS patients, and 37-77% for those with back and leg pain due to surgery associated conditions and etiologies across the studies
  • Most common adverse event: Need for an additional intervention (surgical revisions to correct lead migration, IPG discomfort, battery depletion, infection, fractured leads)
  • Other reported adverse events: Pain, unpleasant sensation, infection, inadequate stimulation, discomfort


  • ICD-10-CM (diagnosis) Coding Guide for Spinal Cord Stimulation
  • Documentation for medical necessity
  • Payer Medical Policy for Spinal Cord Stimulation



ADMELOG (insulin lispro injection), subcutaneous or intravenous use


INDICATION: Improve glycemic control in adults and pediatric patients 3 years and older with type 1 diabetes mellitus and adults with type 2 diabetes mellitus


  • > 30 million diabetics in US
  • Increases risk of serious health complications, including heart disease, blindness, and nerve and kidney damage
  • Improvement in blood sugar control through insulin treatment
  • First short-acting insulin approved as a “follow-on” product


  • Relied on FDA’s finding finding of safety and effectiveness for Humalog (insulin lispro injection, Eli Lilly) to support approval
  • Demonstration that relianmalog safety and effectiveness was scientifically justified
  • Provided Admelog-specific data to establish the drug’s safety and efficacy for its approved uses


  • Clinical trials, adult and pediatric patients , Type I and II diabetes
  • Mean reduction in HbA1c that was non-inferior to that achieved with Comparator


  • Most common adverse reactions: Hypoglycemia, itching, and rash
  • May cause low blood sugar (hypoglycemia), which can be life-threatening
  • Severe, life-threatening, generalized allergic reactions, including anaphylaxis, may occur


  • Increase competition in the market for prescription drugs
  • Lower-cost alternative


CaptureIXIFI (infliximab-qbtx) injection


INDICATIONS: Crohn’s Disease, Pediatric Crohn’s Disease, Ulcerative Colitis, Rheumatoid Arthritis in combination with methotrexate, Psoriatic Arthritis, Plaque Psoriasis,  Psoriatic Arthritis and Plaque Psoriasis

ADDRESSING UNMET NEED: Third FDA-approved biosimilar to U.S.-licensed Remicade (infliximab)


  • Biosimilarity based on a showing that it is highly similar to Remicade
    • No clinically meaningful differences in safety and effectiveness
    • Only minor differences in clinically inactive components 
  • Required pediatric assessments and postmarketing commitments

MECHANISM OF ACTION: Tumor necrosis factor (TNF) blocker


Image result for nucala logoNUCALA (mepolizumab) injection


INDICATION:  Treatment of adult patients with eosinophilic granulomatosis with
polyangiitis (EGPA)


  • Approximately 0.11 to 2.66 new cases per 1 million people are diagnosed each year with EGPPA, with an overall prevalence of 10.7 to 14 per 1,000,000 adults
  • First approved treatment for challenging, rare disease that can provide significant improvement in symptoms


  • Priority Review and Orphan Drug designations
  • Previously approved in 2015 to treat patients age 12 years and older with specific subgroup of asthma


  • Randomized, placebo-controlled, multicenter, 52-week trial, n=136, NUCALA vs placebo  while continuing their stable daily oral corticosteroids (OCS) therapy
  • Co-primary Endpoints: Total accrued duration of remission defined as Birmingham Vasculitis Activity Score (BVAS) = 0 (no active vasculitis) and proportion of subjects in remission
  •  Significantly greater accrued time in remission with NUCALA; significantly higher proportion of patients achieved remission at both week 36 and week 48
  • Significantly more patients achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period


  • Most common adverse reaction: Headache, injection site reaction, back pain, and fatigue

REIMBURSEMENT: GSK Patient assistance program


CaptureLUXTURNA (voretigene neparvovec-rzyl)  intraocular suspension for
subretinal injection 

Spark Therapeutics

INDICATION: Adeno-associated virus vector-based gene therapy indicated for treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Patients must have viable retinal cells as determined by the treating physician(s).


  • Biallelic RPE65 mutation-associated retinal dystrophy affects approximately 1,000 to 2,000 patients in U.S.
  • Patients now have a chance for improved vision
  • First directly administered gene therapy targeting a disease caused by mutations in a specific gene
  • Reinforces potential of breakthrough approach in treating a wide-range of challenging diseases


  • Priority Review and Breakthrough Therapy designations, Orphan Drug designation
  • Granted Rare Pediatric Disease Priority Review Voucher
  • Post-marketing observational study to evaluate long-term safety


  • Designed to deliver normal copy of gene encoding RPE65 to cells of the retina
  • RPE65 produced in the retinal pigment epithelial (RPE) cells and converts all-trans-retinol to 11-cis-retinol during visual cycle critical in phototransduction
  • Mutations in the RPE65 gene blocks visual cycle resulting in impairment of vision


  • Open-label, two-center, randomized trial in pediatric and adult patients with biallelic RPE65 mutation-associated retinal dystrophy, n= 31 enrolled
  • Endpoint:  Multi-luminance mobility testing (MLMT) score change from Baseline to Year 1,  MLMT score change of two or greater considered clinically meaningful benefit in functional vision
  • Median MLMT score of 2 or greater with LUXTURNA vs 0 in control


  • Most common adverse reactions: Eye redness (conjunctival hyperemia), cataract, increased intraocular pressure and retinal tear


  • Could cost $1 million or more per patient
  • Will require assessment of coverage and reimbursement models


Image credits: Boston Scientific, Sanofi, GSK, Pfizer, Spark


FDA News and Views: 2018 Policy Goals, Gene Therapy, Homeopathic product Enforcements, Subjective Cognitive Decline infographic (CDC)

FDA BRIEF: Week of Dec 18, 2017

Dr. Scott GottliebLooking ahead: Some of FDA’s major policy goals for 2018

By: Scott Gottlieb, M.D., Commissioner

Modernize approach to work and improve efficiency, while fulfilling mandate to protect and promote public health and uphold gold standard for regulatory decision-making

  • Serve public health by advancing innovations that improve patient care, enhance choice and provide competition
  • Take action against serious threats to public health
  • Empower patients, consumers, healthcare providers with accurate and up-to-date information
  • Recognize need for new, more flexible regulatory approaches

Key priorities

  • Addressing the Nicotine Addiction Crisis
  • Advancing Drug Safety
  • Promoting Food Safety
  • Empowering Consumers
    • Providing Better Information on Drugs
    • Broadening Access to Nonprescription Drugs
  • Modernizing Standards
    • Harmonizing Global Standards
    • Modernizing Mammography Standards
    • Embracing Electronic Submissions
    • Removing Outdated Rules


Gene Therapy

What Is Gene Therapy? How Does It Work?

Gene therapy can used to modify cells inside or outside the body

  • Inside: Inject vector carrying the gene directly into the part of the body that has defective cells
  • Outside: Modify cells outside of body; blood, bone marrow, or another tissue taken from patient, and specific types of cells separated out. Vector containing desired gene is re-introduced into cells, multiplied and injected back into the patient
  • FDA is committed to helping speed up development by prompt review of groundbreaking treatments that have the potential to save lives


CaptureNew, Risk-based Enforcement Priorities to Protect Consumers from Potentially Harmful, Unproven Homeopathic Drugs

Homeopathy, an alternative medical practice first systematized in the late 1700s with two principles:

  • Substance that causes symptoms can be used in diluted form to treat symptoms and illnesses (“like-cures-like”)
  • The more diluted the substance, the more potent it is (“law of infinitesimals”)

Risk-based approach for drug products labeled as homeopathic and marketed without required FDA approval; enforcement and regulatory actions for products

  • With reported safety concerns
  • With ingredients associated with potentially significant safety concerns
  • For routes of administration other than oral and topical
  • Intended to be used for the prevention or treatment of serious and/or life
    threatening diseases and conditions
  • For vulnerable populations
  • Deemed adulterated under section 501 of the FD&C Act





Image credits: FDA, CDC

FDA News and Views: Antimicrobial Resistance Tool, US Early Feasibility Studies, Clinical and Patient Decision Software Policies, 510(k) Modernization, Toxicology Roadmap, 3D printed Drugs, Type I Diabetes Devices

FDA BRIEF: Weeks of Dec 4 and Dec 11, 2017


New Tool for Sharing Information that Allows Doctors to Better Manage Antibiotic Use; Improve Patient Care

Antimicrobial resistance one of  most pressing public health challenges

  • Policy efforts to encourage new drug development, limit use in livestock
  • New steps for appropriate use in patient care; part of Cures Act

New Tool – Antimicrobial Susceptibility Test (AST) results to select appropriate antibacterial/antifungal drug for treatment

  • Tests rely on criteria — susceptibility test interpretive criteria or “breakpoints” — to help determine whether specific bacteria/fungi susceptible to antibacterial/ antifungal drugs
  • Bacteria and fungi change over time decreasing susceptibility to some drugs
  • Breakpoints updated accordingly – FDA-recognized breakpoints
  • Drug manufacturers will have to update labeling to reference FDA web page containing breakpoint information


Medical Device imageBringing Early Feasibility Studies for Medical Devices Back to the United States

Early Feasibility Studies Program (EFS) provides route for innovators, sponsors, FDA review teams, and clinicians to work together

  • Facilitate early clinical evaluation of medical devices in US
  • Limited clinical study in early development, typically before final device design
  • Evaluate device design concept with respect to initial safety and functionality
  • The EFS Program includes enhanced opportunities for collaboration, increased regulatory flexibility, and consideration of benefit-risk principles, while maintaining appropriate patient protection measures

IDEs submitted for EFS has more than doubled

  • Most studies receive timely FDA approval
  • Support device innovation and enhance early patient access to new technologies

Sponsor resources:  MDIC EFS working groups,  Early Feasibility Studies Webpage


FDA advances new digital health policiesAdvancing New Digital Health Policies to Encourage Innovation, Bring Efficiency and Modernization to Regulation

Three new, significant policy documents to advance development and proper oversight of innovative digital health tools

  • To support consumers and health care providers increasingly embracing digital health technologies to inform everyday decisions
  • Consumers makes more efficient decisions, improve lifestyles, health choices, and often experience better outcomes
  • Regulatory approach must foster, not inhibit, innovation; enhance access
  • Strike the right balance between ensuring patient safety and promoting innovation

(1) Draft guidance: Clinical and Patient Decision Support Software – CDS and PDS

  • Types of CDS would no longer be defined as medical device
    • Allows provider to independently review basis for  recommendations
  • Will enforce oversight of software programs
    • Intended to process or analyze medical images, Signals from in vitro diagnostic devices, Patterns acquired from a processor e.g. ECG
  • Not enforce oversight for lower-risk PDS
    • Should follow a similar regulatory structure as CDS
    • However, software that does not allow independent review of recommendation subject to FDA active oversight

(2) Draft guidance: Changes to Existing Medical Software Policies

  • Digital health provisions included in Section 3060 of Cures Act
  • FDA’s interpretation of types of software no longer considered medical devices
    • Low risk to patients, but provide great value to consumers
  • Update guidances on General Wellness and Mobile Medical Applications

(3) Final Guidance: Software as a Medical Device: Clinical Evaluation– SaMD

  • Harmonization with International Medical Device Regulators Forum (IMDRF)
  • Globally recognized principles in evaluating safety, effectiveness and performance


Capture.JPGFDA-Required Post-Marketing Studies of Approved Drugs Make a Big Difference for Public Health

Certain drug issues need additional evaluation after approval

  • to confirm clinical benefit when approved under accelerated approval provisions
  • further evaluation of potential safety issue
  • better characterize risk factors for known safety issue

FDA Amendments Act of 2007 (FDAAA) requires post-marketing requirements (PMRs) and post-marketing commitments (PMC) when new safety information

  • Committed to making sure industry fulfills  PMRs and PMCs
  • Public availability in a searchable database
  • Annual Federal Register (FR) report
  • Informs Congress on status and “backlog”



Advancing Policies to Promote Safe, Effective MedTech Innovation

Voluntary, alternative pathway for demonstrating substantial equivalence for 510(k) premarket notifications

  • More flexibility to use more modern criteria as reference standard
  • Permit comparisons to standards that more closely approximate the novel technology

Make review process more benefit-risk based

  • Adopt more modern tools for evaluating safety and benefits of new products
  • Embed patient-centric measures of risk and benefit

New Steps to Reform, Modernize 510(k) Review

  • Include FDA-recognized standards, FDA-developed guidance documents, or a combination of the two
  • For pre-specified categories of mature devices
  • Review framework to conform to international consensus standards


FDA's Toxicology Roadmap

Predictive Toxicology Roadmap to Enable Advances in Toxicity Testing

Toxicology testing plays a pivotal role in ensuring the safety of FDA-regulated products

  • Testing performed on people or animals to identify any potential risk from chemical, physical, or biological agents
  • Novel methods such as organs on a chip or mathematical modeling being developed for toxicity testing
  • Generating opportunities to improve ability to quickly and more accurately predict potential toxicities and reduce associated risks

FDA’s Predictive Toxicology Roadmap

  • Six-part framework for integrating predictive toxicology methods into safety and risk assessments
  • FDA research to identify data gaps and support intramural and extramural research
  • Development, validation and integration of promising technologies into product pipeline




 Promise and Potential of 3D Printed Pharmaceuticals

3D printing can change conventional methods  (large-scale processes, equipment, long production time) to offer personalized medicines

  • Allows for manufacture of solid drug products in various shapes, geometric designs, strengths and spatial distributions of the active and inactive ingredients
  • Release profile of active ingredients can be tailored to meet needs of specific patients
  • 3D printed Spritam®–FDA approved for epilepsy treatemnt; designed for large dose to disintegrate within seconds after a sip of water

Addressing 3D Printing Questions Through Research

  • FDA Office of Testing and Research conducting research on application of technology
  • Effects of material attributes, 3D geometric designs and 3D printing process parameters on dosage form performance
  • Mechanistic models for 3D printing processes to predict drug’s performance
  • Best ways to approach rapidly changing technology


Artificial Pancreas Diagram


Communication, Breaking Down Walls, and a Huge Step Forward for People with Type 1 Diabetes

Correct public assumptions about FDA’s overly cautious approach to diabetes treatment

  • Open a line of communication between FDA and the diabetes community
  • Artificial pancreas team worked to better understand daily struggles of living with type 1 diabetes
  • Productive relationships with key academic investigators and thought leaders on clinical trials
  • Approval of Medtronic’s Minimed 670G hybrid closed loop system
  • First FDA-approved,  first-in-the-world approved device to automatically monitor glucose; provide appropriate basal insulin doses
    • Came three years earlier than anticipated by company


Image credits: FDA

FDA Guidances: Additive Manufacturing, IDE and CMS coverage, Clinical and Patient Decision Support Software, Software as a Medical Device, Existing Software Policy Changes

CaptureTechnical Considerations for Additive Manufactured Medical Devices

Outline technical considerations with Additive Manufacturing (3D printing) and recommendations for testing and characterization

  • Builds object by sequentially building 2D layers, joining each to the layer below to rapidly produce alternative designs
  • Process Flow


Design and Manufacturing Process Considerations

  • Overall Device Design
  • Patient-Matched Device Design
  • Software Workflow
  • Material Control
  • Post-Processing
  • Process Validation and Acceptance
  • Quality Data

Device Testing Considerations

  • Device Description
  • Mechanical Testing
  • Dimensional Measurements
  • Material Characterization
  • Removing Manufacturing Material Residues and Sterilization
  • Biocompatibility


  • patient identifier, use, final design iteration or version used to produce the device


Capture.JPGFDA Categorization of Investigational Device Exemption (IDE) Devices to Assist the Centers for Medicare and Medicaid Services (CMS) with Coverage Decisions

Efficient CDRH categorization of investigational medical devices to support CMS’s Medicare coverage (reimbursement) determinations

  • Process and information to determine appropriate IDE category
  • Change of assigned category

FDA Interpretation of Medicare Coverage Categories A and B

  • Category A-Experimental: No PMA approval, 510(k) clearance, or De Novo,  being studied for new indication/new intended use; prior information  does not resolve initial safety/effectiveness questions
  • Category B- Nonexperimental/Investigational: No PMA approval, 510(k) clearance, or De Novo, being studied for a new indication/new intended use; prior information does resolve initial safety/effectiveness questions

Considerations When Changing from Category A to B – data to support

  • Peer-reviewed studies on similar device
  • Premarket or postmarket data from ex-US studies with similar device
  • Commercialization of similar device
  • Preliminary clinical data
  • Additional non-clinical data


CaptureClinical and Patient Decision Support Software

FDA’s regulatory oversight of:

(1) clinical decision support (CDS) software intended for healthcare professionals

(2) patient decision support (PDS) software intended for patients and caregivers who
are not healthcare professionals.

Scope of FDA oversight of CDS/PDS software:

  1. do not meet the definition of device as amended by the Cures Act
  2. may meet definition of device but will not require premarket clearance and premarket approval
  3. will require regulatory oversight

FDA Definitions:

CDS: Software functions that are considered as device:

  • intended to acquire, process, analyze a medical image/signal from in
    vitro diagnostic device or pattern or signal from signal acquisition system
  • intended for displaying, analyzing, or printing medical information
  • intended for supporting or providing recommendations to health care

Function excluded from the definition of device with additional criterion

  • intended for enabling health care professional to independently review basis for software recommendations and does not rely primarily on recommendation
    for clinical diagnosis or treatment decision

Examples of functions that are and are not considered as devices provided

PDS: Low risk devices and fall outside functionalities of regulatory oversight

  • enforcement discretion policy
  • software function should clearly explain:
    • purpose or intended use
    • intended user (e.g., patient, non-health care professional caregiver)
    • inputs used to generate recommendation
    • rationale or support for recommendation

Examples provided


CaptureCapture.JPGSoftware as a Medical Device (SAMD): Clinical Evaluation

Global regulatory framework and principles for SaMD

  • adopts internationally converged principles agreed upon by IMDRF
  • FDA adoption of principles

Clinical Evaluation of SaMD 

  • Valid Clinical Association
  • Analytical / Technical Validation
  • Clinical Validation of a SaMD


General Principles and Context of Clinical Evaluation Process 

  • Definition Statement and Category
  • Clinical Evaluation Processes

Clinical Evaluation Process Flow Chart 

  • Considerations for Generating and Assessing Evidence

Importance of Independent Review of Clinical Evaluation 

Continuous Learning Leveraging Real World Performance Data



Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act

Section 3060(a) of 21st Century Cures Act amended section 520 of (FD&C Act) removing certain software functions from definition of devic

  • affects FDA’s guidances related to medical device software.

Level 2 updates to be made to following guidance documents:

  • General Wellness: Policy for Low Risk Devices
  • Mobile Medical Applications
  • Off-The-Shelf Software Use in Medical Devices
  • Medical Device Data Systems, Medical Image Storage Devices, and Medical Image
    Communications Devices

Withdrawing following guidance document:

  • Submission of Premarket Notifications for Medical Image Management Devices

Interpretation of Cures Act and modifications to existing guidances:

  • Software Function Intended for Administrative Support of Health Care Facility
  • Software Function Intended for Maintaining or Encouraging Healthy Lifestyle
  • Software Function Intended to Serve as Electronic Patient Records
  • Software Function Intended for Transferring, Storing, Converting Formats, Displaying Data and Results.



Device Marketing Authorization: F1CDx Test (FDA approval + CMS coverage), RHA Dermal Fillers, TRIVISC

FDA BRIEF: Week of November 27, 2017

Capture.JPGFOUNDATIONONE CDx (F1CDx), in vitro diagnostic Test 

Foundation Medicine

Next generation sequencing (NGS)-based in vitro diagnostic (IVD) test that can detect genetic mutations in 324 genes and two genomic signatures in any solid tumor type


  • Run of one test to evaluate several appropriate disease management options
  • Avoids invasive process of extracting tumor samples multiple times
  • Help cancer patients and their health care professionals make more informed care decisions- eligibility for a single treatment or enrollment in a clinical trial


  • Sequencing DNA from patient’s tumor sample to determine the presence of gene mutations and alteration
  • Also detects certain molecular changes (microsatellite instability and tumor mutation burden)


  • Established through least burdensome means by comparing F1CDx to previously FDA-approved companion diagnostic tests
  • F1CDx ability to detect select mutation types (substitutions and short insertions and deletions) representative of the entire 324 gene panel is accurate approximately 94.6% of the time
  • Provides information on a number of different genetic mutations that may help in the clinical management of patients with cancer
  • Additionally, based on individual test results, can identify which patients with any of five tumor types may benefit from 15 different FDA-approved targeted treatment options
  • One test report to patients and health care professionals; avoiding duplicative biopsies


  • First device with the FDA’s Breakthrough Device designation
  • Coordinated, cross-agency approach; CDRH conducted clinical review with support from the FDA Oncology Center of Excellence

REIMBURSEMENT PATHWAY:  National Coverage Determination (NCD)

  • CMS provides coverage of NGS IVD tests to assist patients and their treating physicians in making informed cancer treatment decisions that improve health outcomes
  • Use of test as a diagnostic also help patients and their treating physicians determine candidacy for cancer clinical trials


  • FDA-CMS Parallel Review Program
  • Open to certain PMA applications for devices with new technologies and fall within the scope of a Part A or Part B Medicare-benefit category; have not been subject to NCD
  • CMS issued a proposed national coverage determination concurrent with FDA approval

Federal Register: Program for Parallel Review of Medical Devices

CaptureRHA® 2, RHA® 3, and RHA® 4 Dermal Fillers

Teoxane SA



  • RHA® 2 is indicated for injection into the mid-to-deep dermis for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF), in adults aged 22 years or older
  • RHA® 3 is indicated for injection into the mid-to-deep dermis for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF), in adults aged 22 years or older
  • RHA® 4 is indicated for injection into the deep dermis to superficial subcutaneous tissue for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF), in adults aged 22 years or older


  • Product Code : LMH (Implant, Dermal, For Aesthetic Use)


  • Viscoelastic, sterile, non-pyrogenic, clear, colorless, biodegradable gel devices
  • Produced with sodium Hyaluronic Acid (NaHA) using  Streptococcus equibacterial strain, crosslinked with 1,4-butanediol diglycidyl ether (BDDE)
  • Contain 0.3% lidocaine hydrochloride to reduce pain on injection
  • Exist in three formulations, from the least to the most cross-linked:  RHA® 2 (least cross-linked), RHA® 3,  RHA® 4 (most cross-linked)


  • 2 controlled, randomized, double-blinded, within subject (split-face), multicenter, prospective clinical studies; RHA vs non-treatment group, 15 months
  • Noninferioriority to respective control at 24 weeks after treatment, for the correction of NLF
  • Wrinkle Severity Rating Scale: Average improvement in the WSRS from preinjection was ≥ 1-grade
  • Improvement in Patient perspectives: Global Aesthetic Improvement (GAI),  FACE-Q, patient satisfaction survey


  • No reports of deaths, Treatment-Related Serious Adverse Events or Unexpected Adverse Device Effects in the study
  • All Treatment-Related Adverse Events were typically experienced following the injection of a dermal filler


CaptureTRIVISC (Sodium Hyaluronate ) injection


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



  • Product Code: MOZ


  • Sterile, viscoelastic, non-pyrogenic solution of purified, high molecular weight sodium hyaluronate, derived from a bacterial fermentation process
  • Sodium hyaluronate is a polysaccharide containing repeated disaccharide units of glucuronic acid and N-acetylglucosamine
  • TriVisc is supplied in a 3 mL glass syringe; sterile and non-pyrogenic


  • Adequate evidence of the sufficient similarity of TriVisc and VISCO-3™ with regard to chemical constituents, concentrations of constituents, solution characteristics, and molecular weight profiles of the sodium hyaluronate component
  • Application of FDAMA Section 216 to confirm evidence presented support reasonable assurance of its effectiveness of VICSO-3 is directly applicable towards
    establishing reasonable assurance of the effectiveness of TriVisc


Image Credits: Foundation Medicine, Teoxane, OrthogenRx 


FDA BRIEF: Week of Nov 27, 2017

FDA approved

OGIVRI (trastuzumab-dkst) injection



  • Adjuvant Breast Cancer: Adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature
  • Metastatic Breast Cancer: In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer, single-agent treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease
  • Metastatic Gastric Cancer: In combination with cisplatin and capecitabine or 5-fluorouracil, for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

ADDRESSING UNMET NEED:  First biosimilar to Herceptin (trastuzumab, Genentech, Inc.)


  • Approved as biosimilar, not as an interchangeable product
  • Approval was based on comparisons of extensive structural and functional product characterization, animal data, human pharmacokinetic and pharmacodynamic data, and clinical studies including clinical immunogenicity between Ogivri and U.S.-licensed Herceptin
  • Data demonstrate Ogivri is highly similar to U.S.-licensed Herceptin
  • No clinically meaningful differences between the products.


CaptureSUBLOCADE ( buprenorphine ) monthly subcutaneous injection


 Indivior Inc.

INDICATION: Treatment of moderate to severe opioid use disorder (OUD) in patients who have initiated treatment with a transmucosal buprenorphine‐containing product, followed by dose adjustment for a minimum of 7 days.
Should be used as part of a complete treatment plan that includes counseling and psychosocial support


  • Given scale of the opioid crisis, FDA expanding access to treatments that can help people pursue lives of sobriety
  • New treatment option for patients in recovery; benefit of once-monthly injection vs. other forms of buprenorphine
  • Reducing burden of taking medication daily as prescribed
  • Medication-assisted treatment (MAT); part of comprehensive recovery plan opioid use disorder


  • Buprenorphine currently approved to administer as a tablet, film or implant
  • Independent FDA advisory committee supported the approval
  •  Priority Review and Fast Track designations
  • Schedule III

MECHANISM OF ACTION & DESCRIPTION:  Partial agonist at the mu‐ opioid receptor and an antagonist at the kappa‐opioid receptor

  • Drug-device combination product that utilizes buprenorphine and the Atrigel Delivery System in a pre-filled syringe


  • A double‐blind efficacy and safety study and an opioid blockade study , n=848, subjects with moderate-to-severe OUD who began treatment with buprenorphine/naloxone sublingual film followed by  Sublocade by injection vs. placebo
  • MAT Response: Urine drug screening and self-reporting of illicit opioid use during six-month treatment period
  • More weeks without positive urine tests or self-reports of opioid use vs. placebo
  • Higher proportion of patients with no evidence of illicit opioid use throughout the treatment period vs. placebo


  • Boxed warning : Risks of intravenous self-administration; solid mass could cause occlusion, tissue damage or embolus
  • Prescribed and dispensed as part of a Risk Evaluation and Mitigation Strategy (REMS)


Image credits: Mylan, Indivior



FDA News and Views: Sentinel Initiative, Innovation and International Regulation, PEPFAR, 3D Printing

Week of Nov 27, 2017


CDER Conversation: The FDA’s Sentinel Initiative

The Sentinel Initiative is national electronic system that monitors safety of marketed drugs, vaccines, biologics and medical devices

  • Includes Active Risk Identification and Analysis (ARIA) system
  • 17 data partners such as insurance companies, HMOs, and hospitals
  • Access to 223 million members
  • Data derived from administrative claims databases that healthcare insurers use for reimbursement for diagnoses, procedures, and medications
  • Used as a resource for new product reviews

Sentinel System different from other systems 

  • Distributed data approach – data partners maintain physical and operational control over electronic data using Sentinel Common Data Model
  • Secure access to multiple data sources to achieve far larger sample sizes
  • Allow data aggregation while safeguarding patient privacy
  • Routine Querying Tools




FDA, International Regulators Look at Common Challenges, ‘Innovation’

 Global regulatory experts from 28 countries, including FDA, discussed ‘Innovation’ issues of mutual concern

  • regenerative medical products
  • international collaboration to fight antimicrobial resistance (AMR)
  • developing strategies to combat substandard or falsified medical products

FDA presentations

  • Use of real world evidence (RWE) in pre- and post-market activities
  • Align their approaches to the evaluation of antibiotics
  • Working with WHO in combating falsified/substandard medical products
  • Need for international cooperation and increased sharing of inspectional results, collaborating on pharmacovigilance needs, and advancing regulatory science



PEPFAR: FDA Approves 200th HIV/AIDS Therapy

FDA tentatively approved  the 200th antiretroviral drug application under the President’s Emergency Plan for AIDS Relief (PEPFAR)

  • PEPFAR launched in 2003 to address global HIV/AIDS epidemic by stimulating  development of new HIV therapies
  • FDA used guidance, outreach and expedited review process
  • FDA encouraged submission for single entity, fixed dose combination (FDC), and co-packaged versions of previously approved antiretroviral therapies

Advancements to facilitate treatment in areas of the world lacking advanced health care infrastructure, particularly in parts of Africa 

  • FDC even in circumstances with patent or exclusivity market protection for one or more of the components in the U.S
  • Due to the significant public health impact of these products, FDA prioritized review
  • Products purchased with U.S. funds under the President’s PEPFAR Fund



FDA ushering in new era of 3D printing of medical products

FDA has reviewed >100 3D printed devices currently on the market

  • Patient-matched devices tailored to fit patient’s anatomy – knee replacements, implants
  • Drug produced on 3D printer with more porous matrix
  • Envision 3D printed new skin cells for burn wounds

State-of-the-art 3D printing facilities on FDA campus

  • CDER scientists determine how 3D drug printing impacts manufacturing
  • CDRH scientists investigate the effect of design changes on device performnace
  • Understand policy framework to ensure quality and safety of 3D printed products

Providing comprehensive policy framework to manufacturers

  • CDER’s Emerging Technology Program
  • New guidance on technical aspects of 3D printing (additive manufacturing)
  • Review regulatory issues related to bioprinting of biological, cellular and tissue-based product


Image credits: FDA, PEPFAR



FDA Marketing Authorizations: NUCLEUS COCHLEAR Telehealth, RxSIGHT Lens, MSK-IMPACT Tumor Profiling Assay, JULUCA, HEMLIBRA



NUCLUES COCHLEAR IMPLANT telemedicine platform

Cochlear Americas

INDICATION FOR USE: Remote feature for follow-up programming sessions for the Nucleus Cochlear Implant System through a telemedicine platform. The remote programming feature is indicated for patients who have had six months of experience with their cochlear implant sound processor and are comfortable with the programming process


  • 58,000 cochlear implants have been implanted in adults and 38,000 in children
  • Designed to produce useful hearing sensations for severe to profound hearing loss, by electrically stimulating nerves inside the inner ear
  • Often require regular programming visits with an audiologist
  • First telehealth option to program cochlear implants remotely


  • Product Code : MCM


  • Clinical study, n=39, aged 12 or older, with cochlear implant for at least one year
  • One in-person programming session and two remote programming sessions
  • Endpoint:  Speech perception tests showed no significant difference between in-person and remote programming
  • Endpoint: Patients’ self-assessment of hearing speech in presence of other sounds,  sense direction, distance and motion of sound
  • Endpoint: Cybersecurity measures for remote interaction


  • Telehealth as a service option in healthcare systems today- hospital networks, CMS




INDICATION FOR USE:   Reduction residual astigmatism to improve uncorrected visual acuity after removal of the cataractous natural lens by phacoemulsification and implantation of the intraocular lens in the capsular bag, in adult patients

  • With pre-existing corneal astigmatism of  ≥ 0.75 diopters
  • Without pre-existing macular disease

The system also reduces the likelihood of clinically significant residual spherical refractive errors


  • Refractive errors  common following cataract surgery; corrected with glasses, contact lenses or refractive surgery
  • First system to make small adjustments to artificial lens’ power after cataract surgery to improve visual acuity without glasses


  • Product Code: PZK


  • The RxSight Intraocular lens (IOL)  made of unique material that reacts to UV light delivered by Light Delivery Device, 17-21 days after surgery
  • Three or four light treatments over a period of 1-2 weeks


  • Randomized clinical study, n=600, Light Adjustable Lens vs. commercially available monofocal lens
  • Endpoint: Improvement of about one additional line down the vision chart, for distance vision without glasses vs. conventional IOL
  • Endpoint: Reduction in astigmatism in 75% patients

IMPACT tumor profiling test 

Memorial Sloan Kettering Cancer Center

INDICATION FOR USE: Qualitative in vitro diagnostic test that uses targeted next  generation sequencing of formalin-fixed paraffin-embedded tumor tissue matched with  normal specimens from patients with solid malignant neoplasms to detect tumor gene  alterations in a broad multi gene panel. The test is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and microsatellite instability for use by qualified health care professionals in accordance with professional guidelines, and is not conclusive or prescriptive for labeled use of any specific therapeutic product. MSK-IMPACT is a single-site assay performed at Memorial Sloan Kettering Cancer Center


  • NGS technologies can examine hundreds, if not millions, of DNA variants at a time
  • By identifying what genetic mutations are present in tumor, test results can provide useful insight for best treatment
  • Established Class II regulatory pathway for review of other NGS-based tumor profiling tests


  • Accreditation of the New York State Department of Health (NYSDOH) as an FDA third-party reviewer of in vitro diagnostics, including tests similar to IMPACT
  • NGS-based tumor profiling tests by NYSDOH do not need 510(k) clearance

GENERIC DEVICE TYPE:  Next generation sequencing (NGS) based tumor profiling test

  • Qualitative in vitro diagnostic test intended for NGS analysis of tissue specimens from malignant solid neoplasms to detect somatic mutations in a broad panel of targeted genes to aid in the management of previously diagnosed cancer patients by qualified health care professionals


  • High accuracy: > 99%  and capable of detecting a mutation at a frequency of approximately 5 %  (range of 2-5%)
  • Detection of certain molecular changes (microsatellite instability): concordant >92% across multiple cancer types in 175 cases vs. traditional detection methods



JULUCA (dolutegravir and rilpivirine) tablets

GlaxoSmithKline (ViiV)

INDICATION:  Treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions  associated with resistance to the individual components of JULUCA


  • Estimated 1.1 million people in US living with HIV
  • Limiting number of drugs in HIV treatment regimen can help reduce toxicity


MECHANISM OF ACTION:  Fixed-dose combination of the HIV-1 antiretroviral agents, dolutegravir and rilpivirine


  • 2 open-label, 148-week, randomized, multicenter, parallelgroup, non-inferiority trials, n=1,024 adult HIV–1-infected subjects; randomized 1:1 to continue current
    antiretroviral regimen or switched to JULUCA
  • Endpoint: HIV-1 RNA <50 copies/mL – Similar (95%)


  • Most common side effects: Diarrhea and headache
  • Serious side effects: Skin rash and allergic reactions, liver problems, depression or mood changes


Image result for hemlibra logoHEMLIBRA (emicizumab-kxwh) injection

Genentech, Inc.

INDICATION: Routine prophylaxis to prevent or reduce the frequency of bleeding
episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors


  • New option for reducing the frequency or preventing bleeding episodes
  • Important part of disease management for patients with hemophilia


  • Priority Review, Breakthrough Therapy designation, Orphan Drug designation

MECHANISM OF ACTION:  Bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis


  • An adult and adolescent trial  and a pediatric trial (HAVEN 2)
  • Randomized, multicenter, open-label, n= 109 adult and adolescent males with hemophilia, emicizumab-kxwh prophylaxis s. no prophylaxis
  • Endpoint: Annualized bleeding rate (ABR) 2.9 (95% CI; 1.7, 5.0) vs. 23.3 (95% CI: 12.3, 43.9), p<0.0001
  • Improvements in patient-reported hemophilia-related symptoms and physical functioning with prophylaxis
  • Single-arm, multicenter, open-label, n=23 pediatric males
  • ABR for treated bleeds was 0.2 (95% CI: 0.1, 0.6). ABR for all bleeds was 2.9 (95% CI: 1.8, 4.9)


  • Most common adverse reactions:  Injection site reactions, headache, and arthralgia
  • Cases of thrombotic microangiopathy and thrombotic events
  • Boxed warning: Thrombotic microangiopathy and thrombotic events


Image Credits:Cochlear Americas, RxSight, Memorial Sloan Kettering Cancer Center, GSK, Genentech




FDA News and Views: NGS and Tumor Profiling, Regenerative Therapy Guidances, FDA Hiring and Diversity, Office of Criminal Investigation, Generic Abuse-Deterrent Opioids

FDA BRIEF: Weeks of November 13 and 20, 2017

CaptureCDRH Approach to Tumor Profiling Next Generation Sequencing (NGS) Tests

Marketing authorization of two tumor profiling NGS tests

  • Thermo Fisher Scientific’s Oncomine Dx Target Test1 and MSK-IMPACT2
  • Real-world application of precision oncology

Three-Tiered approach for reporting biomarkers

  • Level 1: Companion Diagnostics
  • New Level 2: Cancer Mutations with Evidence of Clinical Significance
  • Level 3: Cancer Mutations with Potential Clinical Significance
  • A Fluid Approach to Reporting within Levels 2 and 3


Capture.JPGBig Day for Regenerative Therapy

Comprehensive policy framework for development and oversight of regenerative medicine products, including novel cellular therapies

  • Builds upon the FDA’s existing risk-based regulatory approach
  • Proposes efficient, science-based process to ensure safety and effectiveness
  • Risk-based framework for enforcement actions against significant safety concerns

Two final guidance documents and Two draft guidance documents


CaptureFDA Workforce and Diversity Plan

FDA challenged with building and retaining diverse, talented, dedicated workforce

  • Building stronger workforce by key process improvements in hiring and retention
  • Congress authorized new resources and authorities for talented workforce

FDA Hiring Initiative

  • Comprehensive evaluation of our hiring practices and procedures
  • Assess current challenges and provide roadmap for future
  • Initial Assessment of FDA Hiring and Retention report
  • Hiring pilot to modernize and streamline hiring practices; use new IT tools and eliminating unnecessary processes
  • Digital and social media tools for modern recruitment and outreach techniques

FDA Diversity and Inclusion Strategic Plan

  • Cultivate and promote diverse, inclusive culture
  • Promote continuous learning and discussion of diversity and inclusion topics
  • Recruit qualified candidates of different backgrounds, experiences, talents
  • Leverage every individual’s perspectives, passions, and background;  positive
    impact on innovation



Capture.JPGRemarks by Commissioner Gottlieb at FDA Office of Criminal Investigation Meeting

 Office of Criminal Investigations’s (OCI) nationwide presence

  • To advance FDA’s criminal law enforcement operations
  • To address criminal wrongdoing involving FDA-regulated products
  • Key to stopping dangerous counterfeit, unapproved, misbranded medical products into domestic supply chain

Comprehensive approach to President’s declaration of opioid crisis a public health emergency

  • Issuing guidance to encourage development of therapies to treat opioid addiction
  • Encouraging widespread use of existing, safe, effective FDA approved therapies to help combat addiction
  • Requirement for opioid manufacturers make training available to prescribers, potentially making them mandatory
  • Guidances to develop abuse deterrent opioids and non-addictive alternatives in the treatment of pain
  • Careful balancing of risks and benefits  when making approval decisions or market withdrawals

Dealing with bad actors that see addiction as an opportunity for profit

  • Using regulatory authorities and pursuing criminal charges
  • Will require manufacturers to  follow FDA market withdrawal notices e.g. Endo
  • Aggressive steps to identify and disrupt affirmative misconduct
  • Criminal enforcement actions in recent months e.g. Insys
  • Build cases against individuals who tamper with opioids at pharmacies, hospitals
  • Taking further action relating to a botanical substance known as kratom due to risks of abuse, addiction, and death
  • Increasing OCI’s Cybercrime Investigations Unit, Strategic Intelligence Unit, and Intelligence Analysis Branch



Steps to promote development of generic versions of opioids formulated to deter abuse

Opioids with abuse-deterrent formulations (ADFs) intended to make abuse, such as crushing, snorting, dissolving, more difficult or less rewarding

  • Approved 10 opioid drugs with these properties
  • But low uptake- learning curve, low awareness,prescribing uncertainty, price

FDA plans to permanently transition older formulations to ADFs

  • Improve access to the newer formulations through generic competitors
  • Final guidance on development of generic versions of approved ADF opioids
  • Developing appropriate, improved testing methodologies for evaluating abuse deterrence for both brand name  and generic opioid drug products
  • Flexible, adaptive approach to the evaluation and labeling of ADF opioids
  • Determining effectiveness of ADF products  in  real-world setting
  • Better understanding the attitudes and beliefs of health care professionals and those who are prescribed these products


Image credit: FDA

FDA Device, Combination Product Authorizations: XW-100 ANALYZER, ABILIFY MYCITE, NSS-2 BRIDGE

Capture.JPGXW-100 Automated Hematology Analyzer

Sysmex America, Inc.

INTENDED USE:  For use in patients 2 years of age and older who require a whole blood cell count and white blood cell differential.

Test results can be used with other clinical and laboratory findings to provide early alerts of patients with serious conditions such as severe anemia (low red blood cell or hemoglobin count) and agranulocytosis (low white blood cell count), who require additional testing.

Not intended to diagnose or monitor patients with primary and/or secondary hematologic diseases, including oncology and critically ill patients.

REGULATORY PATHWAY: Dual Submission pathway – 510(k)) and CLIA Waiver

  • Original 510(k) clearance (2015) for use at patient’s point-of-care
  • CLIA Waiver: Simple operator instructions and number of hematology parameters reduced to 12
  • Dual clearance based on substantially equivalence to  2015 model + demonstration ease of use and low risk of false results when used by untrained operators
  • Regulation No. 864.5220
  • Product Code: GKZ


  • 15 µL venous blood to provide CBC with three-part differential
  • White Blood Cell Count (WBC), Red Blood Cell Count (RBC), Hemoglobin (HGB),  Hematocrit (HCT), Mean Corpuscular Volume (MCV), Platelet Count (PLT), Neutrophil Count (NEUT#), Lymphocyte Count (LYM#), Other White Blood Cell Count (Other WBC#), Neutrophil Percentage (NEUT%), Lymphocyte Percentage (LYM%), Other White Blood Cell Percentage (Other WBC%)


  • 582 samples collected from patients 2 to 92 years old.
  • Comparison of XW-100 test results: non-medical personnel in CLIA-waived settings  vs. hematology analyzer in accredited clinical laboratory
  • Accurate testing effectively conducted by untrained personnel following manufacturer’s instructions for use

Capture.JPGABILIFY MYCITE (aripiprazole with sensor) tablets

Otsuka Pharmaceuticals, Proteus Digital Health


Drug-device combination product comprised of aripiprazole tablets embedded with Ingestible Event Marker (IEM) sensor to track drug ingestion, is indicated for :
• Treatment of adults with schizophrenia
• Treatment of bipolar I disorder
• Adjunctive treatment of adults with Major Depressive Disorder

Limitations of Use:
• Ability to improve patient compliance not been established
• Use to track drug ingestion in “real-time” or emergency not recommended


  • Being able to track ingestion of medications prescribed for mental illness
  • New technology might benefit patients and prescribers


  • Abilify : NDA first approved in 2002 to treat schizophrenia
  • Ingestible sensor: De Novo order in 2012
  • Required Postmarketing Pediatric Studies:  Human factors usability studies in schizophrenia, bipolar I disorder, irritability associated with autistic disorder


  • Aripiprazole tablet embedded with IEM sensor
  • Patch (wearable sensor) that detects signal from IEM sensor after ingestion and
    transmits data to smartphone
  • APP – to display information for the patient
  • Web-based portal for healthcare professionals and caregivers


  • Safety and efficacy of aripiprazole tablets for the treatment of adults with schizophrenia, acute treatment of adults with manic and mixed episodes associated with Bipolar I disorder, and adjunctive treatment of adults with major depressive disorder  established based on prior adequate and well-controlled trials of aripiprazole tablets
  • Ensuring  compatibility with their specific smartphone and downloading APP; facilitated by the healthcare provider
  • Skin irritation with patch


  • Only select number of health plans and providers
  • Learnings for prescribers, health plans, and Otsuka for implementing broader access


Capture.JPGNSS-2 BRIDGE Neurostimulation System

Innovative Health Solutions, Inc.

INDICATION FOR USE: Percutaneous nerve field stimulator (PNFS) system, that can be used as an aid to reduce the symptoms of opioid withdrawal, through application to branches of Cranial Nerves V, VII, IX and X, and the occipital nerves identified by transillumination


  • Innovative new way to address epidemic of opioid addiction
  • Additional help  to live lives of sobriety with medically assisted treatment

REGULATORY PATHWAY: De Novo Request, to expand use

  • Regulation Number: 21 CFR 882.5896
  • Regulation Name: Percutaneous nerve stimulator for substance use disorders
  • Regulatory Class: Class II
  • Product Code: PZR
  • Prior (2014) clearance of EAD (electro auricular device)for use in acupuncture
GENERIC TYPE OF DEVICE: Percutaneous nerve stimulator for substance use disorders
  • Device that stimulates nerves percutaneously to aid in the reduction of withdrawal symptoms associated with substance use disorders


  • Small electrical nerve stimulator placed behind patient’s ear
  • Battery-powered chip emits electrical pulses to stimulate branches of certain cranial nerves
  • Stimulations may provide relief from opioid withdrawal symptoms


  • Single-arm clinical study, n=73, undergoing opioid physical withdrawal
  • Endpoint: Clinical opiate withdrawal scale (COWS) score
  • COWS reduction of at least 31 %  within 30 minutes of device use
  • Transitioned to medication assisted therapy: 88% after 5 days of device use


  • Adverse tissue reaction – Biocompatibility evaluation, Labeling
  • Electrical, mechanical, or thermal hazards leading to user discomfort or injury –
    Electromagnetic compatibility testing, Electrical, mechanical, and thermal safety testing, Non-clinical performance testing, Software verification, validation and hazard analysis, Labeling
  • Infection Sterility testing- Shelf life testing, Labeling

Image credit: Sysmex, Otsuka, Innovative Health Solutions


FDA approved

Capture.JPGZELBORAF (vemurafenib) Tablet

 Hoffmann-La Roche, Inc./Genentech, Inc.

INDICATION: Treatment of patients with Erdheim-Chester Disease (ECD) with BRAF
V600 mutation


  • ECD is slow-growing blood cancer that originates in the bone marrow; very limited life expectancies
  • Rare cancer with no approved therapies
  • Application of knowledge of underlying genetic characteristics of certain malignancies to other cancers


  • First approval in 2011 for wild-type BRAF melanoma
  • Priority Review, Breakthrough Therapy, Orphan Drug


  • Open-label, multicenter, single-arm, multiple cohort study, patients ≥ 16 years of age with non-melanoma BRAF V600 mutation–positive diseases, n=22
  • Endpoint: Best overall response rate maintained on two occasions at least four weeks apart, assessed by RECIST v 1.1
  • Responders: 54.5%, Complete Response in 1, Partial Response in 11, Median time to response of 11 months


  • Severe side effects: Development of new cancers,  growth of tumors in patients with BRAF wild-type melanoma, hypersensitivity reactions, severe skin reactions, heart abnormalities (QT prolongation), liver damage, photosensitivity, severe reactions in the eye, immune reactions,  kidney failure, thickening of tissue in hands and feet, harm to fetus
  • Common side effects: Arthralgia, maculo-papular rash, alopecia; fatigue; change in the heart’s electrical activity (prolonged QT interval) and papilloma


  • ICD-10-CM: E88.89
  • NDC: 10-digit and 11-digit
  • Codes not all-inclusive; appropriate codes can vary by patient, setting of care and payer


Capture.JPG ALECENSA (alectinib)


 Hoffmann-La Roche, Inc./Genentech, Inc.

INDICATION:  Treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test

REGULATORY PATHWAY: sNDA, Fulfillment of postmarketing requirement

  • Breakthrough therapy designation
  • Accelerated approval in 2015, for second line treatment of ALK-positive metastatic NSCLC


  • Open-label, randomized, active-controlled, multicenter study, patients with  ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay, ALECENSA vs. crizotinib, n=303
  • Major efficacy outcome: Progression-free survival (PFS) determined RECIST v1.1
  • Other: Time to CNS progression, objective response rate (ORR) , duration of response (DOR), overall survival (OS)
  • Improvement in PFS: Hazard ratio  0.53 (95% CI: 0.38, 0.73; p<0.0001)
  • Estimated median PFS: 25.7 months vs. 10.4 months
  • Time to cause-specific CNS also significantly improved
  • Confirmed ORR : 79% vs. 72%


  • Most common adverse reactions: Fatigue, constipation, edema, myalgia, and anemia


  • Diagnosis: ICD-10-CM: C34.00—C34.02, C34.10—C34.12, C34.2, C34.30—C34.32, C34.80—C34.82, C34.90—C34.92
  • Codes are not all-inclusive; appropriate codes can vary by patient, setting of care and payer


Capture.JPGPREVYMIS (letermovir) tablets and injection


INDICATION:   Prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT)


  • >27,000 allogeneic HSCTs/year worldwide (8,500 transplants in US); 65-80%  recipients previously exposed to CMV and at high risk for CMV infection
  • First drug indicated to help prevent CMV infection and disease in adults who have been exposed to CMV and have received HSCT


  • Breakthrough Therapy and Orphan Drug designation

MECHANISM OF ACTION: Antiviral drug against CMV


  • Multicenter, double-blind, placebo-controlled, adult CMV-seropositive recipients
    [R+] of an allogeneic HSCT, PREVYMIS vs. placebo, n= 565
  • Primary efficacy endpoint: Incidence of clinically significant CMV infection through
    Week 24 post-transplant (prophylaxis failure)
  • Proportion of subjects who failed prophylaxis: 38% vs. 61%


  • Contraindicated with pimozide and ergot alkaloids and in patients receiving pitavastatin or simvastatin when co-administered with cyclosporine.
  • Most common side effects: Nausea, diarrhea, vomiting, swelling in the arms and legs, cough, headache, tiredness and stomach (abdominal) pain


CaptureADCETRIS (brentuximab vedotin)

Seattle Genetics

INDICATION: Treatment of primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therap


  • Breakthrough Therapy Designation, Orphan Designation, and Priority Review
  • Initial approval in 2011


  • Randomized, open-label, multicenter clinical trial, patients with MF or pcALCL withe prior therapy, n=131, ADCETRIS vs physician’s choice of methotrexate or bexarotene
  • Endpoint: Improvement in objective response rate lasting 4 months (ORR4), complete response (CR) rate, and progression-free survival (PFS)
  • ORR4: 56% vs 12% (p<0.001)
  • CR: 16% vs 2% (p=0.007)
  • PFS: Estimated hazard ratio of 0.27, p<0.001, median PFS of 17 mo.


  • Boxed Warning:  Progressive multifocal leukoencephalopathy (PML)
  • Most common adverse reactions: Anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue, and neutropenia

 CaptureMEPSEVII (vestronidase alfa-vjbk) injection

Ultragenyx Pharmaceutical, Inc.

INDICATION: Treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome


  • MPS VII is an extremely rare, progressive condition that affects most tissues and organs; impacts less than 150 patients worldwide
  • First drug to be apprived for MPS VII


  • Fast Track designation, Orphan Drug designation, Rare Pediatric Disease Priority Review Voucher
  • 12th rare pediatric disease priority review voucher issued by the FDA
  • Postmarketing REquirement: Long term risk of immunogenicity, pre- and post-natal development study, measurement of PD marker


  • Clinical trial and expanded access protocols, n=23 , 5 months to 25 years of age
  • Dosin every two weeks for up to 164 weeks
  • Efficacy endpoint : Six-minute walk test in ten patients
  •  Mean difference in distance walked relative to placebo: 18 meters, continued improvement and stabilization
  • Marked improvement in pulmonary function in 2 patients
  • Most common side effects: Infusion site reactions, diarrhea, rash and anaphylaxis

 Image Credit: Hoffmann La-Roche, Merck, Seattle Genetics, Ultragenyx


FDA Guidances: 510(k) for Device/Software Changes, DDI Studies, Breakthrough Devices Program, De Novo Process and Review, Sharing Patient-Specific Information

fda guidances


Deciding When to Submit a 510(k) for a Change to an Existing Device

510(k)s for changes to a legally marketed device should consider Quality System (QS) regulation

  • For some types of changes submission of new 510(k) not required
  • Reliance on existing QS requirements is the least burdensome approach

Guiding Principles

  • Changes made with intent to significantly affect safety or effectiveness
  • Initial risk-based assessment
  • Unintended consequences of changes
  • Use of risk management
  • Role of testing in evaluating effect on safety and effectiveness
  • Evaluating simultaneous changes
  • Appropriate comparative device and cumulative effect of changes
  • Documentation requirement
  • 510(k) submissions for modified devices
  • Substantial equivalence determinations


  • Labeling Changes
  • Technology, Engineering, and Performance Changes
  • Materials Changes
  • Technology, Engineering, Performance, and Materials Changes for In Vitro Diagnostic Devices
  • Considerations for Risk-Based Assessments of Modified Devices



Deciding When to Submit a 510(k) for a Software Change to an Existing Device

When software (including firmware) change to medical device may require 510(k)

  • Enhance predictability, consistency, transparency of the “when to submit”
  • Provide a least burdensome approach, regulatory framework, policies, practices

Guiding Principles

  • Changes made with intent to significantly affect safety or effectiveness
  • Initial risk-based assessment
  • Unintended consequences of changes
  • Use of risk management
  • Role of testing in evaluating effect on safety and effectiveness
  • Evaluating simultaneous changes
  • Appropriate comparative device and cumulative effect of changes
  • Documentation requirement
  • 510(k) submissions for modified devices
  • Substantial equivalence determinations

Additional guidance

  • Use flowchart in concert with the Guiding Principles
  • With multiple changes, use all applicable parts of flowchart and companion text, including the Guiding Principles



Clinical Drug Interaction Studies — Study Design, Data Analysis, and Clinical Implications

Conduct of clinical studies to evaluate Drug-Drug Interaction (DDI) potential

  • Timing and design of clinical studies
  • Interpretation of study results
  • Options for managing DDIs in patients

Goals of studies to determine

  • Whether investigational drug alters pharmacokinetics of other drugs
  • Whether other drugs alter pharmacokinetics of investigational drug
  • Magnitude of changes in pharmacokinetic parameters
  • Clinical significance of observed or expected DDIs
  • Appropriate management strategies for clinically significant DDIs


  • Timing, Types, Design and conduct of DDI sudies
  • Stand-Alone and Nested Prospective DDI Studies
  • CYP-Mediated Interactions
  • Transporter-Mediated Interactions
  • Reporting and Interpretations
  • Labeling recommendations


Capture.JPGBreakthrough Devices Program

Breakthrough Devices Program for certain medical devices for life-threatening or irreversibly debilitating diseases or conditions


  • Expedites development, assessment, FDA review, while preserving statutory standards
  • Supersedes the Expedited Access Pathway (EAP)


  • Program Principles
  • Program Features
  • Designation Request
  • Designation Review Process
  • Designation Withdrawal



Manufacturers Sharing Patient-Specific Information from Medical Devices with Patients Upon Request

Patients play an active role in their own healthcare

  • May request personal information that has been recorded, stored, processed, retrieved, and/or derived from marketed medical device
  •  Sharing “patient-specific information”  upon request may assist in being more engaged with healthcare providers in making sound medical decisions

Categories of patient-specific information for sharing

  • Data healthcare provider inputs in device to record status and ongoing treatment
  • Information stored by device to record usage, alarms, or outputs (e.g., pulse oximetry data, heart electrical activity)
  • Case logs entered into device by healthcare provider



De Novo Classification Process (Evaluation of Automatic Class III Designation)

To provide guidance on the process for the submission and review of a De Novo classification request

  • for cases where there is no predicate device or has received an NSE determination on a 510(k) submission
  • specific device and device type is classified in class I or class II
  • publish a notice in the Federal Register announcing classification and controls necessary to provide reasonable assurance of safety and effectiveness



Acceptance Review for De Novo Classification Requests

To explain FDA procedures and criteria for acceptability for substantive review of De Novo classification request  

  • Making “Accept” or “Refuse to Accept” (RTA) decisions

De Novo Acceptance Review Policies and Procedures

  • Acceptance Review Policies and Procedures
  • FDA Review Clock
  • Notification of Acceptance Review Result
  • Refuse to Accept Principles

Checklist Acceptance Review

  • Organizational Elements
  • Elements of a Complete De Novo Request (RTA Items)
  • Applying the Checklist of RTA Items
  • Elements Marked as “Not Applicable” (N/A)
  • Adequacy of Information
  • Elements Marked “No”

Recommended Content Checklist

  • Purpose
  • Prior Submission(s) Relevant to the De Novo Request Under Review


  • Acceptance Checklist for De Novo Classification Requests
  • Recommended Content Checklist for De Novo Classification Requests



FDA News and Views: Pediatric Clinical Trials, Genetic Health Risk Testing, Shared REMS, Type 2 Diabetes CE Course

FDA BRIEF: Week of November 6, 2017


FDA Awards Funding to Support Pediatric Clinical Trials Research

Some 60%-90%  drugs used in children and neonates not approved for pediatric use

  • Failure in clinical trials
  • Could not complete study recruitment
  • FDA to facilitate the plan, start up, conduct, close out of clinical investigations

FDA award to Institute for Advanced Clinical Trials for Children (IACT for Children) and Duke University

  • $1 million to each awardee for this year under Global Pediatric Clinical Trials Network Cooperative Agreement
  • Leverage basic science research to support extrapolation from adult data
  • Understand maturation of metabolic pathways for modeling and simulation to optimize dosing strategies
  • Develop innovative trial designs to optimize data from multiple sources
  • Leverage and standardize all sources of information
  • Develop multiple types of biomarkers
  • Develop clinically meaningful short- and long-term efficacy and safety endpoints


FDA statement on implementation of agency’s streamlined development and review pathway for consumer tests that evaluate genetic health risksCapture.JPG

Genetic health risk (GHR) testing helps understanding of  individual risk for developing diseases

  • Make more informed lifestyle choices
  • Direct-to-consumer (DTC) access to GHR tests available
  • Opportunities for  detection of additional genetic conditions and diseases

GHR Testing has its own risks

  • Incorrect or misleading information leading to health choices without medical advice
  • Adaptive regulatory framework for unique  challenges of new technology
  • Balance efficient pathway to customer access without sacrificing FDA oversight

Flexible approach for regulating novel medical advances such as GHR

  • Lessons learned from authorization of  first DTC GHR and carrier screening tests (23andMe)
  • GHR tests to be exempted from premarket review under certain conditions
  • Manufacturers would have to come to FDA for a one-time review; no furtjer review of new tests
  • Established special controls  in a separate de novo classification order

READ23andMe label

Capture.JPGFDA statement on new steps to improve FDA review of shared Risk Evaluation and Mitigation Strategies to improve generic drug access

Risk Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of the drug outweigh the risks

  • Medication Guide or patient package insert
  • Communication plan
  • “Elements to Ensure Safe Use” (ETASU) e.g. prescriber training, patient counseling

Use of shared REMS to prevent use as a tool to block generic competition

  • Encourage use of shared system between innovator and generic companies
  • Reduce  likelihood for branded drug companies to use existing REMS to slow generic competition
  • Streamline submission and review process for shared system REMS
  • Use of a single Drug Master File (DMF) for shared system REMS submissions


Leveraging Health Literacy and Patient Preferences to Reduce Hypoglycemia Events in Patients with Type 2 Diabetes

CDERLearn: Health Literacy and Patient Preferences to Reduce Hypoglycemia Events in Patients with Type 2 Diabetes

  • Free one-hour Continuing Education (CE) course for healthcare providers (physicians, pharmacists, nurses, and others)
  • Describe the prevalence of hypoglycemic events among patients with type 2 diabetes mellitus and risk factors leading to an event
  • Introduce methods of assessing health literacy and numeracy of patients and caregivers
  • Review effective ways to incorporate patient preferences into care plans and differentiate A1C target values for individuals
  • List the action steps to reduce the likelihood of a hypoglycemic event for a high-risk patient


Image credit: FDA, 23andMe, IACT


FDA BRIEF: Week of October 23 and October 30, 2017


Image of the device.

HEARTMATE 3™ Left Ventricular Assist System (LVAS)

Thoratec Corporation

INDICATION: Providing short-term hemodynamic support (e.g., bridge to transplant or bridge to myocardial recovery) in patients with advanced refractory left ventricular heart failure



  • HeartMate 3 left ventricular assist device (LVAD) and and external components
  • LVAD composed of implanted centrifugal blood pump, outflow graft with bend relief, apical cuff, and pump cable
  • LVAD connected via percutaneous cable (driveline) to microprocessor-based external System Controller
  • System Controller powered by either the Power Module (for hospital use) or the Mobile Power Unit that connects to the AC mains power, or by two batteries that the patient carries
  • System Controller performs all power handling and monitoring functions, including
    supplying power to the LVAD; communicating with the LVAD; storing system operating parameters; logging performance data; generating diagnostic information; producing visual and audible alarms; providing uninterrupted power to the LVAD during main power exchange; and displaying alarm messages, alarm history, and key operating parameters


  • Prospective, multicenter, randomized pivotal study comparing the HeartMate 3 LVAS with the HeartMate II LVAS; 1:1 randomization to either HeartMate 3 or HeartMate II.
  • At 6 months post implantation, 86% of patients in the HeartMate 3 arm achieved success in the composite primary endpoint as compared to 77% of patients in the HeartMate II arm demonstrating non-inferiority
  • Clinically significantly higher number of pump exchanges and urgent transplants in the HeartMate II arm (7.8%) as compared to the HeartMate 3 arm (0.7%)
  • Overall survival rate at 6-months post implantation was comparable between the HeartMate 3 (89%) and HeartMate II arms (87%)
  • Death (HeartMate 3: 11.3% vs. HeartMate II: 13.0%)
  • Major infection (37% vs. 30%)
  • Bleeding (30% vs. 37%)
  • Right heart failure (30% vs. 25%)
  • Cardiac arrhythmias (26% vs. 33%)
  • Respiratory failure (22% vs. 17%)
  • Renal dysfunction (11% vs. 9%)
  • Stroke (8% vs. 11%)
  • No suspected pump thrombosis events in the HeartMate 3 arm



Capture.JPGCALQUENCE (acalabrutinib) capsule

AstraZeneca Pharmaceuticals 

INDICATION: Treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy


  • MCL is a rare and fast-growing type of non-Hodgkin lymphoma; particularly aggressive cancer
  • New treatment option showing high rates of response for some patients


  • Priority Review, Breakthrough Therapy designation, Orphan Drug designation
  • Accelerated approval based on overall response rate; continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

MECHANISM OF ACTION:   Inhibitor of Bruton tyrosine kinase (BTK) leading to malignant B-cell proliferation and survival


  • Open-label, Phase 2 Study, n=124 patients with MCL who had received at least one prior therapy
  • Tumor responses assessed according to Lugano Classification for Non-Hodgkin’s lymphoma
  • Major efficacy outcome: Overall response rate (ORR) and the median follow-up was 15.2 months
  • 81% had complete or partial response (40 percent complete response, 41 percent partial response)


  • Serious side effects: Hemorrhage), infections, atrial fibrillation, additional cancers
  • Common side effects: Headache, diarrhea, bruising, fatigue, myalgia, anemia, thrombocytopenia, neutropenia


  • Limited distribution network via oncology pharmacy services
  • CALQUENCE Patient Savings Program to assist with out of pocket costs


(Photo: Business Wire)SOLIRIS (eculizumab) intravenous infusion


SUPPLEMENTAL INDICATION:  Treatment of adult patients with generalized Myasthenia Gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody positive


  • First new treatment in many years for MG; rare and chronic neuromuscular disorder
  • First monoclonal antibody approved for use in patients with MG


  • Risk Evaluation and Mitigation Strategy (REMS) requirements for serious and life-threatening meningococcal infections


  • 26-week randomized, double-blind, parallel-group, placebo controlled,
    multicenter trial, n=125, SOLIRIS vs. placebo
  • Primary efficacy endpoint: The primary efficacy endpoint change from baseline  in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score at Week 26
  • MG-ADL total scores:  -4.2 points in SOLIRIS vs.  -2.3 points in placebo (p=0.006)


  • Life-threatening and fatal meningococcal infections
  • Increased susceptibility to infections, especially with encapsulated bacteria
  • Frequently reported adverse events: Musculoskeletal pain


  • No public information for new indication


Image credit: Thoratec, Astra Zeneca, Alexion















































































































































































































FDA Approves New Indication for Soliris (Eculizumab) As Treatment for Myasthenia Gravis 
On October 23, 2017, FDA approved a new indication for Soliris (eculizumab),  Myasthenia Gravis who are anti-acetylcholine receptor antibody-positive. Soliris can lower the ability of the immune system to fight infections and therefore increases the chance of getting serious and life-threatening meningococcal infections. For more information, please read the medication guide, the Full Prescribing Label, or theapproval letter sent to the manufacturer.







PD-L1 IHC 22C3 pharmDx – P150013/S006

Image of PD-L1 IHC 22C3 pharmDx








Philips IntelliSite Pathology Solution (PIPS) DEN160056 Classification Order Decision Summary
MiSeqDx Universal Kit 1.0 DEN130042 Classification Order Decision Summary

FDA News and Views: Opioid Packaging, Device Cybersecurity, Global Manufacturing Inspections, Marijuana Warnings, Health Literacy

FDA BRIEF: Week of October 30, 2017


Statement from FDA Commissioner Scott Gottlieb, M.D., on new strategies for addressing the crisis of opioid addiction through innovation in packaging, storage and disposal

Steps to reduce the scope and human tragedy of opioid addiction epidemic

  • New ways to work more creatively with public and private partners
  • Reduce exposure to opioid drugs
  • Proposer prescriptions and duration of treatment

Packaging innovations

  • Packaged in a manner that limits the number of pills dispensed
  • Easier to track the number of doses that have been taken
  • Improve storage and encourage prompt disposal
  • Allow health care providers, pharmacists or family members to monitor patient use of prescription opioids

public workshop, Dec. 11-12, 2017, to advance this issue


Thumbnail image of fact sheet.FDA’s Role in Medical Device Cybersecurity

Breach potentially impacting safety and effectiveness of a medical device can threaten patient health

  • CDRH coordinated approach of vigilance, responsiveness, resilience, and recovery
  • Total product lifecycle approach- starting at the product design phase to planning how to reduce the likelihood of future risks
  • Encouraging medical device manufacturers to proactively update and patch devices in a safe and timely manner
  • Need to balance protecting patient safety and promoting the development of innovative technologies and improved device performance
  • Published guidances for manufacturers
  • Planning  to address cybersecurity risks is as essential to the device development process as coming up with a novel new product

prevalent myths concerning FDA


Capture.JPGFDA takes unprecedented step toward more efficient global pharmaceutical manufacturing inspections 

FDA will recognize eight EU drug regulatory authorities as capable of conducting inspections of manufacturing facilities that meet FDA requirements

  • Austria, Croatia, France, Italy, Malta, Spain, Sweden, UK
  • Implementation of US-EU Mutual Recognition Agreement
  • Will now rely on the inspectional data obtained by these eight regulatory agencies

EU Commission determined (6/17) that the FDA “has the capability, capacity and procedures in place to carry out GMP inspections at a level equivalent to the EU.”

  • Enables the FDA and the EU to avoid duplication of drug inspections
  • Allows regulators to devote resources to other high risk manufacturing facilities



FDA warns companies marketing unproven products, derived from marijuana, that claim to treat or cure cancer

Increasing concern with cannabidiol (CBD) products claiming to treat or cure cancer

  • Marketed in a variety of product types e.g. oil drops, capsules, syrups, teas
  • Not approved for any indication
  • Substances containing marijuana components treated like any other products making unproven claims to shrink cancer tumor

Warning letters to four companies for unsubstantiated claims

  • Greenroads Health
  • Natural Alchemist
  • That’s Natural! Marketing and Consulting
  • Stanley Brothers Social Enterprises LLC


Health Literacy: Getting the Info You Need

Health literacy is the ability to get and understand information on health issues and medical services so that patients you can make informed decisions 

  • ~ 12%  US adults have skills to manage health and prevent disease
  • Difficult to improve their health

FDA Promotes Health Literacy

  • Plain language for clear communications
  • Patient package inserts,  instructions for use, and Medication Guides
  •  Drug Safety Communications
  •  Recalls and Withdrawals
  • Free online resources
  • FDA Patient Network
  •  FDA Consumer Updates


Image credits: FDA, EMA



FDA News and Views: Opioid Public Health Emergency, Biosimilars, Medical Device Innovation, Medical Device Development Tool, Drug-Drug Interactions

FDA BRIEF: Week of October 23, 2017


Statement from FDA Commissioner Scott Gottlieb, M.D., on the Trump Administration’s important efforts to address the opioid crisis

Epidemic of opioid addiction – new declaration of a public health emergency

  • Aggressive steps to prevent new addictions and opioid-related deaths; help currently addicted regain control
  • Reframing pre- and post-market benefits and risks of opioids
  • Promoting development of abuse-deterrent opioids and non-opioids
  • Increase use of and access to antidote naloxone
  • Safe adoption of FDA-approved medically-assisted treatments
  • Working with federal and international partners to stop the flow of heroin, fentanyl
  • Break stigma associated with addiction and the use of sobriety medications


Biosimilars Education Campaign

Biosimilars are Potentially Cost-Saving Options

Biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product

  • May offer more affordable treatment options to patients.
  • Abbreviated approval pathway that does not lower approval standards
  • Evaluation does not include determination of interchangeability; substitution dependent on state pharmacy law

Several approved biosimilars (reference product)

  • Zarxio (Filgrastim-sndz)
  •  Inflectra (Infliximab-dyyb)
  •  Erelzi (Etanercept-szzs)
  •  Amjevita (Adalimumab -atta)
  •  Renflexis (Infliximab-abda)
  • Cyltezo (Adalimumab-adbm)
  •  Mvasi (Bevacizumab-awwb)

FDA has developed educational materials   for health care providers


Capture.JPGStatement from FDA Commissioner Scott Gottlieb, M.D., on new steps to advance medical device innovation and help patients gain faster access to beneficial technologies

Medical Innovation Access Plan to keep pace with quickly evolving medical technology

  • First qualification of a Medical Device Development Tool (MDDT) to provide objective platform for developing devices in cardiovascular health
  • Breakthrough Devices Program for quicker access to devices that diagnose or treat life-threatening or irreversibly debilitating diseases
  • Guidances on when to submit new 510(k) prior to making a change to a legally-marketed device or software – to enhance predictability and consistency for innovators


Medical Device Development Tools imageMedical Device Development Tools: Helping to Speed Medical Device Evaluation and Approval

FDA’s voluntary Medical Device Development Tools (MDDT) program can “qualify” tools for use in medical device development

  • Tool can be used to provide more efficient and accurate ways to measure risk/ benefit as part of the medical product development process
  • Lead to more efficient and robust development, e.g. minimizing animal use,  reducing testing duration or sample sizes, optimizing patient selection
  • Three categories: Clinical Outcome Assessment, Biomarker Test, Nonclinical Assessment Mode
  • Offers developers opportunities to discuss early concepts of tool development, foster collaboration, increase potential that tools will be used and adopted

First MDDT Tool qualified – 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ)

  • Clinical Outcome Assessment- measures patient-reported outcomes from patients with congestive heart failure or weakened heart muscle due to prior heart attacks, heart valve problems, viral infections, or other causes
  • Can be used in clinical trials by medical device industry to support both device submissions and post-approval studies

MDDT Webpage


Zineh_Issam_Drug_InteractionsCDER Conversation: Evaluating the Risk of Drug-Drug Interactions

What is a drug-drug interaction? 

  • Occurs when co-administration of two or more drugs alters absorption, distribution, metabolism, elimination
  • Can decrease or increase the action of either drug or both drugs, cause adverse effects, unintended consequences
  • Certain foods, vitamins and supplements can also interact

Risk for drug-drug interactions? Anyone – older population  at higher risk

Why important to assess drug-drug interactions? Risk-benefit balance can be altered

How many people are taking more than one drug? About 20% U.S. adults take three or more drugs

When and how to evaluate drug-drug interactions? 

  • In vitro studies to assess the investigational drug’s metabolism pathways
  • Clinical drug interaction studies completed before phase 3 clinical studies
  • Some drug interaction data may be collected after drug approval – for Breakthrough drugs

Drugs pulled from the market due to drug-drug interactions? terfenadine, asteminzole, cisapride, cerivastatin, mibefradil

FDA communication of drug-drug interactions? Drug labels, drug safety communications, Clinical Pharmacology Corner

New draft guidances. Federal Register Notice


Image credits: FDA



Drug and Device Approvals: YESCARTA, IMPELLA RP

Week of October 16, 2017


YESCARTA™ (axicabtagene ciloleucel) suspension for intravenous infusion

Kite Pharma, Inc. (Gilead company)

INDICATION: Treatment of 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, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitation of Use: Not indicated for the treatment of patients with primary central nervous system lymphoma


  • DLBCL most common type of NHL in adults;  72,000 new cases of NHL diagnosed in the U.S. each year, and DLBCL represents approximately one in three cases
  • Milestone in the development of a whole new scientific paradigm for the treatment of serious diseases
  • Second gene therapy approved by the FDA; first for certain types of non-Hodgkin lymphoma (NHL)


  • Orphan Drug Designation; no pediatric requirements
  • Postmarketing requirements: Assessment of long-term safety
  • REMS requirements:  Elements to assure safe use, implementation system
    and timetable for submission of REMS assessments

MECHANISM OF ACTION: CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells. Studies demonstrated that following anti-CD19 CAR T cell engagement with CD19-expressing target cells leads to sequence of events killing of CD19-expressing cells

ADMINISTRATION: Each dose is a customized treatment created using a patient’s own immune system to help fight the lymphoma. The patient’s T-cells, a type of white blood cell, are collected and genetically modified to include a new gene that targets and kills the lymphoma cells. Once the cells are modified, they are infused back into the patient


  • Single-arm, open-label, multicenter trial, n=100 patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma, single infusion of YESCARTA
  • Efficacy: Complete remission (CR) rate, duration of response (DOR)
  • CR= 52 patients, median DOR= 9.2 months


  • Boxed Warning: Cytokine release syndrome (CRS) and neurologic toxicities that can be fatal or life-threatening
  • Other side effects: Serious infections, low blood cell counts, weakened immune system. Side effects from treatment with Yescarta usually appear within the first one to two weeks
  • REMS : Certification of  hospitals and their associated clinics to recognize and manage CRS and nervous system toxicities


  • Available only in authorized treatment centers
  • Ongoing and active discussions with payers
  • Pricing based on discussions with government agencies that reimburse for drug costs and private insurers, and cancer centers.





INDICATION FOR USE: Providing temporary right ventricular support for up to 14 days in patients with a body surface area ≥1.5 m2, who develop acute right heart failure or decompensation following left ventricular assist device implantation, myocardial infarction, heart transplant, or open-heart surgery

ADDRESSING UNMET NEED: Smallest heart pump for right heart failure


  • Regulation Number: 870.4360
  • Product Code: PYX
  • Postmarketing requirement: Real-world evidence on safety and effectiveness

DESCRIPTION: Comprised of three components

  • Impella RP Catheter: a 22 Fr micro-axial flow pump catheter and its accessories
  • Automatic Impella Controller (AIC): a reusable external drive console
  • Impella Purge Cassette: an infusion pump used to flush the Impella RP Catheter


  • Pooled from the following three (3) datasets: Impella RP System pivotal study: 30 patients, Impella RP System continued access protocol (CAP) study: 4 patients,  Impella RP System post-approval study (PAS): 26 patients
  • Use of System to provide percutaneous hemodynamic support for right heart failure: Survival rate of 73.3% at 30 days
  • Main adverse events:  Major bleeding and hemolysis, no pulmonary embolism


  • Hospital ICD-10 procedure code specific to percutaneous heart assist
  • Separate physician payment for insertion, repositioning, and removal (CPT)
  • Coverage by Medicare and major payers


Image Credits: Kite, Abiomed



FDA News and Views: Patient Engagement in Clinical Trials, PEAC Summary, Real-World Evidence, Device Manufacturing in Puerto Rico

FDA BRIEF: Week of October 16, 2017


Clinical Trials & Medical Devices

Safe & effective medical device use increasingly depends on effective patient engagement

  • More involved in shared decision-making and disease management
  • Increasingly use devices at home
  • Communicate and connect to share information with other “real-world patients”

2016-2017 CDRH Strategic Priority: Partner with patients

  • Promote a culture of meaningful patient engagement by facilitating CDRH interaction with patients
  • Increase use and transparency of patient input as evidence in our decision-making

Culture of Patient Engagement



Patient Engagement Advisory Committee (PEAC) Summary

The FDA Patient Engagement Advisory Committeemet on October 11-12, 2017

  • To discuss patient input into medical device clinical trials
  • Discussions included topics such as patient involvement in clinical trial design; patient recruitment, enrollment and retention; communication of study results to trial participants

The future topics

  • Postmarket processes for medical devices
  • Data privacy and cybersecurity
  • Patient Reported Outcomes
  • Digital health and mental health

meeting materials



Real-World Data (RWD) : Data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources

Real-World Evidence (RWE) : Clinical evidence regarding the usage and potential
benefits or risks of a medical product derived from analysis of RWD

FDA Final RWE Guidance describes:

  • Generation and collection of RWD
  • Analysis of RWD
  • When results might be considered valid scientific evidence
  • Data Quality – Relevance and Reliability


Hurricanes Irma and JoseStatement by FDA Commissioner Scott Gottlieb, M.D. on medical device manufacturing recovery in Puerto Rico

More than 50 medical device manufacturing plants in Puerto Rico, employing about 18,000 people.

  • Manufacture more than 1,000 different kinds of medical devices
  • Simple but essential products like surgical instruments and dental products as well as highly complex devices such as cardiac pacemakers and insulin pumps

FDA monitoring 50 types of medical devices critically important to patient care

  • Working closely with manufacturers to prevent product shortages
  • Addressing  obstacles specific to unique product production requirements
  • Addressing challenges in securing components critical to device development.
  • Focus on blood-related medical devices


Image credits: FDA




ZILRETTA (triamcinolone acetonide extended-release injectable
suspension), for intra-articular use

Flexion Therapeutics, Inc.

INDICATION: For the management of osteoarthritis pain of the knee.
Limitation of Use: Not intended for repeat administration

ADDRESSING UNMET NEED: Non-opioid therapy for pain


MECHANISM OF ACTION: Corticosteroid with anti-inflammatory and immunomodulating properties; activates glucocorticoid receptor, leading to activation of anti-inflammatory transcription factors


  • Multi-center, international, randomized, double-blind, parallel-arm, placebo- and active-controlled  (immediate release formulation) study in patients (n=484)  with osteoarthritis pain of knee, followup for 24 weeks
  • Primary efficacy endpoint:  Average Daily Pain intensity scores (ADP) as assessed by a 0-10 Numeric Rating Scale
  • Statistically significant reduction in pain intensity vs. placebo
  • Statistical significance not demonstrated vs. immediate-release formulation


  • Serious adverse events: Neurologic adverse reactions with epidural and intrathecal administration, joint infection and damage, increased risk of infections, alterations in endocrine function, cardiovascular effects, renal effects, increased intraocular pressure, gastrointestinal perforation, alternations in bone density, behavioral and mood disturbances



SENHANCE Surgical Robotic System

TransEnterix Surgical Inc

USE: Intended to assist in the accurate control of laparoscopic instruments for visualization and endoscopic manipulation of tissue including grasping, cutting, blunt and sharp dissection, approximation, ligation, electrocautery, suturing, mobilization and retraction in laparoscopic colorectal surgery and laparoscopic gynecological surgery. The system is for use on adult patients by trained physicians in an operating room environment


  • New robotically-assisted surgical device (RASD) for minimally invasive surgery
  • Minimally invasive surgery helps reduce pain, scarring and recovery time
  • RASD technology enhances surgeon’s access and visualization within confined operative sites


  • Predicate Device: da Vinci Si IS3000 device for gynecological and colorectal procedures
  • Device Classification Name:  System,Surgical,Computer Controlled Instrument
  • Regulation Description: Endoscope and Accessories
  • Regulatory Class: Class II
  • Classification Product Code: NAY, GCJ
  • Regulation Number: 876.1500


  • Type of computer-assisted surgical system
  • Provides surgeons with console unit that provides a 3-D high-definition view of  surgical field
  • Allows control of three separate robotic arms remotely
  • End of each arm equipped with surgical instruments based on traditional laparoscopic instrument designs
  • Unique technological characteristics
    • Force feedback: Helps surgeon “feel” stiffness of tissue being grasped
    • Eye-tracking: To control movement of surgical tools and laparoscopic-type
  • Not a robot because it cannot perform surgery without direct human control


  • Use of Real-World Evidence (RWE) 
    • Clinical study, n=150 patients undergoing various gynecological operations
    • Outcomes compared to RWE from 8,000 gynecological operations described in eight peer-reviewed publications using another RASD
  • Operative Results in Real-World Setting
    • Clinical study, n=45 patients undergoing colorectal procedures
    • Outcomes compared to RWE from peer-reviewed research publications
  • Performance testing
    • Simulated use and worst-case scenario conditions vs Predicate Device


Siemens Medical Solutions Inc.

INDICATION FOR USE: As a magnetic resonance diagnostic device (MRDD) that produces transverse, sagittal, coronal, and oblique cross-sectional images and that displays the internal structure and/or function of head and extremities. Other physical parameters derived from the images may also be produced. These images and physical parameters derived from the images when interpreted by a trained physician yield information that may assist in diagnosis. Intended for patients > 30 kg (66 lbs)


  • First seven tesla (7T) MRI device, more than doubling the static magnetic field strength available for use in the US (Average 3T)
  • Improved image quality, better visualization of smaller structures and subtle pathologies that may improve disease diagnosis


  • Regulation Name: Magnetic Resonance Diagnostic Device
  • Regulatory Class: Class II
  • Product Code: LNH, LNI, MOS
  • Regulation Number: 21 CFR 892.1000


  • Comparative study, n=35 healthy patients, images using 7T device vs. 3T device
  • Board-certified radiologists confirmation that 7T images were of diagnostic quality and potentially improvement over 3T
  • Safety of  subsystem through computational modeling, simulations and rigorous experimental validation

Image credits: Flexion, TransEnterix, Siemens



Guidance: ANDA vs 505b(2) Pathway


Determining Whether to Submit an ANDA or a 505(b)(2) Application

Criteria, Considerations and Directions to applicants regarding abbreviated approval pathways, section 505(j) and 505(b)(2)

  • 505(b)(2) application: NDA with safety and effectiveness reports, with at least some information from studies not conducted by/for applicant and applicant has not obtained right of reference/use
  • 505(j) ANDA application: Duplicate of a previously approved drug product ( reference listed drug-RLD), with no safety and effectiveness reports,  have same active ingredient(s), conditions of use, route of administration, dosage form, strength, labeling and bioequivalent to RLD
  • Petitioned ANDA:  Drug product that differs from RLD in  dosage form, route of administration, strength, or active ingredient, with a suitability petition to not provide safety and effectiveness reports

Regulatory Considerations for ANDAs and 505(b)(2) Applications

  • Duplicates
  • Petitioned ANDAs
  • Bundling

Scientific Considerations for ANDAs and 505(b)(2) Applications

  • Limited Confirmatory Studies
  • Active Ingredient Sameness Evaluation
  • Intentional Differences Between the Proposed Drug Product and the RLD



FDA News and Views: Puerto Rico, Patient Representative Program, Patient Engagement, Opioid Abuse Deterrent Formulations

FDA BRIEF: Week of October 9, 2017

Hurricanes Irma and Jose

FDA’s continued assistance following the natural disaster in Puerto Rico

Pharmaceutical products and medical devices manufactured in Puerto Rico contribute substantially to medical products consumed by Americans

  • Facility closings and potential for shortages

FDA maintaining close watch on the most critical medical products

  • List of products for which shortage could have substantial impact on public health
  • Daily communication with the companies to stay on top of evolving challenges
  • Act quickly to prevent drug and device shortages
  • Help firms secure fuel to maintain production lines
  • Get clearance to move logistical support


FDA Patient Representative Program

Patient Representative Program is managed by the Office of Health and Constituent Affairs within Office of the Commissioner

  • Coordinates recruitment, training, and retention for over 200 FDA Patient Representatives, who are patients or primary caregivers to patients

Recruit Patient Representatives on an as-needed basis to 

  • Help advise us drugs, devices, and biologics being considered for approval
  • Early input in regulatory medical product development and review process

Looking for Patients or caregivers with advocacy experience who have been diagnosed or experience with

  • gastric cancer, hepatocellular carcinoma, retinitis pigmentosa, type II diabetes,  renal cell carcinoma,  bladder cancer,  male hypogonadism,  ALS (amyotrophic lateral sclerosis),  phenylketonuria, sarcoma, cochlear implants,  female hyposexual desire disorder,  retinal implants, naloxone use,  childhood cerebral adrenoleukodystrophy, neuroendocrine tumors,  glaucoma, metastatic melanoma,   merkel cell carcinoma,  keratoconus



Statement by FDA Commissioner Scott Gottlieb, M.D. on new steps by FDA to advance patient engagement in the agency’s regulatory work

First meeting of Patient Engagement Advisory Committee, PEAC, held on October 11th

  • Comprised solely of patients, care-partners, and those who represent their needs
  • Founded by CDRH to keep patients at the center of their work

Encourage inclusion of patient perspectives across the total medical device life cycle

  • Across device design and ideation, clinical trial process, postmarket evaluation
  • Inclusion in PMAs, HDE applications, de novo requests, and device labeling
  • Patient risk tolerance and benefit perspectives part of benefit-risk assessment

Integrate real world evidence into regulatory decision making process

  • Leveraging information in electronic health records, insurance claims databases, registries
  • Interactions with these patient-led registries
  • Use of smartphone platforms for collection of  real-world health information

Parameters for rigorous, systematically gathered patient preference information

  • Coordination of certain agency-wide and multi-center projects related to patient engagement
  • Facilitate cross-center policy making
  •  Facilitate development and use of patient-focused methods in regulatory activities
  • Develop and elevate common standards for how to integrate patient voice


CaptureMeasuring the Impact of Opioid Analgesic Formulations with Properties Designed to Deter Abuse in the Real World

Opioid formulation with “properties designed to deter abuse”

  • specifically formulated to make manipulation for abuse by specific routes, such as intranasal (snorting) or injection more difficult or less rewarding

Testing and approval of abuse deterrent formulations (ADF)

  • Category 1-3 studies to compare new product to an already approved product
  • Labeling based on these data

Challenges associated with ADF evaluation

  • Post-marketing requirements to evaluate whether product actually decreases abuse and related adverse outcomes in the real world
  • Challenges because existing data sources have substantial limitations

July 2017 workshop

  • Best practices in evaluating the real-world effectiveness of ADFs
  • Need for innovative and creative collaborations to address opioid crisis


Image credits: FDA


FDA News and Views: Cybersecurity Month, Expanded Access, Rare Disease Grants, Mammography Compliance, Priority Review Vouchers, Opioid Policy Steering Committee, Complex Generic Drug Development

FDA BRIEF: Week of October 2, 2017

National CyberSecurity Awareness Month

Medical devices increasingly interconnected through wired and wireless connections
  • more vulnerable to cybersecurity threats
  • could potentially impact patient safety
FDA works with industry to identify cybersecurity issues to consider in design and development of medical device
  • Shared responsibility including: medical device manufacturers, government agencies, health care organizations, health care professionals, cybersecurity researchers, and medical device users
  • FDA works with several public and private organizations to raise awareness of medical device safety and cybersecurity


Expanded Access: FDA Describes Efforts to Ease Application Process

Expanded access (Compassionate Use) programs that provide investigational drugs and devices to patients with serious conditions

  • FDA authorizes 99% of applications; simplified via Form FDA 3926
  • Time is critical for seriously ill patients who do not have  alternative therapies

Lifting another potential burden for applications

  • Simplification of IRB process
  • Just one IRB member can now approve the treatment

Addressing uncertainty about assessment of  adverse event data from expanded access

  • Recognize patients outside of controlled clinical trial setting; with more advanced disease, be receiving other drugs and have other diseases
  • Guidance clarifies that suspected adverse reactions must be reported “only if there is  causal relationship”

Other activities

  • Addressing issues raised by Government Accountability Office (GAO) on adverse event data
  • New online tool called the Expanded Access Navigator
  • Working with the Reagan-Udall Foundation to include FDA’s Rare Disease Program



FDA Rare Disease Grants: For clinical trials, For Natural History Studies


Awarded 15 new clinical trial research grants totaling more than $22 million

  • Through the Orphan Products Clinical Trials Grants Program ( creation in 1983) funded by Congressional appropriations
  • To boost development of products for patients with rare diseases
  • Awarded to principal investigators from academia and industry
  • A total of 76 grant applications received; funding rate of 20%

Grants awarded for

  • Rare forms of cancer: glioblastoma, anaplastic astrocytoma, pediatric neuroblastoma
  • Hyperphagia in Prader-Willi syndrome, idiopathic osteoporosis in premenopausal women, sickle cell disease, pulmonary tuberculosis (TB), including multidrug-resistant TB



Awarded 6 grants for natural history studies in rare diseases totaling $6.3 million 

  • First time to fund through Orphan Products Grants Program for natural history studies
  • Inform medical product development by better understanding diseases progression
  • More than 80 grant applications reviewed by more than 60 rare disease and natural history experts

Grants awarded for

  • Friedreich’s ataxia, pregnancy and lactation-associated osteoporosis, sarcoidosis, chronic kidney disease, Angelman syndrome, Myotonic Dystrophy Type 1

Photos of Mammography devices

Good News for Public Health: Most Mammography Facilities are in Full Compliance with MQSA Regulations

Mammography Quality Standards Act (MQSA) established in 1992

  • Facilities must meet specific standards and abide by FDA regulations
  • Services must be accredited by FDA- approved accrediting body
  • Facility must hold an active MQSA certificate

> 87% of mammography facilities have no MQSA violations

  • 8,700 MQSA certified mammography facilities, perform > 39 million mammograms/year, using ~ 18,000 mammography units
  • MQSA inspection includes performance, quality assurance records, quality control testing, personnel qualifications, medical records, and medical audit and outcome analysis records
  • Certified MQSA inspectors have performed > 175,000 MQSA inspections

Laptop, gavel and stethoscope, representing medical product-related legislation

Priority Review Vouchers 

Priority Review Vouchers (PRVs) can be used to obtain priority review designation for a subsequent application that does not itself qualify for priority review 

  • May be transferred (including by sale) the entitlement;  no limit on the number of transfers
  • Application for drug/biological product must contain no previously approved active ingredient (including salt/ester)

Tropical Disease PRV: Application for the prevention or treatment of a “tropical disease”

Rare Pediatric Disease PRV: Application for “rare pediatric disease”  that is serious or life-threatening,  affecting individuals aged from birth to 18 years, including age groups often called neonates, infants, children, and adolescents

Medical Countermeasure PRV:  Application intended to prevent or treat harm from a biological, chemical, radiological, or nuclear agent


 Opioid Policy Steering Committee

Opioid Policy Steering Committee (OPSC) proposed

  • To address opioid addiction and the resulting overdoses and deaths
  • FDA seeking public input on how use of its authorities to address crisis

Seeking public input on 3 key areas

  • What more can FDA do to ensure that the full range of available
    information, including about possible public health effects, is considered
    when making opioid-related regulatory decisions
  • What steps can FDA take with respect to dispensing and packaging
    to facilitate consistency of and promote appropriate prescribing practice
  • Should FDA require some form of mandatory education for health care professionals who prescribe opioid drug products, and if so, how should such a system be implemented


Image of a hand reaching for a pill bottle in a medicine cabinet

Reducing the Hurdles for Complex Generic Drug Development

Drug Competition Action Plan to advance new policies aimed at bringing more competition to the drug market

  • Improve the efficiency of the generic drug approval process
  • Closing loopholes that allow branded drug companies to game FDA rules to forestall generic competition
  • Facilitate generic competition to complex drugs

Complex drugs

  • Such as metered dose inhalers used to treat asthma, injectable drugs
  • Have feature(s) difficult to “genericize”
  • Have lost exclusivity, but have no generic competition
  • Can be a high-value opportunity for a generic drug maker

Provide scientific and regulatory clarity with respect to complex generic drugs

  • Adopt more rigorous and sophisticated science, including sophisticated quantitative methods and computational modeling, in drug development, evaluation, and review
  • Draft guidance on pre-ANDA meeting requests to discuss regulatory strategy
  • Draft guidance  on ANDAs for peptides manufactured using recombinant DNA technology such as namely, glucagon, liraglutide, nesiritide, teriparatide, teduglutide

Other Initiatives

  • Address challenges with bioequivalence testing
  • Identify gaps in the science and develop more tools, methods, and efficient alternatives to clinical endpoint testing
  • Workshops on  quantitative modeling approaches,  new analytical tools  for  demonstrating active ingredient sameness in complex products


Image credits: FDA

Device Approvals: COBAS ZIKA, REMEDE

FDA BRIEF: Week of October 2, 2017



Roche Molecular Systems, Inc.

INTENDED USE: Qualitative in vitro nucleic acid screening test for the direct detection of Zika virus RNA in human plasma. Intended for use to screen donor samples for Zika virus RNA in plasma samples from individual human donors, including donors of whole blood and blood components, and other living donors.

Also intended for use to screen organ and tissue donors when donor samples are obtained while the donor’s heart is still beating. Plasma from all donors should be screened as individual samples.

Not intended for use as an aid in diagnosis of Zika virus infection, on samples of other body fluids, on samples of cord blood.


  •  First approval of a Zika virus detection test for use with screening the nation’s  blood supply
  • Critical to preventing infected donations from entering the U.S. blood supply


  • Collaboration between FDA, manufacturer and blood collection industry
    • 2016 FDA guidance recommending screening whole blood and components with cobas Zika test available under IND
    • Several blood collection establishments used test providing data
    • Additional studies by manufacturer to demonstrate effectiveness


  • Fully automated sample preparation (nucleic acid extraction and purification) followed by PCR amplification and detection
  • For use on the fully automated cobas 6800 and cobas 8800 systems
  • Systems consist of the sample supply module, the transfer module, the processing module, and the analytic module
  • Automated data management is performed by software which assigns test results for all tests as non-reactive, reactive, or invalid
  • Results reviewed directly on system screen and printed as report


  • Reproducibility: Testing twelve member panel of three negative plasma samples and three positive;  reproducible performance across variables assessed for detecting Zika
  • Specificity: Testing individual samples from blood donations (n= 358,038 ) at five external laboratories;  clinical specificity was 99.997%
  • Sensitivity: Using 25 confirmed Zika-positive clinical samples at an internal testing site; detected 100%


the-remede-system-productRemedē System

Respicardia Inc.

USE:  Implantable stimulation device designed to improve cardiovascular health by  restoring natural breathing at night.

Includes wires for sensing and stimulation, a neurostimulation device, and a portable tablet programmer.

Designed to replace inappropriate signal from the brain that delivers electrical pulses at night, during sleep, to restore a more normal breathing pattern and improve  cardiovascular health in patients with Central Sleep Apnea


  • Central sleep apnea can lead to poor sleep quality and may result in increased risk for high blood pressure, heart attack, heart failure, stroke, obesity, and diabetes
  • Implantable device offers patients another treatment option for central sleep apnea



  • Battery pack surgically placed under the skin in the upper chest area
  • Small, thin wires inserted into blood vessels in chest near phrenic nerve that stimulates breathing
  • System monitors patient’s respiratory signals during sleep, delivers a small electrical stimulus to phrenic to move diaphragm and restore normal breathing
  • Has 2 modes – generate pulses at a fixed rate (asynchronous therapy) or deliver a pulse only when it detects a pause in breathing (synchronous therapy)
  • Physician sets stimulator to deliver most appropriate therapy
  • Has safeguards to make sure that therapy is only delivered during sleep


  • Study on 141 patients to assess reduction in apnea hypopnea index (AHI), a measure of the frequency and severity of apnea episodes, after 6 months
  • Reduced by 50%  or more in 51% patients vs. 11% reduction with in patients without the system
  • Most common adverse events: Concomitant device interaction, implant site infection, swelling and local tissue damage or pocket erosion

Image credits: Roche, Respicardia


Compounding Risk Alert

Compounding Risk Alert

To alert health care professionals of adverse event reports related to compounded drugs

  • Protect patients from unsafe, ineffective, and poor quality compounded drugs

Recent posts

  • Hemorrhagic Occlusive Retinal Vasculitis (HORV) Following Intraocular Injections of a Compounded Triamcinolone, Moxifloxacin, and Vancomycin Formulation
  • Adverse Events associated with Guardian’s compounded triamcinolone and moxifloxacin product for intravitreal injection
  • Two serious adverse events associated with ImprimisRx’s compounded curcumin emulsion product for injection


Image credit: FDA

FDA Guidances: IRB Minutes, REMS Counseling, Emerging Technology Submissions, Drug vs Device Classification, De Novo and MDUFA IV, Organ Preservation Devices

fda guidances


Minutes of Institutional Review Board (IRB) Meetings

IRBs have been cited in Office for Human Research Protections and  FDA Warning Letters for failing to prepare and maintain adequate minutes

  • Minutes are missing
  • Minutes reflect an inaccurate account of meeting attendance
  • Minutes lack sufficient detail to show vote on actions
  • Minutes are incomplete and only describe voting actions as “passed unanimously.”
  • Minutes do not clearly indicate IRB approvals
  • Minutes fail to include  discussion of controverted issues

Minutes need to include:

  • Attendance
  • Actions taken
  • Vote on Actions-for, against, abstaining
  • Requiring changes or disapproving research
  • Controverted issues and resolution



A Framework for Benefit-Risk Counseling to Patients About Drugs with a REMS

Additional risk management steps are required for certain prescription drugs with serious risks, to ensure that the benefits outweigh the risks

  • Part of Risk Evaluation and Mitigation Strategy – REMS
  • Additional steps include  risk communications, patient‒provider agreements, patient counseling tools
  • Warrant higher level of understanding of risks, greater degree of vigilance, activities to ensure benefits outweigh risks
  • Require individualized and collaborative counseling approach

Proposed 4-E Framework 

  1.  Evaluate (and continuously re-evaluate): Individualized health profile, treatment goals, and counseling needs
  2. Educate: Treatment needs and options, potential risks and benefits, importance of  adhering to REMS
  3. Engage: Patient participation in health care decisions and ensuring safe drug use
  4. Ensure: Patient counseling on key risk information and mitigation



Emerging Technology Program : Submission of chemistry, manufacturing, and controls (CMC) information containing emerging technology to FDA

  • Support and enable pharmaceutical innovation and modernization
  • Support flexible approaches  to advance product design, modernize pharmaceutical manufacturing, improve quality
  • Adopt innovative approaches by leveraging existing FDA resources to facilitate  regulatory assessment of novel technology submissions

Discussion of Scope and Process




Classification of Products as Drugs and Devices & Additional Product Classification Issues

To address Requests for Designation (RFDs)  whether a product should be classified as either a drug or a device

  • RFD guidance on obtaining formal determination of product’s classification
  • FDA’s decision-making process for classification determinations

Statutory Definitions

  • Drug
  • Device

Key provisions of Device definition

  • “Similar or related article”
  • “Primary intended purposes”
  • “Chemical action”
  • “Within or on the body”
  • Illustrative Examples



FDA and Industry Actions on De Novo Classification Requests: Effect on FDA Review Clock and Goals

MDUFA IV authorizes user fees for De Novo classification requests

  • Additional funds  to improve the device review process
  • Meet certain performance goals
  • Implement improvements for device review process

FDA Actions 

  •  Issue an Order Granting the Request to Classify the Device
  • Issue an Order Declining the Request
  • Request Additional Information (AI)
  • Issue a Notice of Withdrawal

De Novo Performance Goals for MDUFA IV

  • Submission
  • FDA Review
  • MDUFA IV Goals
  • Missed MDUFA Decision Communication

Requester Actions 

  • Response to an AI Request
  • Request for Withdrawal of the De Novo Request





Shortage of organs available for transplants has propelled innovation in organ preservation technologies

  • Best practices for utilizing animal studies for the evaluation of organ preservation devices
  • To support IDE, PMA, HDE, 510(k), De Novo applications/requests

Overview and General Study Design Considerations

  • Procedure Duration
  • Contamination
  • Transportability

Reperfusion Models

  • Ex Vivo Models
  • In Vivo Models

Sample Panel of Biomarkers in Liver

  • Liver Injury Biomarkers
  • Liver Function Biomarkers


Image credit: FDA



FDA BRIEF: Week of September 25, 2017

PENTAX ED34-i10T Duodenoscope 


INTENDED USE: Provide visualization and access to the upper gastrointestinal (GI) tract to treat bile duct disorders and other upper GI problems.


  • First duodenoscope with a disposable distal cap, a new feature that will improve access for cleaning and reprocessing
  • Lowering the risk of future infections associated with these devices


  • Regulation Name: 876.1500
  • Classification Code: FDA
  • Classification Name: Duodenoscope And Accessories, Flexible/Rigid


  • Lightweight, ergonomically-designed control body to minimize hand fatigue during prolonged procedures
  • Redesigned elevator improves device control
  • New detachable distal-end cap may improve reprocessing efficiency
  • HD+ imaging for enhanced visualization of mucosal detail to help improve accuracy during mucosal assessment
  • Combined with i-scan image enhancement, clearly visualizes the mucosa in fine detail and may help physicians locate minor papillae
  • Redesigned to improve stability for better device control, which may facilitate cannulation
  • Newly designed distal end with detachable cap to provide improved access for cleaning and reprocessing post-procedure

FreeStyle Libre Flash Glucose Monitoring System

Abbott Diabetes Care Inc.

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.


  • New technology  to help care of people living with chronic conditions, such as diabetes, easier and more manageable
  • System allows diabetics avoid additional step of fingerstick calibration—with a wave of the mobile reader


  • Generic Name: Sensor, glucose, invasive, non-adjunctive, factory-calibrated,
  • Procode: PZE
  • Post Approval Study (PAS) required for confirmatory evaluation of safety and effectiveness in intended use population


  • Uses an electrochemical sensor to monitor glucose levels in interstitial fluid (ISF)
  • Sensor held in place by an adhesive and incorporates both subcutaneously implanted sensor and associated electronics\
  • Sensor uses glucose oxidase enzyme to oxidize glucose and transfer electrons to a metal electrode, producing a current
  • Strength of current is proportional to the amount of glucose present in the subcutaneous space.
  • System converts electrical current signal to a glucose value for display to the user on a handheld Reader
  • 3 primary components: Sensor, Sensor Insertion Device, Reader


  • Primary effectiveness measurements based on performance evaluation of the System compared to the blood glucose values measured by a laboratory glucose analyzer during in-clinic sessions that spanned the wear period of the device (days 1, 4, 7 and 10)
  • Accuracy established across claimed measuring range (40 to 500 mg/dL glucose), precision, 10 day wear period (following the warm-up period) for sensor,  notifications (Glucose Messages), and number of readings displayed during wear period
  • Risks: Hypoglycemia or hyperglycemia for inaccurate readings and treatment decisions, mild skin irritations


  • Coverage limited to patients for whom professional CGM is medically necessary
  • Medicare does not have National Coverage Determination for professional CGM
  • Most local contractors do not have a policy limiting professional CGM


SOFIA 2 Fluorescent Immunoassay Analyzer


INTENDED USE: Bench top analyzer intended to be used with Cassette-based  Immunofluorescent in vitro diagnostic assays for professional and laboratory use

  • Measurand (analyte): Respiratory Syncytial Virus (RSV) A and B nucleoprotein antigens



  • Lateral flow immunoassay with sandwich design to qualitatively detect RSV A and RSV B nucleoprotein from nasopharyngeal (NP) swab and nasopharyngeal aspirate/wash (NA/W) specimens collected from pediatric patients
  • Four main components: (1) sample pad for receiving specimen (2) label pad containing dried, fluorescently dyed microparticles coated with RSV-specific monoclonal antibodies (3) nitrocellulose test strip for the capture of RSV analyte (4) absorbent pad to drive capillary flow


  • Demonstrating “Simple”: Designed to be simple and easy to use by incorporating the several following features
  • Demonstrating “Insignificant Risk of an Erroneous Result”-Failure Alerts and FailSafe Mechanisms
  • Demonstrating “Accuracy”
  • Proposed Labeling
  • Operator Questionnaire Results

REIMBURSEMENT: Appropriate CPT and ICD-9-CM codes to accurately reflect patient condition(s) and testing procedure(s)

User manual

Capture.JPGVERZENIO (abemaciclib) Tablet

Eli Lilly


  • in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy
    • as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting


  • New targeted treatment option for certain patients with breast cancer who are not responding to treatment
  • Can be given as a stand-alone treatment to patients


  • Priority Review and Breakthrough Therapy designations
  • Postmarketing Requuirement:  Clinical trial to evaluate effect of severe diarrhea
  • Postmarketing Commitment: Overall Survival data, Physiologically based Pharmacokinetic modeling (PBPK) analysis

MECHANISM OF ACTION:  Inhibitor of cyclin-dependent kinases 4 and 6; impacts cell cycle progression, and cell proliferation in estrogen receptor-positive (ER+) breast cancer cell lines


  • Randomized, placebo-controlled, multicenter study in women (n=669) with HR-positive, HER2-negative metastatic breast cancer,  in combination with fulvestrant, VERZENIO vs. placebo
  • % Number of patients with an event: 49.8% Vs. 70.4%, p<0.0001
  • Median months: 16.4 vs. 9.3
  • % Objective response rate: 48.1 vs. 21.3


  • Serious side effects: Diarrhea, neutropenia, elevated liver blood tests, deep venous thrombosis/pulmonary embolism, harm to developing fetus
  • Common side effects: Diarrhea, neutropenia and leukopenia, nausea, abdominal pain, infections, fatigue, anemia, decreased appetite, vomiting and headache


Image credit: Pentax, Abbott, Quidel, Lilly

FDA News and Views: Illegal Online Drug Marketing, Patient Preferences for Devices, Digital PreCert Program Selection, Drug Patents and Exclusivities, Compounded Medications

FDA BRIEF: Week of September 25, 2017


FDA conducts major global operation to protect consumers from potentially dangerous prescription drugs sold online

Operation Pangea X, a global cooperative effort led by Interpol, to combat unlawful sale and distribution of illegal, counterfeit, substandard medical products on the internet

  • Action against > 500 websites illegally selling dangerous, unapproved versions of prescription medicines –  including opioids
  • Remove products from supply chain
  • Prevent health risks as well as credit card fraud, identity theft and computer viruses



How Patient Preferences Contribute to Regulatory Decisions for Medical Devices

Examples of using Patient Preference Initiative as part of medical device regulatory decision-making process

  • Expanded indication for home hemodialysis machine to be used without presence of care partner
  • Worked with medical device company, NxStage, to develop Patient Preference Framework
  • Enhancing safety of continuous glucose monitors – Dexcom G5 Continuous Glucose Monitoring (CGM) System and Animas Vibe System.
  • Used patient feedback to develop risk mitigation strategies such as lockout feature to prevent accidental boluses

Companies invited to discuss on patient preference information during Pre-Submission meetings



FDA selects participants for new digital health software Precertification pilot program

Selection of companies to participate in a first-of-its kind pilot program to revolutionize digital health regulation in the U.S.

  • Pre-cert pilot program is precertify software developers based on systems for software design, validation and maintenance, meeting quality standards
  • Precertified companies could potentially submit less FDA information before marketing a new digital health tool
  • >100 applicants; selection based on company size, demonstrated record of quality and organizational excellence, represent unique approaches  digital health technology development

Apple, Cupertino, California

Fitbit, San Francisco, California

Johnson & Johnson, New Brunswick, New Jersey

Pear Therapeutics, Boston, Massachusetts

Phosphorus, New York, New York

Roche, Basel, Switzerland

Samsung, Seoul, South Korea

Tidepool, Palo Alto, California

Verily, Mountain View, California


CapturePatents and Exclusivities for Generic Drug Products


  • Property right granted by US -PTO -term of 20 years from the date of filing with the PTO
  • FDA does not enforce patents, or evaluate patent validity or infringement
  • Product manufacturers submit patent information to FDA for inclusion in “Orange Book”  –  informs when a generic drug application may be approved


  • Provides limited market protection from new competition; precludes approval of certain ANDAs for prescribed periods of time – Hatch Waxman Amendments
  • Also for brand-name “orphan” drug products- Orphan Drug Act
  • Also for certain pediatric-related uses and for qualifying antibiotic drug products.
  • FDA administers exclusivities

Types of Exclusivities:

  • Five-Year New Chemical Entity
  • Three-Year New Clinical Studies
  • Orphan Drug.
  • Pediatric
  • “Generating Antibiotic Incentives Now” (GAIN)
  • 180-Day



New efforts to encourage compounding of better quality drugs 

Important for health care providers to have access to compounded drugs

  • When patient needs cannot be met by FDA-approved drugs
  • Oversight based on Drug Quality and Security Act (DQSA) to prevent manufacturing issues and associated patient risks
  • Posting  new report  on drugs that entities registered as outsourcing facilities have produced
  • Sharing guide, “Outsourcing Facility Information,” for outsourcing facilities
  • Collaboration with state partners at sixth intergovernmental meeting on drug compounding
  • Assist more compounders register as outsourcing facilities


Image credits: FDA




Weeks of September 11 and 18, 2017


MVASI (bevacizumab-awwb) solution for intravenous infusion 

Amgen, Inc


  • Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
  • Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrmidine-oxaliplatin-based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product-containing regimen. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
  • Non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.
  • Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate. No data is available demonstrating improvement in disease-related symptoms or survival with bevacizumab products.
  • Metastatic renal cell carcinoma, in combination with interferon alfa.
  • Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

ADDRESSING UNMET NEED: First biosimilar (to Avastin)  approved in the U.S. for the treatment of cancer

REG PATHWAY: BLA (biosimilar, not an interchangeable product)

  • Postmarketing commitments: Drug substance stability, method validation, endotoxin detection method

DESCRIPTION:  Recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems

BIOSIMILARITY: Extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and clinical safety and effectiveness data


  • 4 Studies in Metastatic Colorectal Cancer: Double blind, open label, survival improvement
  • Adjuvant Treatment of Colon Cancer: No efficacy
  • Unresectable Non–Squamous Non–Small Cell Lung Cancer:  Single, large, randomized, active-controlled, open-label, multicenter study. Higher Overall Survival
  • Glioblastoma: Open-label, multicenter, randomized, non-comparative study.Efficacy based on WHO radiographic criteria and by stable or decreasing corticosteroid use
  • Metastatic Renal Cell Carcinoma:  Multicenter, randomized, double-blind,
    international study.  Statistically significantly prolonged progression free survival
  • Persistent, Recurrent, or Metastatic Carcinoma of the Cervix: Randomized, four-arm, multi-center trial. Higher overall survival


  • Boxed Warning: Increased risk of gastrointestinal perforations; surgery and wound healing complications; severe or fatal pulmonary, gastrointestinal, central nervous system and vaginal bleeding
  • Serious expected side effects:  Perforation or fistula, arterial and venous thromboembolic events), hypertension, encephalopathy syndrome, proteinuria, ovarian failure
  • Common expected side effects: Epistaxis), headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis


Image result for solosec logo

SOLOSEC (secnidazole) oral granules

Symbiomix Therapeutics

INDICATION: Treatment of bacterial vaginosis in adult women


  • New medication for bacterial vaginosis
  • First one-dose oral regimen for most common vaginal infection in adult women


  • Qualified Infectious Disease Product (QIDP) designation
  • Fast Track designation, Priority Review
  • Deferred pediatric assessments

MECHANISM OF ACTION:  Nitroimidazole antimicrobial drug


  • Two randomized placebo-controlled clinical trials, n=144 and 189, patients with diagnosed bacterial vaginosis
  • Efficacy: Clinical outcome in 21 to 30 days, “normal” vaginal discharge, negative
    “whiff” test, and clue cells <20%
  • Statistically significantly greater % clinical outcome with Solosec


  • Most common adverse reactions: Vulvo-vaginal candidiasis, headache, nausea, diarrhea, abdominal pain, vulvovaginal pruritus


Aliqopa™ (copanlisib) Logo

ALIQOPA  (copanlisib) for injection

Bayer Healthcare Pharmaceuticals

INDICATION: Treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.


  • 72,240 people in US diagnosed with some form of non-Hodgkin lymphoma this year; approximately 20,140 patients will die from disease in 2017
  • Approval provides additional choice for treatment, filling an unmet need


  • Accelerated approval, Priority Review designation, Orphan Drug designation
  • Accelerated approval based on overall response rate; continued approval contingent upon verification of clinical benefit in confirmatory trial
  • Other postmarketing requirements: Long term safety, clinical pharmacology studie
  • Pediatric assessment exemption

MECHANISM OF ACTION:  Inhibitor of phosphatidylinositol-3-kinase with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells; induces tumor cell death


  • Single-arm, multicenter, Phase 2 clinical trial, n=142 subjects with relapsed follicular B-cell non-Hodgkin lymphoma
  • Efficacy Endpoints: Tumor response according to the IWG criteria for malignant lymphoma. Overall Response rate (ORR) by Independent Review Committee.
  • ORR: 59%, with median duration of response of 12.2 months


  • Common side effects: Hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, thrombocytopenia
  • Serious side effects: Infections, hyperglycemia, hypertension, non-infectious pneumonitis, neutropenia, severe skin reactions, harm to developing fetus or newborn baby


Image credits: Amgen, SymbiomixBayer








FDA News and Views: Radio-Frequency Wireless Coexistence Standard, Tardive Dyskinesia, Medication-Assisted Treatment, Biomarker Qualification Program 

FDA BRIEF: Week of September 18, 2017

Image result for association for the Advancement of Medical Instrumentation logoImage result for ANSI Logo

Recognized Consensus Standards: Radio-Frequency Wireless Coexistence For Medical Devices And Systems

FDA publication of standards-recognition notice (Recognition List #47) that includes

  • American National Standards Institute (ANSI) American National Standard for Evaluation of Wireless Coexistence C63
  • Association for the Advancement of Medical Instrumentation (AAMI) Technical Information Report (TIR) 69: Risk management of radio-frequency wireless coexistence for medical devices and systems.

First standard to specifically address wireless coexistence testing to assess ability of wireless equipment to coexist with other wireless equipment in its intended use environment

  • For  all medical devices that incorporate wireless technology for data transmission, communications or control
  • For 510(k), PMA, PDP, HDE, GMP, Design controls

Relevant FDA Guidances

  • Radio Frequency Wireless Technology In Medical Devices – Guidance For Industry And Food And Drug Administration Staff, Document Issued On: August 13, 2013
  • Information To Support A Claim Of Electromagnetic Compatibility (EMC) Of Electrically-Powered Medical Devices – Guidance For Industry And Food And Drug Administration Staff. Document Issued On: July 11, 2016


Spotlight on CDER Science

In Pursuit of Tardive Dyskinesia: The Breakthrough Designation and Approval of Valbenazine

Tardive dyskinesia – a side effect of taking antipsychotic medicines

  • Neurological disorder with repetitive, involuntary movements such as lip smacking or pursing, as well as tongue movements
  • Impacts the health and quality of life and is often irreversible


  • First-generation antipsychotics and second-generation antipsychotics (“atypicals”) revolutionized psychiatric care but caused tardive dyskinesia
  • May be caused by irregular dopamine signaling
  • Interest in studying tetrabenzine and valbenazine to treat involuntary movements

A Breakthrough Therapy and Expedited Approval

  • Breakthrough Therapy designation based on promising clinical results
  • Facilitated discussions between the FDA and valbenazine sponsor (Neurocrine Biosciences)
  • Priority Review and drug approval in 8 months after NDA submission



FDA’s continued efforts to promote the safe adoption of Medication-Assisted Treatment for opioid addiction

Medication-assisted treatment (MAT) – the use of medication combined with counseling and behavioral therapies

  • Major pillars of federal response to opioid epidemic

However,  significant challenges with use of MAT drugs contain methadone or buprenorphine – which are also opioids

  • Increased risk of serious side effects when combining MAT drugs with benzodiazepines – often prescribed to treat anxiety, insomnia, or other conditions
  • Strengthened labeling for MAT drug buprenorphine to emphasize indefinite treatment and continued treatment as long as it contributes to treatment goals
  • Develop treatment plan to closely monitor concomitant use of benzodiazepines and taper use while considering other treatment options


FDA Encourages New Treatments for Sickle Cell Disease

Sickle Cell Disease (SCD)

  • “Sickled” or abnormally shaped red blood cells that get stuck in small blood vessels and block the flow of blood and oxygen to major organs
  • Cause severe pain, organ damage, or even stroke
  •  Is chronic and lead to shortened lifespans

Limited Treatment Options

  • Approved 1998: Hydroxyurea- for red blood cells to stay round and flexible
  • Approved 2017: Endari (L-glutamine oral powder) to reduce acute complications of sudden, severe attacks of pain (sickle cell crises)

Encouraging New Treatment Development

  • Working with stakeholders—patients, academics and companies
  • “Fast track” designation, to bring new products to market faster
  • “Breakthrough therapy” designation if promising preliminary data
  • “Orphan status” if intended to treat rare diseases affecting < 200,000 people
  • Meeting with patients and learning the patient perspective to integrate into new product development



Biomarker Qualification Program 

Biomarker Qualification Program (BQP) encourages biomarker development

  •  For use in drug development, facilitate an efficient review process, make information publicly available
  • Qualified biomarker can be used in multiple drug development program without
    need to reconfirm suitability of  biomarker’s qualified context of use.
  • Potential to streamline drug development paradigm

Three submission stages

  • Letter of Intent
  • Qualification Plan
  • Full Qualification Package

FDA Engagement throughout the process

  • At each milestone, formal written FDA determination letter
  • Seek clarification regarding determination letter
  • Obtain additional information about qualification process



Image credits: FDA, AAMI, ANSI, Neurocrine

FDA Marketing Permit: reSET

Week of September 11, 2017



Pear Therapeutics

INDICATION FOR USE:  Provide cognitive behavioral therapy, as an adjunct to a contingency management system, for patients 18 years of age and older who are currently enrolled in outpatient treatment under the supervision of a clinician. reSET is indicated as a 12 week (90 days) prescription-only treatment for patients with substance use disorder (SUD), who are not currently on opioid replacement therapy, who do not abuse alcohol solely, or who do not abuse opioids as their primary substance of abuse. It is intended to:

 increase abstinence from a patient’s substances of abuse during treatment
 increase retention in the outpatient treatment program.


  • Alcohol, cocaine, marijuana and stimulant SUDs cause clinically and functionally significant impairments
  • Innovative digital technology to provide additional tools during their treatment

REG PATHWAY: De Novo Request

  • Regulation Number: 21 CFR 882.5801
  • Regulation Name: Computerized behavioral therapy device for psychiatric disorders
  • Regulatory Class: Class II
  • Product Code: PWE

GENERIC DEVICE TYPE:  Computerized behavioral therapy device for psychiatric disorders

Prescription only device intended to provide a computerized version of condition-specific behavioral therapy as an adjunct to clinician supervised outpatient treatment to patients with psychiatric conditions. The digital therapy is intended to provide patients access to therapy tools used during treatment sessions to improve recognized treatment outcomes.


  • Mobile medical application system: Patient application + clinician dashboard
  • Delivers cognitive behavioral therapy to teach the user skills that aid in the treatment of SUD
  • Intended to increase abstinence from substance abuse and increase retention in outpatient therapy programs
  • Used in conjunction with outpatient therapy and in addition to a contingency management system (widely-used program for treating SUD)


  • Multi-site, unblinded 12-week clinical trial, n=399, patients with alcohol, cocaine, marijuana and stimulant SUD, standard treatment + desktop-based version of reSET Vs. standard treatment
  • Statistically significant increase in adherence to abstinence : with reSET (40.3%) vs. who did not (17.6%)
  • Not effective in patients reporting opioids as their substance of abuse
  • No indication of side effects


  • Device provides ineffective treatment, leading to worsening condition: Clinical data
    Software verification, validation, and hazard analysis, Labeling
  • Device software failure, leading to delayed access: Software verification, validation, and hazard analysis
  • Use error / improper device use: Labeling


Image credit: Pear Therapeutics

FDA News and Views: Orphan Drug Act, Continuous Manufacturing, Priority Therapeutic Areas

FDA BRIEF: Week of September 11, 2017


FDA is Advancing the Goals of the Orphan Drug Act

By: Scott Gottlieb, M.D., FDA Commissioner

Orphan Drug Modernization Plan

  • eliminate a backlog of about 200 orphan drug designation requests t
  • pursue policies better advance the goals of the Orphan Drug Act (ODA).

Process improvements for review efficiency

  • Reorganization to leverage expertise across FDA’s medical product centers
  • New workflow to eliminate redundancies and delays

New policy steps for incentives

  • Hold public meeting on complex scientific and regulatory issues and appropriate orphan incentives
  • Examine aspects of granting designations to meet goals intended by Congress
  • Issue guidance documents to address loopholes for avoiding pediatric studies



 “Continuous Manufacturing” – Common Guiding Principles Can Help Ensure Progress


Priority Therapeutic Areas for Development

Standardizing study data specific to therapeutic areas (TAs) facilitate evaluation of medical products

  • Prioritization of TAs based on (1) areas of particular medical need, (2) areas with existing data standardization projects underway, and (3) areas with greater drug development pipeline activity
  • New roadmap for TAs in priority groupings
  • Collaboration of FDA, CDISC, Critical Path Institute, HL7’s Clinical Interoperability Council to define related clinical concepts


Image credits: FDA

FDA DEVICE Guidance: Advisory Committee Meetings, Small Business Qualification, Real-World Evidence, Inter-Operable Devices, Age-, Race-, and Ethnicity Data

fda guidances


Procedures for Meetings of the Medical Devices Advisory Committee

Background and Scope:

  • Provide information on  processes for Medical Devices Advisory
    Committee meetings
  • Excludes Medical Devices Dispute Resolution Panel (DRP)
  • Does not apply to Device Good Manufacturing Practice Advisory Committee,
    National Mammography Quality Assurance Advisory Committee, Technical
    Electronic Product Radiation Safety Standards Committee


  • Panel Meeting Topics
    • Advice on a Premarket Submission
    • Regulatory Issues: Classification/Reclassification, General Issues
  • Panel Expertise
    • Two or more voting members with relevant clinical expertise
    • One voting member knowledgeable about device technology
  • Preparation for Panel Meetings:
    • Premarket Submission Meetings, Briefing Material Contents, CDRH-Applicant Interactions, Regulatory Issues Meetings
  • Conduct of Panel Meetings
    • Medical Device Industry Presentations
    • CDRH Presentation
    • Open Public Hearing
    • Panel Deliberations and CDRH Questions
    • Panel Voting
  • Post Meeting Activities
  • Teleconference Panel Meetings



FY 2017 Medical Device User Fee Small Business Qualification and Certification

Background and Scope:

  • Business qualified and certified as a “small business” is eligible for a substantial reduction in most of these user fees
  • Process to request qualification and certification as a small business – US and Foreign


  • Eligibility
  • U.S. Businesses
  • Foreign Businesses
  • National Taxing Authority

Small Business Fees:




Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices

Background and Scope:

  • Real-World Data (RWD): Data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources
  • Real-World Evidence (RWE): Clinical evidence regarding the usage, and potential
    benefits or risks, of a medical product derived from analysis of RWD
  • Data derived from real world sources can be used to support regulatory decisions


  • Regulatory Context in Which RWE May be Used: General  considerations,  Application of IDE Requirements
  • Characteristics of RWD:  Relevance,  Reliability (Data accrual, Data assurance)
  • Examples Where RWE is Used
    • Expanded Indications for Use
    • Postmarket Surveillance Studies
    • Post-Approval Device Surveillance as Condition of Approval
    • Control Group
  • Supplementary Data
  • Objective Performance Criteria and Performance Goals




Design Considerations and Premarket Submission Recommendations for Interoperable Medical Devices

Background and Scope:

  • Advancing the ability of medical devices to exchange and use information safely and effectively with other medical devices as well as other technology
  • Potential to increase efficiency in patient care
  • Promote development and availability of safe and effective interoperable
    medical devices


  • Design Considerations for Interoperable Medical Devices
    • Purpose of the Electronic Interface
    • Anticipated Users.
    • Risk Management Considerations
    • Verification and Validation Considerations
    • Labeling Considerations
    • Use of Consensus Standards
  • Recommendations for Contents of Pre-market Submissions
    • Device Description
    • Risk Analysis
    • Verification and Validation
    • Labeling



Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical Studies

Background and Scope:

  • Improve data quality, consistency, transparency regarding  device performance within specific age, racial, and ethnic groups
  • Can benefit patients, clinicians, researchers, regulators, and others
  • Recommendations to overcome barriers to enrollment


  • FDASIA: Considerations for age-, race- and ethnicity-specific differences
    • Participation of subgroups in clinical trials.
  • Recommendations for Appropriate Enrollment
    • Study Design, Early Enrollment Stage
    • Premarket Submission Stage
    • Postmarket Submission Stage
  • Planning for Diverse Study Recruitment
    • Study Design, Early Enrollment Stage
    • Premarket Submission Stage
    • Postmarket Submission Stage
  • Considerations for Study Follow-Up Visits
  • Interpretation of Study Results
  • Assessing Heterogeneity Across Subgroups
  • Recommendations for Subgroup Specific Statistical Elements
  • Recommendations for Submissions to Agency



FDA Clearance: SENOGRAPHE PRISTINA with Self-Compression 

FDA BRIEF: Week of September 4, 2017

GE Healthcare, Senographe Pristina mammography system, launch, RSNA 2017, patient comfort

 Senographe Pristina with Self-Compression 

GE Healthcare

INDICATION FOR USE (based on predicate Senographe Pristina): Generates digital mammographic images that can be used for screening and in the diagnosis of breast cancer. Allows patients to increase or decrease the amount of compression applied to their own breast before the mammogram x-ray is taken.


  •  First 2D digital mammography with patient-assisted compression remote control
  • Enable patient, with the help of a technologist, to set compression that feels right for her
  • Minimize women’s perceived pain and discomfort by giving active role in the application of compression


  • Predicate Device: Senographe Pristina
  • Device Classification Name: Full Field Digital,System,X-Ray,Mammographic
  • Regulation Number: 892.1715
  • Classification Product Code: MUE


  • Senographe Pristina: Full Field Digital Mammography (FFDM) system
  • X-ray image acquisition system dedicated to breast imaging includes Cesium Iodine digital detector, x-ray tube, integrated high voltage generator, compression paddles
  • Control station for image acquisition, processing and display includes touch-screen user interface
  • Pristina Dueta: Addition of handheld wireless remote control to adjust compression force after breast positioning, guided by technologist


  • Clinical validation: Addition of remote to allow self-compression did not negatively impact image quality
  • Performing a mammogram with patient-assisted compression vs. compression solely applied by the technologist did not significantly increase time of the exam
  • IPSOS Patient satisfaction study (n=160):  Improved the comfort of exam (79%), less anxiety (54%)

510(k) Notification


Image credit: GE


FDA News and Views: Interoperability, Public Engagement in Regulatory Framework, Therapeutic Protein Products

FDA BRIEF: Week of September 2, 2017

Medical Device and Hurricane Emergencies

Hurricanes Irma and Jose

Medical Device and Hurricane Emergencies

During natural disasters medical devices may be exposed to fluctuating power, contaminants, or unusual levels of heat or humidity.

FDA provides information on using medical devices during and following emergency situations

  • Re-Use of Devices
  • Disposal of Contaminated Devices
  • Reopening Dialysis Clinics
  • Medical Devices Requiring Refrigeration
  • Medical Devices Exposed to Heat and Humidity
  • Blood Glucose Meters
  • Mammography Facilities


Image credit: FDA

FDA News and Views: Stem Cell Therapies Enforcement, Real -World Evidence, KEYTRUDA alert, Drug Manufacturing Oversight, AIDS Look Back,

FDA BRIEF: August 28, 2017


 FDA’s new policy steps and enforcement efforts to ensure proper oversight of stem cell therapies and regenerative medicine

Promising new field involving pathways involved in tissue damage and regeneration with potential applications across a wide range of diseases and conditions

  • However, ‘unscrupulous actors’  making corrupt, assurances to patients based on unproven and dangerous products
  • Promote unproven, illegal, expensive treatments that offer little hope, and pose significant risks to the health and safety

Stepped Up Enforcement

  • Steps in Florida and California to address troubling products being marketed
  • Will take additional actions in the coming months
  • New working group to pursue unscrupulous clinics

Efficient Regulation

  • Promote science-based policy to expedite development of innovative, scientifically proven regenerative cell therapies
  • New framework  based on current risk-based, flexible regulatory framework and provisions of the Cures Act
  • Issue compliance policy for current product developers to interact with FDA to determine marketing authorization needs


mom and child, 3 people, baby

Use of RealWorld Evidence to Support Regulatory Decision-Making for Medical Devices

Final guidance on the Use of RealWorld Evidence to Support Regulatory Decision-Making for Medical Devices

  • Clarifies how realworld data may be sufficient for use in regulatory decisions,
  • Clarifies evaluation plan to determine relevancy and reliability
  • Clarifies when Investigational Device Exemption (IDE) may be needed to collect and use realworld data

Guidance is cornerstone of strategic priority to build a national evaluation system for health technology (NEST)


Related image

FDA Alerts Healthcare Professionals and Oncology Clinical Investigators about KEYTRUDA (pembrolizumab) in Multiple Myeloma

Inform public, health care professionals, and oncology clinical investigators about risks with KEYTRUDA® (pembrolizumab)

  • In combination with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of patients with multiple myeloma
  • Based on data review from two clinical trials – KEYNOTE-183 and KEYNOTE-185
  • Interim results demonstrated an increased risk of death for patients
  • Patients on KEYTRUDA® for an approved use : Melanoma, Lung Cancer, Head and Neck Cancer, Classical Hodgkin Lymphoma, Urothelial Carcinoma, Microsatellite Instability-High (MSI-H) Cancer


New Steps To Strengthen FDA’s Inspection And Oversight Of Drug Manufacturing

CDER and the Office of Regulatory Affairs (ORA) implementing a new, concept of operations agreement

  • integrate drug review programs with facility evaluations and inspections
  • “Integrated Quality Assessment”  team for closer risk assessments for drug substance, drug product, manufacturing processes, and facilities
  •  ORA reorganized into program-aligned commodity areas mirroring FDA’s centers and industries
  • New model will cover Pre- and Post-Approval Inspections, Surveillance Inspections, and For-Cause inspections at domestic and international drug manufacturing facilities


Commemorating 20 Years AIDS poster

A Look Back: The AIDS Crisis and FDA … 30 Years Later

Office of AIDS and Special Health Issues established in 1994 at the height of the AIDS epidemic

  • Advocacy group ACTUP (AIDS Coalition to Unleash Power) functionally closed down the FDA in 1988
  • Individuals continually called up various offices of FDA complaining that no one was paying attention to AIDs
  • There were “fax attacks” – to disrupt “business as usual,”
  • FDA responded to these needs

FDA engagement with AIDS Community particularly the patients

  • Patients played an important role in AIDS drug development
  • Pushed for use of accelerated approval based on viral load – a surrogate endpoint
  • Pushed for expanded access
  • Highlighted that policy had to move in tandem with science
  • Participated in Advisory Committee Meetings

In 1996, when protease inhibitors were approved, everything turned around


Image Credit: FDA

FDA Approvals: KYMRIAH, MYLOTARG, VABOMERE, Benznidazole

FDA BRIEF: Week of August 28, 2017

FDA approved

CAR T Cell


KYMRIAH (tisagenlecleucel) suspension for intravenous infusion



INDICATION:  CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse


  • First gene therapy available in the US
  • New approach to treatment of cancer and other serious and life-threatening diseases
  • New treatment option where very limited options existed,  with promising remission and survival rates in clinical trials


  • Priority Review and Breakthrough Therapy designations
  • Coordinated, cross-agency approach
  • Clinical review : Oncology Center of Excellence
  • All other review aspects and final product approval determination: CBER

MECHANISM OF ACTION:  CD19-directed genetically modified autologous T cell immunotherapy which involves reprogramming patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. Upon binding to CD19-expressing cells, CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the KYMRIAH cells.


  • Open-label, multicenter single-arm trial, n=107, pediatric and young adults with R/R B-cell precursor ALL, lymphodepleting chemotherapy  followed by a single dose of KYMRIAH
  • Endpoints: Complete Remission (CR) within 3 mo., CR duration, proportion of patients with CR and minimal residual disease (MRD) <0.01% by flow cytometry (MRD-negative)


  • Boxed Warning: Cytokine release syndrome (CRS)  causing high fever and flu-like symptoms, and for neurological events
  • Severe side effects: Serious infections, hypotension, acute kidney injury, fever, hypoxia
  • Destruction of normal B cells that produce antibodies – increased risk of infections for a prolonged period of time



  • Modernization of current healthcare payment systems need to ensure access to new high-cost therapies
  • Innovative payment arrangements including outcome-based pricing in relation to clinical outcomes
  • Center for Medicare and Medicaid Innovation (CMMI)  to test payment and service delivery models on value-based payment arrangements
  • Issue guidance on sponsor engagement in innovative payment arrangements


Capture.JPGMYLOTARG (gemtuzumab ozogamicin) injection



  • Newly-Diagnosed CD33-positive Acute Myeloid Leukemia (AML): Treatment of newly-diagnosed CD33-positive acute myeloid leukemia in adults
  • Relapsed or Refractory CD33-positive AML: Treatment of relapsed or refractory CD33-positive acute myeloid leukemia in adults and in pediatric patients 2 years and older


  • AML is rapidly progressing cancer, forms in bone marrow, results in increased white blood cell
  • ~21,380 diagnosed this year in US,  10,590 will die of disease
  • Importance of examining alternative dosing, scheduling, and administration of therapies

REG PATHWAY: BLA, Orphan Drug Designation

  • Accelerated Approval  in 2000 at higher dose for stand-alone treatment for older patients with CD33-positive AML who had experienced a relapse
  • Voluntary withdrawal in 2010 after confirmatory trial failed to show clinical benefit and higher rate of fatal toxicity
  • This approval includes a lower recommended dose, a different schedule in combination with chemotherapy or on its own, and a new patient population

MECHANISM OF ACTION: CD33-directed antibody-drug conjugate (ADC), small molecule  N-acetyl gamma calicheamicin, is a cytotoxic agent covalently attached to antibody. Activity due to binding of ADC to CD33-expressing tumor cells, internalization of ADC-CD33 complex, intracellular release of small molecule


  • Two, separate trials
  • First trial:  newly diagnosed AML, n=237,  MYLOTARG vs. best supportive care
  • Median Overall Survival: 4.9 months vs. 3.6 months
  • Second trial: Single-arm study,  CD33-positive AML, n=57,  single course of MYLOTARG
  • Complete Remission.  26% that lasted a median 11.6 months


  • Boxed Warning: Hepatotoxicity, veno-occlusive disease or sinusoidal obstruction syndrome
  • Severe side effects: Low blood counts, infections, liver damage, hepatic veno-occlusive disease, infusion-related reactions, hemorrhage
  • Common side effects: Pyrexia, nausea, infection, vomiting, bleeding, thrombocytopenia, stomatitis, constipation, rash, headache, elevated liver function tests, neutropenia


Image result for vabomere logo

VABOMERE™ (meropenem and vaborbactam) for injection

Rempex Pharmaceuticals (The Medicines Company)

INDICATION: Treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex


  • Antibacterial product to treat serious or life-threatening infections
  • Additional treatment option for patients with cUTI

REG PATHWAY: NDA, Priority Review

  • Designated as a qualified infectious disease product (QIDP) under Generating Antibiotic Incentives Now (GAIN)
  • Postmarketing Requirements/Commitments:   Surveillance study for drug resistance, extractable/leachable studies

MECHANISM OF ACTION: Penem antibacterial drug that inhibits cell wall synthesis in most gram-positive and gram-negative bacteria


  • Double-blind, double dummy, multi-center trial,  N=545 adults with cUTI, including pyelonephritis, VABOMERE vs.  piperacillin/tazobactam
  • Clinical and microbiological response at the end of IV treatment (EOIVT): Clinical outcome of cure or improvement + microbiologic outcome of eradication
  • Clinical and microbiological response at Test of Cure (TOC) visit at 7 d
  • Cure/improvement in symptoms + negative urine culture test: 98% vs 94%
  • TOC with resolved symptoms + negative urine culture: 77% vs 73%


  • Most common adverse reactions: Headache, infusion site reactions and diarrhea
  • Serious risks : Allergic reactions,  seizures


Image result for chagas disease

BENZNIDAZOLE tablets, for oral use

Exeltis USA

INDICATION:   Indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi


  • First approved treatment approved in US
  • There may be ~  300,000 US patients
  • Granted tropical disease priority review voucher under section 524 of FDCA
  • Voucher entitles designation of a human drug/biologic application as qualifying for a priority review
  • Accelerated Approval: Based on negative Immunoglobulin G (IgG) antibody  test
  • Accelerated Approval Requirement:  Prospective, single-arm, multicenter trial, with historical controls, to evaluate safety, efficacy and pharmacokinetics in children
  • Postmarketing Requirements: ADME study, Fertility toxicity study

MECHANISM OF ACTION: Inhibits synthesis of DNA, RNA, and proteins within parasite


  • Two adequate and well-controlled trials
  • Trial 1 (Argentina): Randomized, double-blind, placebo-controlled trial, children 6-12 yr with chronic indeterminate Chagas disease, n=106, benznidazole vs placebo, followed for 4 years
  • Trial 2 (Brazil): Randomized, double-blind, placebo-controlled trial, children 7 -12 yr with chronic indeterminate Chagas disease, n=129, benznidazole vs placebo
  • Endpoint: Antibodies measured by conventional and nonconventional assays
  • Benznidazole treatment resulted in significantly higher percentage of seronegative patients: 55-60% vs  5-14%


  • Most common adverse reactions: Stomach pain, rash, decreased weight, headache, nausea, vomiting, abnormal white blood cell count, urticaria, pruritus, decreased appetite
  • Serious risks: Serious skin reactions, nervous system effects and bone marrow depression
  • Based on animal findings: Could cause fetal harm when administered to pregnant woman


Image credits: FDA, CDC, Pfizer, Medicines Company

FDA Approvals: CYLTEZO

FDA BRIEF: Week of August 21, 2017

FDA approved

Image result for CYLTEZO logo

CYLTEZO (adalimumab-adbm)

Boehringer Ingelheim Pharmaceuticals, Inc.


  • Rheumatoid Arthritis (RA): 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.
  • Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older.
  • Psoriatic Arthritis (PsA): reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.
  • Ankylosing Spondylitis (AS): reducing signs and symptoms in adult patients with active ankylosing spondylitis.
  • Adult Crohn’s Disease (CD): 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. 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 (UC): 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 (Ps): the 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.


  • Second Biosimilar to Humira
  • Highly similar to reference product (Humira) with no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products
  • Several deferred pediatric asessments

Information on Biosimilars


Image Credit: Boehringer Ingelheim



FDA News and Views: Early Feasibility Studies, Pediatric Opioid Medications for Cough, Medication Use during Pregnancy

FDA Brief: Week of August 21, 2017


Early Feasibility Studies and Investigation Device Exemption

Early Feasibility Studies (EFS) Program provides opportunities to gain early clinical experience with innovative technology

  • enrolls small number of subjects
  • is used to evaluate the device design concept with respect to initial clinical safety and device functionality
  • may guide device modifications

CDRH’s  efforts to streamline the clinical trial initiative


Have a Baby or Young Child With a Cold? Most Don't Need Medicines

 FDA is carefully evaluating prescription opioid medications approved to treat cough in children

Vital to understand potential complications in children using opioid-containing medications, even according to labeled instruction

  • Added contraindication to drug labels alerting that codeine should not be used for any reason, including treatment of cough, in children younger than 12 years

Pediatric Advisory Committee scheduled on Sep 11th will focus on

  • use of prescription opioid products containing hydrocodone or codeine for the treatment of cough in pediatric patients
  • current treatment practices
  • benefit-risk considerations
  • help inform Agency’s decision-making processes related to these medications

Additional efforts:

  • tips for consumers on how to safely treat a child’s cold
  • funding research to develop comprehensive, consumer-centered approaches on best practices for the safe use of pediatric cough and cold medications


Pregnancy Research

Working to Improve Information on Medication Use during Pregnancy

Very few prescription medications specifically approved for use during pregnancy

  • About half of the 6.3 million preganant women/year take at least one medication

Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC)

  • Established by the 21st Century Cures Act
  • Research aimed at optimizing therapies for pregnant women and nursing mothers
  • Led by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Labeling requirements for the pregnancy and lactation subsections

  • Implemented in 2015
  • Provided framework for clearly communicating benefits/risks
  • Removed the decades-old pregnancy category letter system

Pregnancy research initiatives

  • Led by Office of Women’s Health
  • Using predictive modeling to anticipate response to drug
  • Understand safety, efficacy and effects of products e.g.  vaccine safety, MRI effects, drug toxicity

Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP)

  • Research collaboration between FDA, academia and health insurers
  • Learn  about medication effects by linking healthcare records for moms and babies
  • Epidemiologic study to evaluate effect of prescription opioids

Real-World Research and Safety Monitoring

  • Pregnancy Registry
  • Pregnancy outreach activities


Image credit: FDA



FDA BRIEF: Week of  August 14, 2017

FDA approved

Lynparza logo

LYNPARZA (olaparib) tablets


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

ADDRESSING UNMET NEED: Addition of new indication and new formulation (tablet)


  • Initial approval of capsule formulation in 2014 for the treatment of BRCA-mutated advanced ovarian cancer
  • New tablet formulation also approved for this indicaiton and new indication
  • Tablets and capsules are not interchangeable; capsules will be phased out of market and will be available only through Lynparza Specialty Pharmacy Network
  • Postmarketing commitments:  progression-free survival (PFS) and molecular characteristics,  overall response rate (ORR) and duration of response (DOR) from ongoing clinical studies 

MECHANISM OF ACTION: Inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes that are involved in DNA transcription and DNA repair


  • Two randomized, placebo-controlled, double-blind, multicenter studies, n=295, 265, patients with recurrent ovarian cancers who were in response to platinum-based therapy
  • Major efficacy outcome: Investigator-assessed PFS evaluated according to RECIST, version 1.1.
  • Study 1 (recurrent germline BRCA-mutated cancer): Estimated median PFS was 19.1 vs. 5.5 months (olaparib vs. placebo),  p<0.0001)
  • Study 2 (regardless of BRCA status):  Median PFS was 8.4 months vs. 4.8 months, p<0.0001


  • Most common adverse reactions: Anemia, nausea, fatigue (including asthenia), vomiting, nasopharyngitis, diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, and stomatitis
  • Most common laboratory abnormalities: Decrease in hemoglobin, increase in mean corpuscular volume, decrease in lymphocytes, decrease in leukocytes, decrease in absolute neutrophil count, increase in serum creatinine, and decrease in platelets


Image for trademark with serial number 86916876

BESPONSA (inotuzumab ozogamicin) for injection


INDICATION:  Treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)


  • 5,970 in United States will be diagnosed with ALL in 2017; ~1,440 will die from disease
  • Low life expectancy for B-cell ALL patients with nonresponsive / relapsed cancer
  • New, targeted treatment option

REG PATHWAY: BLA, Orphan drug designation, Priority Review, Breakthrough Therapy

  • Postmarketing requirements: Characterize toxicity after hematopoietic stem cell transplantation (HSCT) in adult and pediatric patients, randomized trial in patients with relapsed or refractory acute lymphoblastic leukemia, Bioburden and endotoxin test method qualification

MECHANISM OF ACTION:  CD22-directed antibody-drug conjugate (ADC), is a cytotoxic agent covalently attached to antibody via linker. Anticancer activity due to binding of the ADC to CD22-expressing tumor cells


  • Randomized (1:1), open-label, international, multicenter study in patients with relapsed or refractory ALL, n= 326, BESPONSA vs.  Investigator’s choice of chemotherapy
  • Efficacy: Complete Response (CR), duration of remission (DoR) and Overall Survival



  • Boxed warning: Severe liver damage (hepatotoxicity), including blockage of veins in the liver
  • Other serious side effects: Myelosuppression, infusion-related reactions, QT interval prolongation, reproductive toxicity
  • Common side effects:  Thrombocytopenia, neutropenia, leukopenia, infection, anemia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, liver damage, abdominal pain, hyperbilirubinemia


Image credit: AstraZeneca, Pfizer

FDA News and Views: Prescription Drug Advertising, Tools for Zika

FDA BRIEF: Week of August 14, 2017

Be Smart About Prescription Drug Advertising: A Guide for Consumers

Content of Risk Information in the Major Statement in Prescription Drug Direct-to-Consumer Broadcast Advertisements

Prescription Drug Advertising regulations require direct-to-consumer (DTC) advertisements with product claims include information on  major side effects and contraindications

  • Called the major statement
  • Also provide adequate provision for dissemination of approved package labeling
  • FDA issued Guidance

FDA interested in ensuring advertisements provide clear and useful information

  • Concern that major statement not fulfilling purpose
  • Too long, minimization of important risk information, therapeutic noncompliance caused by fear of side effects

Office of Prescription Drug Promotion (OPDP), CDER,  investigating effectiveness of a limited risks plus disclosure strategy

  • Limiting  major statement to those that are severe (life-threatening), serious, or actionable
  • Disclosure that  other product risks not included in the advertisement
  • Present fair balance of risk information and avoid misleading presentation on  risk-benefit profile
  • Requesting comments on Federal Register notice

Federal Register notice

FDA In Brief

ZikaNew FDA tools for development and proper evaluation of tests for detecting Zika virus infection

FDA has made available a panel of human plasma samples for regulatory evaluation of serological tests to detect recent Zika virus infection

  • FDA worked with manufacturers to encourage development of diagnostic tests
  • Ensure they were available using Emergency Use Authorization (EUA)

Two primary blood diagnostic tests

  • Nucleic acid tests: Identify infection by confirming  virus’ RNA
  • Serological tests: Identify antibodies produced by body’s immune system upon Zika detection
  • Development of tests challenging because Zika antibodies produced by the body difficult to differentiate from other related virus antibodies (dengue, West Nile)

FDA’s sample panel

  • Plasma samples from individuals infected with Zika, West Nile, or dengue
  • Diagnostic developers use to check if test can distinguish Zika vs. others
  • Also use to compare test vs. other Zika tests approved via EUA
  • Available to developers who have interacted with the FDA through the pre-EUA process and have devices in final stages of validation


Image credit: FDA












FDA News and Views: Software PreCert Pilot, Medical Device Tool Development, GUDID Data Quality, China joins ICH

FDA BRIEF: Week of August 7, 2017

Software Precertification Pilot program

Part of Digital Health Innovation Acton Plan,  conforming to software
provisions of the 21st Century Cures legislation

  • Voluntary program for medical device software manufacturers
  • Need to demonstrate Culture of Quality and Organizational Excellence (CQOE)

Pre-Cert status allows

  • Ability to get software to market faster
  • Iterate based on real world experience
  • Have regulatory predictability

FDA Goals

  • Modern and efficient regulatory framework
  • Easy to obtain and maintain FDA Pre-Cert
  • High quality, safe and effective software throughout product life
  • Enable companies to demonstrate CQOE and measure Key Performance Indicators
  • Enable scalability, variation and evolution of software development
  • Learn and adapt based on program effectiveness


Collage; 1st picture is cross section of a human head; 2nd is a body with skeleton showing; 3rd is hand holding a blood pressure meterMedical Device Tool Development (MDDT)

MDDT program for qualification of tools for medical device sponsors in the development and evaluation of medical devices

  • Promotes innovation in medical device development
  • Bridge gap between research of devices and the delivery of devices to patients

‘Qualification’ based on FDA evaluation of  evidence that

  • tool produces scientifically-plausible measurements
  • works as intended within the specified context of use

Context of Use

  • tool or product area
  • specific output or measure
  • role in device development
  • applicable phases of device development


  • Clinical outcome assessment
  • Biomarker test
  • Nonclinical assessment model