Drug Authorizations: ZULRESSO for postpartum depression, SUNOSI for daytime sleepiness, MAYZENT for multiple sclerosis, DOVATO for HIV, BALVERSA for metastatic bladder cancer

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ZULRESSO (brexanolone) intravenous injection 

Sage Therapeutics

INDICATION: Treatment of postpartum depression (PPD) in adults

ADDRESSING UNMET NEED:

  • First drug approved specifically for PPD
  • PPD is a serious condition that can be life-threatening

MECHANISM OF ACTION: Related to positive allosteric modulation of GABA receptors

EFFICACY:

  • Two multicenter, randomized, double-blind, women (18 to 45 years) with PPD, ZULRESSO vs placebo
  • Primary endpoint: Mean change from baseline in depressive symptoms as measured by HAM-D total score at the end of the infusion
  • Superiority to placebo in improvement of depressive symptoms,  improvement in depression was also observed at the end of the 30-day follow-up period.

SAFETY:

  • Boxed Warning: Patients at risk of excessive sedation or sudden loss of consciousness during administration; must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring
  • Most common adverse reactions: Sleepiness, dry mouth, loss of consciousness and flushing

REGULATORY PATHWAY: NDA

  • Priority Review and Breakthrough Therapy designations
  • Approved with a Risk Evaluation and Mitigation Strategy (REMS)- only available through restricted distribution program
  • Recommend scheduling of Zulresso under the Controlled Substances Act (CSA)- DEA scheduling pending
  • Required Pediatric Assessment: In adolescent females, 15 – <18 diagnosed with postpartum depression.

LABEL 


Capture.JPGSUNOSI (solriamfetol) tablets

Jazz Pharmaceuticals

INDICATION: To improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA)

MECHNANISM OF ACTION: Could be mediated through its activity as a dopamine and norepinephrine reuptake inhibitor

EFFICACY:

Narcolepsy

  • 12-week, multi-center, randomized, double-blind, placebo-controlled,
    parallel-group study, n=239 patients with narcolepsy
  • Co-primary Endpoints:  Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS). Statistically significant improvements with SUNOSI

OSA:

  • 12-week multi-center, randomized, double-blind, placebo-controlled study, n=476 patients with OSA
  • Statistically significant improvements with SUNOSI on MWT and ESS

SAFETY:

  • Warnings and Precautions: Blood Pressure and Heart Rate Increases, Psychiatric Symptoms
  • Most common adverse reactions: Headache, nausea, decreased appetite, insomnia, anxiety.

REGULATORY PATHWAY: NDA

  • Recommended scheduling under Controlled Substances Act (CSA)- DEA scheduling pending
  • Postmarketing requirements: Prospective, registry study on maternal, fetal, infant outcomes, additional pregnancy study, lactation study

LABEL


Capture.JPGMAYZENT (siponimod) tablets 

Novartis

INIDCATION: Treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

ADDRESSING UNMET NEED:

  •  MS is among the most common causes of neurological disability in young adults and occurs more frequently in women than in men
  •  Can have a profound impact on person’s life
  • Approval provides  a  treatment option

MECHANISM OF ACTION: Sphingosine-1-phosphate (S1P) receptor modulator; binds with high affinity to S1P receptors-  reduces lymphocyte migration into CNS

EFFICACY:

  • Randomized, double-blind, parallel-group, placebo-controlled, time-to-event study, n=1651 in patients with secondary progressive multiple sclerosis (SPMS), MAYZENT vs placebo
  • Primary endpoint:  Time to three-month confirmed progression in disability
  • Progression of disability statistically significantly lower in Mayzent vs. placebo
  • Decreased number of relapses group with Mayzent

SAFETY:

  • Medication Guide:  May increase the risk of infections, may cause macular edema,  may cause transient decreases in heart rate and may cause a decline in lung function and liver fucntion
  • Most common adverse reactions: Headache, high blood pressure and liver function test increases

REGULATORY PATHWAY: NDA

  • Postmarketing requirements: Clinical Study to assess serious risk of pulmonary toxicity, Prospective pregnancy exposure registry, Pregnancy outcomes study

LABEL


Capture.JPGDovato (dolutegravir and lamivudine) tablet

ViiV Healthcare

INDICATION: complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults with no antiretroviral treatment history and with no
known substitutions associated with resistance to the individual components of DOVATO

ADDRESSING UNMET NEED:

  •  First FDA-approved two-drug, fixed-dose, complete regimen for HIV-infected adults who have never received treatment for HIV
  • Drug-sparing treatment available that uses fewer drugs is beneficial to patients who may have issues taking multiple medications over a long period of time

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

EFFICACY:

  • Two identical, randomized, double-blind, controlled clinical trials, n=1,433 HIV-infected adults with no prior antiretroviral treatment history
  • Primary efficacy endpoint: Proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48
  • Dovato had similar effect of HIV reducion vs drug regimen of dolutegravir, emtricitabine, and tenofovir

SAFETY:

  • Boxed Warning: Patients infected with both HIV and hepatitis B should add additional treatment for hepatitis B 
  • Known risk for neural tube defects with dolutegravir- avoid use at the time of conception through first trimester of pregnancy
  • Most common adverse reactions: Headache, diarrhea, nausea, insomnia and fatigue

REGULATORY PATHWAY:  NDA

  • Supportive of DHHS initiative Ending the HIV Epidemic: A Plan for America,
  • Aim to reduce new infections by 75% in the next 5 years and by 90% in the next 10  years, averting more than 250,000 HIV infections in that span

LABEL


Capture.JPGBALVERSA (erdafitinib) tablets

Janssen

therascreen FGFR RGQ RT-PCR Kit  

Qiagen

INDICATION: Treatment of adult patients with locally advanced or metastatic
urothelial carcinoma (mUC), that has:

  • susceptible FGFR3 or FGFR2 genetic alterations, and
  • progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA

ADDRESSING UNMET NEED: First personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer

MECHANISM OF ACTION: Kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4; inhibits FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations

EFFICACY:

  • Multicenter, open-label, single-arm study, n=87 patients with locally advanced or metastatic bladder cancer, with FGFR3 or FGFR2 genetic alterations, that had progressed following treatment with chemotherapy
  • Major efficacy outcome measures: Objective response rate (ORR), Duration of response (DoR), determined by blinded independent review committee (BIRC) according to RECIST v1.1
  • ORR: 32.2%, with 2.3% having complete response and 30% having partial response
  • DOR: Approximately five-and-a-half months
  • Responses to Balversa were seen in patients who had previously not responded to anti PD-L1/PD-1 therapy

SAFETY:

  • Warnings and Precautions: Ocular disorders, Hyperphosphatemia
  • Common side effects: Increased phosphate level, mouth sores, feeling tired, change in kidney function, diarrhea, dry mouth, nails separating from the bed or poor formation of the nail, change in liver function, low salt (sodium) levels, decreased appetite, change in sense of taste, low red blood cells (anemia), dry skin, dry eyes and hair loss. Other side effects include redness, swelling, peeling or tenderness on the hands or feet (hand foot syndrome), constipation, stomach pain, nausea and muscle pain
  • Balversa because it may cause harm to a developing fetus or newborn baby

REGULATORY PATHWAY: NDA

  • Accelerated Approval, Breakthrough Therapy designation
  • Accelerated approval based on tumor response rate – Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials
  • Accelerated approval requirements: Demonstrating clinical benefit of erdafitinib in patients with locally advanced and metastatic urothelial carcinoma with susceptible FGFR 3 or FGFR 2 genetic alterations

LABEL


Image credit: Sage, Jazz, Novartis, ViiV, Janssen

 

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Device Authorizations: TRILURON for osteoarthritis, LOADPRO for spine surgery, PLENITY for weight management, LEICA 400 filter for glioma

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TRILURON

Fidia Farmaceutici S.p.A.

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

DESCRIPTION:

  • Viscous solution consisting of a high molecular weight (500,000–730,000 daltons) fraction of purified sodium hyaluronate (Hyalectin®) in buffered
    physiological sodium chloride, having a pH of 6.8-7.
  • The sodium hyaluronate is extracted from rooster combs
  •  Hyaluronic acid is a natural complex sugar of the glycosaminoglycan family and is a long-chain polymer containing repeating disaccharide units of Naglucuronate-N-acetylglucosamine
  • Administered by intra-articular injection

EFFECTIVENESS AND SAFETY:

  • Retrospective analysis of data prospectively collected from two randomized, controlled trials to determine the effectiveness of TRILURON vs. Hyalgan (control device)
  • Both have identical chemical formulation and differ only in that a lower
    dose is injected (3 weekly injections for TRILURON™ compared to 5 weekly injections of Hyalgan)
  • Primary effectiveness endpoint: Mean change from baseline at 26 weeks in WOMAC Pain scores: TRILURON was non-inferior to Hyalgan
  • Primary evidence of safety of Hyalgan is directly applicable to TRILURON and has already been established

REG PATHWAY: PMA

  • Device Procode: MOZ

LABEL


Capture.JPGLOADPRO™ Intraoperative Rod Strain Sensor

Intellirod Spine, Inc

INDICATION FOR USE: Intraoperative surgical tool that allows surgeons to measure unidirectional rod microstrain on posterior rods in the sagittal plane when performing spine surgery.

Adjunct to surgeon tactile feedback and is not intended to replace a surgeon’s clinical judgment.

Single use, disposable tool to be used in conjunction with X-Spine Systems Fortex Pedicle Screw System for 5.5mm diameter titanium (ASTM F136) or cobalt chrome (ASTM F1537) rod configurations.

GENERIC DEVICE TYPE: Intraoperative orthopedic strain sensor

  • Adjunct tool intended to measure strain on an orthopedic implant in the intraoperative setting only
  • Not intended to provide diagnostic information or influence clinical decision-making.

RISKS & MITIGATIONS (SPECIAL CONTROLS):

  • Prolonged operative time due to device error or use error: Usability Testing, Non-clinical Performance Testing, Software verification, validation, and hazard analysis, Labeling 
  • Electrical shock or device failure due to interference from other devices: Electromagnetic compatibility testing, Electrical safety testing 
  • Infection: Sterilization validation, Reprocessing validation, Shelf life testing
    Labeling 
  • Adverse tissue reaction: Biocompatibility evaluation

REGULATORY PATHWAY: De Novo request 

  • Regulation Number: 21 CFR 888.3090
  • Regulation Name: Intraoperative orthopedic strain sensor
  • Regulatory Class: Class II
  • Product Code: QFP

CLASSIFICATION ORDER


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PLENITY device for weight management and/or weight loss

Gelesis, Inc.

INDICATION FOR USE: To aid in weight management in overweight and obese adults with a Body Mass Index (BMI) of 25 – 40 kg/m2, when used in conjunction with diet and exercise

GENERIC DEVICE TYPE: Ingested, transient, space occupying device for weight management and/or weight loss

  • Ingested material that transiently occupies space in the stomach
  • Device passes from the body via the natural gastrointestinal tract

RISKS & MITIGATIONS (SPECIAL CONTROLS):

  • Device related gastrointestinal adverse events, including:  Obstruction,  Dilation,  Diarrhea, Constipation, Dehydration: Clinical performance testing, Non-clinical performance testing, Labeling, Shelf life testing
  • Weight gain: Clinical performance testing, Labeling 
  • Interaction with medication: Clinical performance testing, Non-clinical performance testing, Labeling 
  • Adverse tissue reaction: Biocompatibility evaluation
  • Infection: Non-clinical performance testing. Shelf life testing

REGULATORY PATHWAY: De Novo request

  • Regulation Number: 21 CFR 876.5982
  • Regulation Name: Ingested, transient, space occupying device for weight management and/or weight loss
  • Regulatory Class: Class II
  • Product Code: QFQ

CLASSIFICATION ORDER


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Leica FL400 surgical microscope accessory filter

Leica

INDICATION FOR USE: Surgical microscope accessory filter set for viewing fluorescence of fluorophores comprising an excitation filter for blue spectral range 380 nm – 430 nm and an  observation filter comprising the long-wave blue, green, yellow and red spectrum in the spectral band greater than 444 nm.

Surgical microscope accessory used in fluorescent visualization of suspected grade III or IV gliomas during neurosurgery.

GENERIC DEVICE TYPE: Diagnostic neurosurgical microscope filter

  • Device intended for use during neurosurgery to visualize fluorescence and enhance visualization of tissue associated with a specific disease or condition

RISKS and MITIGATIONS (SPECIAL CONTROLS):

  •  False positive: visualization of fluorescence when in fact no target fluorophore is present: Non-clinical performance testing and Labeling
  • False negative: no visualization of fluorescence when in fact the target fluorophore is present:  Non-clinical performance testing and Labeling

REG PATHWAY: De Novo request for Accessory

  • Microscope cleared via 510(k) pathway
  • De novo request for filter as ‘accessory’
  • Regulation Number: 21 CFR 882.4950
  • Regulation Name: Diagnostic neurosurgical microscope filter
  • Regulatory Class: Class II
  • Product Code: QFX

CLASSIFICATION ORDER


Image credits: Fidia, Intellirod Spine, Gelesis, Leica

Enforcement Actions: INOVA Genomics unapproved tests, Duodenoscope contamination, Unapproved Concussion Apps, Reused/Unauthorized Test Strips

ENFORCEMENT ACTIONS

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Inova Genomics Laboratory Warning Letter

Marketing in the US without marketing clearances or approvals, in violation of the Federal Food, Drug, and Cosmetic Act
  • MediMap ADHD, MediMap Mind, MediMap Plus, MediMap Heart, MediMap Baby
  • Being marketed as genetic tests for predicting medication response, reducing negative side effects,  discovering the right drug and right dose for a patient…
  • MediMap tests are devices based on intended uses
  • Clinical validity  not established for their intended uses
  • Pose significant public health concerns- inaccurate test results could impact the decision-making of healthcare providers and patients, seriously detrimental to patient health

Not considered as a Lab Developed Test (LDT) that is exempt from FDA’s premarket review or labeling requirements

WARNING: Inova Genomics


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High Duodenoscope Contamination Rate

  • Postmarket surveillance studies by  all three manufacturers (Fujifilm Medical Systems USA, Inc, Olympus Medical Systems Corporation, Pentax of America)
  • Evaluate % duodenoscopes which remain contaminated after use of labeled reprocessing instructions
  • Preliminary results (3/2019) indicate higher than expected levels (0.4%)  of contamination
  • Root cause analyses are currently underway; importance of strictly adhering to manufacturer’s reprocessing and maintenance instructions

SAFETY: Duodenoscope Reprocessing


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Unapproved or uncleared Apps for concussion

Potential serious risks associated with use of unapproved or uncleared Apps 

  • Marketed to coaches or parents for use during sporting events
  • Could result in an incorrect diagnosis, potentially leading to person with serious head injury returning to their normal activities instead of getting medical care
  • FDA became aware of violative products being marketed to consumers – asked to  remove such claims
  • Will continue to monitor marketplace for devices making unsubstantiated claims and will take further action if necessary
  • Limited number of medical devices that have been FDA cleared or approved to aid in the diagnosis, treatment, or management of concussion – all require evaluation by health care professional

WARNING: Concussion Assessment


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Previously Owned Test Strips or Test Strips Not Authorized for US Sale

Marketing of pre-owned test strips or test strips not authorized for sale in the U.S.

  • Sold through online marketplaces- Amazon, eBay, Craigslist, or directly from seller
  • Pre-Owned Strips :  Unsafe, poor storage, tampering, infection risk from previous owner’s blood – Inaccurate test results
  • Test strips not authorized for US sale: Suboptimal quality, inaccurate results

WARNING: Glucose test strips


Image credit: FDA

 

News & Views: Acting Commissioner, FDA and CBP collaboration, Cannabis-derived product regulation, E-cigarette addiction treatment, Risk-Based Monitoring, Medical Counter Measures, Class I Accessories, Office of Minority Health and Health Equity

Transition of FDA Leadership: Dr. Ned Sharpless as Acting Commissioner

Farewell to Commissioner Gottlieb

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FDA and CBP bolster collaboration to protect public health and safety

FDA and CBP agreement to maximize inspection and detection capabilities

  • Prevent illegal and harmful products entering International Mail Facilities and Ports of Entry
  • Sharing of FDA’s advanced screening technology to identify trends in future entries
  • Shared space and increased scientific presence at high-risk/high-volume facilities

READ


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Continued evaluation of potential regulatory pathways for cannabis-containing and cannabis-derived products

Products containing cannabis or cannabis derivatives marketed as human drugs, dietary supplements, conventional foods, animal foods/drugs, cosmetics

  • Public hearing on May 31 to share experiences and challenges and product safety
  • Formation of high-level internal agency working group on potential pathways for dietary supplements to be lawfully marketed
  • Webpage on FDA’s requirements for these products
  • Issuance of multiple warning letters to companies marketing CBD products with  unfounded claims aimed at vulnerable populations

READ


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Treatment strategies for nicotine addiction and teen use of e-cigarettes

To address troubling epidemic of youth e-cigarette use

  • Youth Tobacco Prevention Plan to ensure no tobacco products marketed to kids
  • Enforcement actions on illegal sales
  • Public education campaigns to warn youth
  • Advanced new policies aimed at preventing youth access to flavored tobacco products, including e-cigarettes and cigars
  • Workshop to examine science and treatment strategies for youth tobacco cessation

READ


Capture.JPGA Risk-Based Approach to Monitoring of Clinical Investigations

Scope: identifying critical data and processes necessary for human subject protection,investigation integrity, risk assessment, specific monitoring plan

  • Tailor monitoring plans to needs of investigation
  • Factors to consider in developing monitoring plan
  • Examples of monitoring methods and techniques
  • Risk-based monitoring important tool to identify and address issue

Monitoring Approach: include information regarding identified risks and how monitoring methods will address those risks

Monitoring Plan Content: A detailed list

Follow-Up and Communication of Monitoring Results: Significant issues identified through monitoring with appropriate Corrective and Preventive Actions

READ


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Medical CounterMeasures (MCMs) update

FDA responsible for safety and effectiveness of MCMs—drugs, therapeutic biologics,vaccines, devices, such as diagnostic tests

  • Smallpox preparedness: TPOXX for treatment of smallpox
  • Chemical nerve agent preparedness: Atropine autoinjector for treatment of poisoning by susceptible organophosphorous nerve agents and Seizalam (midazolam intramuscular injection) for the treatment of status epilepticus
  • Radiological/nuclear emergency preparedness: New indication for Leukine (sargramostim) to increase survival in acute exposure to radiation
  • Viral encephalitis preparedness: IXIARO Japanese Encephalitis Virus Vaccine
  • Zika protection: COBAS Zika to screen Zika virus in blood donations
  • Pandemic influenza preparedness: FLUARIX Influenza Virus Vaccine

READ


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Finalized List of Accessories Suitable for Class I

For  accessory to be eligible for class I distinct from another device if the accessory

  • is not for use in supporting or sustaining human life
  • does not represent potential unreasonable risk of illness or injury
  • general controls sufficient for reasonable assurance of safety and effectiveness
§ 876.1080 Gastroenterology-urology accessories to a biopsy instrument
§ 876.3500 Penile implant surgical accessories
§ 876.4630 Ureteral stent accessories
§ 876.5012 Biliary stent, drain, and dilator accessories
§ 876.5100 Suprapubic catheter accessories
§ 876.5290 Implanted mechanical/hydraulic urinary continence device surgical accessories
§ 878.5080 Air-handling apparatus accessory
§ 886.4355 Corneal inlay inserter handle

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CaptureFDA OMH has a new name: FDA Office of Minority Health and Health Equity (OMHHE)

Reorganization reflects commitment to modernizing structure to:

  • Advance mission to protect and promote public health
  • Meet challenges of rapid innovation across industries regulated by FDA
  • Better captures breadth of portfolio and continue to address needs of racial and ethnic minority populations and underserved communities

New organization chart


Image credit: FDA

 

News & Views: Novel device materials, Modernize clinical trials, 2020 focus areas, New opioid REMS, Modernize mammography, Anthrax diagnostic reg pathway, AI/ML reg framework, Device inspections, Enforcement Actions

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Efforts to evaluate materials in medical devices to address potential safety questions

Materials used in today’s medical devices vary widely

  • Metal, plastic, silicone, an animal-derived product or some combination
  • Come into contact with tissue or other body parts for extended periods of time
  • Premarket review to determine potential adverse biological response
  • Post-marketing tools to monitor a device’s benefit-risk profile in real-world setting

Further enhance understanding of materials science 

  • Causes for exaggerated response in sensitive individuals
  • Advance development of safer materials
  • Case studies: Breast implants, Metals in devices, Animal materials in devices

CDRH’s OSEL conducting research on new advances in device materials

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 New strategies to modernize clinical trials to advance precision medicine, patient protections and more efficient product development

FDA opportunities for agile clinical research enterprise

However, sponsor reluctance to adopt innovative approaches

  • Rigid business model
  • Barriers between real world data and clinical research
  • Limited evidence sharing  across a learning health care system

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Focus Areas for Total Budget of $6.1 B

  • Reduce burden of addiction crisis
  • Foster competition by continued implementation of 21st Century Cures Act
  • Empower consumers/patients by promoting patient focused product development
  • Strengthen Science and Evidence-based decision making to enhance safety

READ


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New steps to strengthen safety requirements aimed at mitigating risks associated with transmucosal immediate-release fentanyl products

To confront opioid  crisis, Risk Evaluation and Mitigation Strategy (REMS) programs to ensure benefits outweigh risks

  • Opioid Analgesics REMS program covers transmucosal immediate-release fentanyl (TIRF) medicines – 9 products on market
  • Indicated to manage breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines to treat around-the-clock pain

Now modifying TIRF REMS – notifying manufacturers of following required changes

  • Document patient’s opioid tolerance concurrently with each prescription for outpatient use
  • Inpatient pharmacies to develop internal policies and procedures to verify opioid tolerance in hospitalized patients
  • Outpatient use requires evidence of safe use conditions, including concurrent documentation of opioid tolerance
  • New patient registry to monitor for serious adverse events including overdose (both fatal and non-fatal)

READ


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 Landmark policy changes to modernize mammography services and improve their quality

Proposed rule would require breast density reporting, enhance the FDA’s ability to enforce mammography facilities’ compliance with standards

  • FDA can directly notify patients and their health care professionals if facility did not meet quality standards
  • Only digital accessory components specifically FDA approved or cleared for mammography can be used
  • Strengthening record-keeping requirements to minimize information loss and improve access to and transfer of patient mammography records

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Finalized requirements for tests to detect anthrax-causing bacteria

FDA plays a critical role in protecting our nation from bioterrorism threats such as anthrax

  • Final rule provides review pathway, testing criteria, how to address potential safety risks for lab workers

Regulatory pathway: In vitro diagnostic devices for Bacillus bacteria detection

  • Class II (moderate-risk) with special controls – requires premarket notification 510(k)
  • Provide information on testing criteria and performance evaluations
  • Restriction on distribution to laboratories that follow public health guidelines to address appropriate biosafety conditions, interpretation of test results, and coordination of findings with public health authorities, to reduce risks associated specimen handling

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Capture.JPGProposed Regulatory Framework for Modifications to Artificial Intelligence/Machine Learning (AI/ML)-Based Software as a Medical Device (SaMD) 

Artificial intelligence and machine learning have the potential to fundamentally transform the delivery of health care

  • Earlier disease detection, more accurate diagnosis, identification of new observations or patterns on human physiology, development of personalized diagnostics and therapeutics
  • Greatest benefits of AI/ML in software is ability to learn from real-world use and experience (training) and improve performance (adaptation)
  • Deliver safe and effective software functionality that improves the quality of care that patients receive.

Use TPLC Model for regulatory framework to balance benefits and risks

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  • Quality systems and good ML practices (GMLP)
  • Premarket review for reasonable assurance of safety and effectiveness and continual management of  patient risks throughout lifecycle
  • Risk management approach for development, validation, execution of algorithm changes
  • Increased transparency to users and FDA using postmarket real-world performance reporting for maintaining continued assurance of safety and effectiveness

Framework to allow for modifications to AL/ML algorithms to be made from real-world learning and adaptation

  • Approved technoloigie use  “Locked” algorithms – don’t continually adapt or learn
  • Locked algorithms modified by manufacturer at intervals for “training” of algorithm using new data, followed by manual verification and validation of the updated algorithm.
  • Proposing Predetermined change control plan:  SaMD Pre-Specifications (SPS) and  Algorithm Change Protocol (ACP)

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Review and Update of Device Establishment Inspection Processes and Standards

Scope 

  • Standardized methods of communication during inspection process
  • Practices for investigators and device establishments to facilitate continuity of inspections

Uniformity in investigators’ approaches to inspections inform firms’ inspection preparation

  • Pre-announcement Notice and Communication:  Telephone notification 5 days prior (domestic) or longer (foreign) – inspection is abbreviated, comprehensive, or pre-approval
  • Standard Inspection Timeframe: Generally 3 to 6 continuous business days
  • Communication During Inspections: Regular verbal communications during inspection, discuss all observations to minimize errors and misunderstandings

READ


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Enforcement Actions: Breast implant manufacturers, illegal online sales of opioids

Breast Implant Manufacturer

Warning letters for

  • Failure to comply with their requirements to conduct post-approval studies
  • To assess the long-term safety and risks of silicone gel-filled breast implants

Mentor Worldwide LLC and Sientra, Inc.

Illegal online sales of opioids

Warning letters for

  • Illegal marketing potentially dangerous, unapproved and misbranded opioid medications, including tramadol
  •  In addition to health risks, pose other risks to consumers, including credit card fraud, identity theft and computer viruses

azmedicinalshop.com and thedonrx.net

Stem Cell Clinics

Warning letter for

  • Manufacturing unapproved umbilical cord blood products
  • Violation of current good manufacturing practice (CGMP) requirements, including failing to validate processes to prevent bacterial contamination, raising potential significant safety concerns that put patients at risk

Cord for Life


Image credit: FDA

Device Authorizations: OSIRIX software for device development, EARLYBIRD bleed monitor, CLEARMATE ventilator, MITRACLIP for mitral regurgitation

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OSIRIX CDE SOFTWARE MODULE (Medical Device Development Tool)

TBI Endpoints Initiative, Unv. of California, San Francisco

CONTEXT OF USE: Contusions, as assessed by an expert rater from MRI using OsiriX CDE Software Module MDDT, may be used for enrichment of clinical trials for therapeutic medical devices intended to improve outcomes at 3 months for patients aged between 18-65 years with acute non-penetrating head trauma and Glasgow Coma Scale (GCS) 13-15 who have undergone acute head CT (e.g., as part of standard clinical care) at a U.S. Level 1 trauma center

ADDRESSING UNMET NEED:

  • First biomarker test tool type
  • Tool for more efficient development of devices in traumatic brain injury (TBI) treatment

TOOL DESCRIPTION AND OPERATION:

  • Software module that provides standardized way to mark boundaries and classify brain contusions (bruises) using Common Data Element (CDE) criteria
  • Information can be used to label abnormalities on MR images for enriching enrollment in clinical trials for therapeutic medical devices intended to improve outcomes of mild Traumatic Brain Injury (TBI) patients
  • Detection of a medical device effect (if present) is more likely than it would be in an unselected population
  • Can be used by medical device developers to identify and enroll patients into TBI studies.

EVIDENCE TO SUPPORT QUALIFICATION:

  • Clinical study evaluate the association between contusions and diffuse axonal injury with 3-month Glasgow Outcome Scale  and Interrater reliability
  • Previous investigations and pilot studies on level of risk associated with MDDT use,  possible advantages/disadvantages

REGULATORY PATHWAY: Qualification through MDDT pathway

  • Program to qualify tools that medical device sponsors can use in the development and evaluation of medical devices
  • ‘Qualification’ means FDA has evaluated the tool and concurs with available supporting evidence that the tool produces scientifically and clinically meaningful measurements within the authorized context of use
  • Qualified tools serve as a resource that can be referenced by any medical device sponsor
  • When used consistent with the qualified Context of Use: Results support regulatory decision-making, eliminates sponsor burden to demonstrate validation, reduces workload of FDA staff e

QUALIFICATION SUMMARY


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EARLY BIRD Bleed Monitoring System

Saranas, Inc

INDICATION FOR USE: For the introduction of catheters, catheter balloons, and other diagnostic and interventional devices into the femoral artery or femoral vein while maintaining hemostasis during diagnostic and interventional endovascular procedures.
The Early Bird provides physicians with an early indication of a potential internal bleeding complication by initial detection and monitoring of extravascular fluid accumulation.

GENERIC TYPE OF DEVICE: Intravascular bleed monitor.

Probe, catheter, or catheter introducer that measures changes in bioimpedance and uses an algorithm to detect or monitor progression of potential internal bleeding complications.

RISKS & MITIGATIONS: 

  • Adverse tissue reaction: Biocompatibility evaluation
  • Infection: Sterilization validation, Pyrogenicity testing, Shelf-life testing, Labeling
  • Blood loss, bleeding, hematoma: Human factors testing, Labeling, Animal performance testing, Non-clinical performance testing
  • Embolization (micro or macro) with ischemia: Human factors testing, Labeling
    Animal performance testing, Non-clinical performance testing
  • Vascular trauma: Human factors testing, Labeling, Animal performance testing, Non-clinical performance testing
  • Electrical shock: Electrical safety testing
  • Device failure due to interference with other devices: Electromagnetic compatibility (EMC) testing, Electrical safety testing
  • Device failure due to software malfunction: Software verification, validation, hazard analysis

REGULATORY PATHWAY: De Novo classification

  • Regulation Number: 21 CFR 870.1345
  • Regulation Name: Intravascular bleed monitor
  • Regulatory Class: Class II
  • Product Code: QFJ

CLASSIFICATION ORDER


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CLEARMATE ventilation device

Thornhill Research, Inc.

INDICATION FOR USE: To be used by emergency department medical professionals as an adjunctive treatment for patients suffering from carbon monoxide poisoning. The use of ClearMate enables accelerated elimination of carbon monoxide from the body by allowing isocapnic hyperventilation through simulated partial rebreathing

ADDRESSING UNMET NEED: 

  • Carbon monoxide poisoning affects thousands of people each year
  • Hyperbaric treatment, necessary for severe poisoning, has low accessibility; only 60 US medical centers with hyperbaric units
  • New device provides access to lifesaving device

DEVICE DESCRIPTION:

  • Gas mixer, valves, meters, breathing circuits, oxygen reservoir, mask and hoses
  • Speeds up elimination of carbon monoxide from body
  • Delivers both 100 % oxygen to patient, as well as a mixture of oxygen and carbon dioxide, to breathe faster
  • Increased breathing accelerates rate of elimination of carbon monoxide in body

GENERIC DEVICE TYPE: Isocapnic ventilation device

Prescription device used to administer a blend of carbon dioxide and oxygen gases to a patient to induce hyperventilation. This device may be labeled for use with breathing circuits made of reservoir bags (21 CFR 868.5320), oxygen cannulas (21 CFR 868.5340), masks (21 CFR 868.5550), valves (21 CFR 868.5870), resuscitation bags (21 CFR 868.5915), and/or tubing (21 CFR 868.5925).

EFFECTIVENESS AND SAFETY:

  • Data from multiple clinical studies for efficacy and safety, n=100
  • Effective at eliminating carbon monoxide; combination of oxygen and carbon dioxide resulted in faster elimination of carbon monoxide but not faster than hyperbaric oxygen therapy
  • Patients did not experience any device-related complications

RISKS & MITIGATIONS:

  • Hypocapnia (lacking CO2): Non-clinical performance testing, Labeling
  • Hypercapnia (excess CO2): Non-clinical performance testing, Labeling
  • Hypoxemia (lacking O2): Non-clinical performance testing, Labeling
  • High airway pressure (e.g., barotrauma): Non-clinical performance testing
    Labeling
  • Adverse tissue reaction: Biocompatibility evaluation

REGULATORY PATHWAY: De Novo classification

  • Regulation Number: 21 CFR 868.5480
  • Regulation Name: Isocapnic ventilation device
  • Regulatory Class: Class II
  • Product Code: QFB

CLASSIFICATION ORDER


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 MITRACLIP NT Clip Delivery System and MITRACLIP NTR/XTR Clip Delivery System

Abbott Vascular

EXPANDED INDICATION:  To include secondary (or functional) mitral regurgitation (MR), when MR is caused by a dysfunctional left ventricle, not by degeneration of the mitral valve itself

ORIGINAL INDICATION (2013): For the percutaneous reduction of significant symptomatic mitral regurgitation (MR ≥ 3+) due to primary abnormality of the mitral apparatus [degenerative MR] in patients who have been determined to be at prohibitive risk for mitral valve surgery by a heart team, which includes a cardiac surgeon experienced in mitral valve surgery and a cardiologist experienced in mitral valve disease, and in whom existing comorbidities would not preclude the expected benefit from reduction of the mitral regurgitation.

ADDRESSING UNMET NEED: 

  • 6.5 million American adults live with chronic heart failure
  • Small percentage also have moderate-to-severe or severe secondary mitral regurgitation, increasing risks and complicating heart failure treatment
  • This small percentage of patients could be candidates for the new indication

DESCRIPTION:

  • MitraClip device repairs MR without open-heart surgery and is delivered to the heart through a small incision in the leg
  • Clips portions of the leaflets, or flaps, of the mitral valve together to reduce the backflow of blood, restoring the heart’s ability to pump oxygenated blood more efficiently

EFFECTIVENESS & SAFETY:

  • Patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation, n=614,  transcatheter mitral-valve repair plus medical therapy (device group)  vs. medical therapy alone (control group)
  • Primary effectiveness end point: All hospitalizations for heart failure within 24 months of follow-up
    • 35.8% per patient-year in device group vs. 67.9% per patient-year in control group, P<0.001
  • Primary safety end point: Freedom from device-related complications at 12 months vs. performance goal of 88.0%
    • 96.6%  vs. 88% performance goal, P<0.001
    • Death from any cause: 29.1% in device group vs. 46.1% in control, P<0.001
  • Potential adverse events: Death, stroke, major bleeding, and atrial fibrillation

CONSUMER INFORMATION


Image Credit: UCSF, Saranas, Thornhill, Abbott 

Drug Authorizations: SPRAVATO for treatment-resistant depression, CABLIVI for thrombotic thrombocytopenic purpura, EGATEN for fascioliasis

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SPRAVATO™ (esketamine) nasal spray, CIII

 Janssen Pharmaceuticals, Inc.

INDICATION: In conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults
Limitations of Use: Not approved as an anesthetic agent

ADDRESSING UNMET NEED:

  •  Long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition
  • FDA review of safety and efficacy along with robust discussion with external advisory committee

MECHANISM OF ACTION: Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor; mechanism of antidepressant effect is unknown

EFFICACY:

  • Three short-term (four-week) clinical trials and one longer-term maintenance-of-effect trial; Spravato vs. placebo nasal spray – all patients on new oral antidepressant (AD) from time of randomization
  • Primary endpoint: Change in baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score
  • SPRAVATO plus AD demonstrated statistical superiority vs. placebo
  • Timecourse: SPRAVATO’s treatment difference observed at 24 hrs; both arms continued to improve to Day 28.
  • In the longer-term maintenance-of-effect trial: SPRAVATO + AD experienced a statistically significantly longer time to relapse of depressive symptoms vs, placebo

SAFETY:

  • Boxed Warning: Risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug
  • REMS with Patient Enrollment Form and patient Medication Guide; self-administration of nasal spray under supervision of health care provider in certified doctor’s office or clinic; spray cannot be taken home
  • Most common side effects: Disassociation, dizziness, nausea, sedation, vertigo, decreased feeling or sensitivity (hypoesthesia), anxiety, lethargy, increased blood pressure, vomiting and feeling drunk.

REG PATHWAY: NDA

  • The FDA approved ketamine (Ketalar) in 1970. This is the first FDA approval of esketamine for any use
  • Fast Track and Breakthrough Therapy designations
  • Postmarketing requirements: Long-term effects esketamine on cognitive function and urinary symptoms, further characterize potential risk of increasing thyroid stimulating hormone levels

LABEL


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 CABLIVI (caplacizumab-yhdp) 

Ablynx N.V.  and Genzyme (Sanofi)

INDICATION: Treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy

ADDRESSING UNMET NEED: Treatment option for a Rare disease

MECHANISM OF ACTION: Targets A1-domain of von Willebrand factor (vWF) and inhibits the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption

EFFICACY & SAFETY:
  • Clinical study, n=145 patients with aTTP stratified per Glasgow Coma Scale score, CABLIVI vs placebo,  median treatment duration of 35 days
  • Endpoint: Time to platelet count response (platelet count ≥150,000/µL followed by cessation of daily plasma exchange within 5 days
  • Time to platelet count response shorter with CABLIVI vs. placebo, lower number of  TTP-related deaths (0 vs. 3) and TTP recurrence (3 vs. 28)
  • Recurrence of TTP in overall study period lower with CABLIVI vs placebo (28/73 patients [38%]; p<0.001)
  • Most common adverse reactions:  Epistaxis, headache, and gingival bleeding.

REG.PATHWAY:  BLA

  • Priority review and orphan product designation
  • Postapproval commitments on manufacturing and testing
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EGATEN™ (triclabendazole) tablets, for oral use

Novartis

INDICATION:  Treatment of fascioliasis in patients 6 years of age and older.
ADDRESSING UNMET NEED:
  • WHO estimates ~ 2.4 million infected people infected in > 70 countries worldwide
  • Treatment option for global markets

MECHANISM OF ACTION: Anthelmintic against Fasciola species

EFFICACY: 

  • Open label, randomized trial, in Vietnam, n=100 children, EGATEN vs. artesunate, 3 months treatment
  • No clinical symptoms in  92% EGATEN vs in 76% placebo, p = 0.035
  • Six nonrandomized, open label studies in Cuba, Bolivia, Peru, Chile, Iran, n=245 adult and pediatric patients with stool-confirmed fascioliasis
  • Cure defined as absence of Fasciola eggs in stool based on Kato-Katz method. Day 60
  • Dose response seen in all studies

SAFETY:

  • Most common adverse reactions: Abdominal pain, hyperhidrosis, nausea, decreased appetite, headache, urticaria, diarrhea, vomiting, musculoskeletal chest pain, pruritus

REG PATHWAY: NDA

  • Fast Track and Orphan Drug designations
  • Tropical Disease Priority Review Voucher to encourage development of products for certain tropical diseases
  • Postmarketing requirements: QT/QTc trial, additional dose evaluation,
Image credits: Janssen, Sanofi, Novartis

 

News & Vews: Farewell Commissioner Gottlieb, Patient participation in cancer clinical trials, CDRH reorganization, Request to Connect for patients, Implanted Brain-Computer Interface devices, Safe Use alerts

Capture.JPGFarewell Commissioner Gottlieb

Sincere gratitude for your leadership and exemplary work during your current FDA tenure. You have been an inspiration.Capture.JPGEXIT INTERVIEW


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New steps to broaden patient participation in cancer clinical trials

FDA issued new recommendations for broadening cancer trial eligibility criteria

  • More representative of patient population
  • Maximize the generalizability of the trial results
  • Maximize understanding of therapy’s benefit-risk profile across the patient population likely to receive the drug in clinical practice

Broadening eligibility criteria to include:  Pediatric patients, Patients with HIV, Hepatitis B and Hepatitis C Virus infections, Patients with brain metastases, organ dysfunction and prior or concurrent malignancies

New Guidances

READ


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Reorganization of CDRH

CDRH reorganization to implement efficiencies to integrate CDRH’s premarket and postmarket program functions

  • Reviewers, compliance officers and other experts would work in teams responsible for device oversight throughout the product’s development and commercialization
  • More integrated approach to device safety throughout the Total Product Life Cycle (TPLC) – already in pilot testing
  • Timeline: March 18, 2019 (begin) – September 30, 2019 (full implementation)

New Offices 

  • Office of Product Evaluation and Quality (OPEQ) :  Combines Office of Compliance, Office of Device Evaluation, Office of Surveillance and Biometrics, and  Office of In Vitro Diagnostics
  • Office of Policy – Two teams, the Guidance, Legislation and Special Projects Team and the Regulatory Documents and Special Projects Team
  • Office of Strategic Partnerships and Technological Innovation – Combines Science & Strategic Partnerships, Digital Health, Health Informatics and Innovation teams

READ


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“Request to Connect” – A New Way for Patients to Connect with FDA

“Request to Connect” portal is live
  • Gives patients and caregivers a single entry point to the Agency for questions and meeting requests
  • Co-developed by Patient Affairs Staff and the medical product centers
  • Will route inquiries to appropriate medical product center or office for responses in effective and efficient manner
  • Opportunity for FDA to better understand patient perspective and advance science of patient input

Implanted Brain-Computer Interface (BCI) Devices for Patients with
Paralysis or Amputation – Non-clinical Testing and Clinical
Considerations

Implanted BCI devices increase ability to interact with environment and provide independence to patients with paralysis or amputation

  • Interface with nervous system to restore motor and/or sensory capabilities
  • Recommendations for non-clinical testing and study design considerations for IDE feasibility and pivotal clinical studies

Non-Clinical Bench Testing Considerations: Risk analysis, Electrodes, Leads and Connectors, Implanted casing and electronics, Output simulation measurements, Output simulation safety, Programmers/control unit, Radiofrequency transmitter and receiver, System level testing, factors for determining and design of animal studies

Clinical Study Considerations: Patient population, Home-Use, Duration and follow-up schedule, Inclusion/Exclusion criteria, Demographics, Treatment parameters, Endpoints including patient input (patient engagement. patient preference information, patient reported outcome measures)

READ


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SAFE USE ALERTS: Surgical Staplers and Staples, Contact Lenses

Surgical Staplers and Staples:

  • Increased number of adverse events reported to the FDA since 2011: 366 deaths, > 9,000 serious injuries, > 32,000 malfunctions
  • FDA Actions:
    • Letter to Healthcare Providers
    • Issue draft guidance on recommendations to manufacturers
    • Hold public meeting of  General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee  to reclassify as Class II (from Class I)
    • Require premarket notification and establish mandatory special controls to help mitigate known risks 

Contact lenses 

  • Risk of several serious conditions including eye infections and corneal ulcers
  • Can develop very quickly, be serious and can cause blindness
  • Video on safe and effective use

Image credits: FDA

News & Views: Flu vaccine supply, Rare Disease Day, Childhood Cancer Advocacy Forum, Heart Devices, Physiologically Based Pharmacokinetic (PBPK) Modeling

Capture.JPGEnsuring Supply of Influenza Vaccine

Starts well before the current flu season ends – a year-round initiative

  1. Vaccine composition changes every year as flu viruses are constantly evolving
  2. Collaboration of FDA, WHO, CDC to evaluate global circulating strains and disease trends
  3. FDA advisory committee recommend 3-4 strains to include in trivalent and quadrivalent influenza vaccines
  4. Manufacturers begin manufacturing process to include the newly selected flu strains and seek FDA approval for lot release – quality control tests, including testing for sterility

READ


CaptureObservation of Rare Disease Day

Created to raise awareness about the 7,000 known rare diseases with theme of Bridging Health and Social Care

READ


CaptureOncology Center of Excellence Childhood Cancer Advocacy Forum

Topics for Discussion:

  • FDA’s External Engagement and Patient Advocacy: A Dialogue to Better Inform FDA of Patient Needs and Priorities
  • Avoiding Pitfalls in Drug Development
  • Approved Cancer Drugs in Children
  • BPCA/WR Study Results
  • Expanded Access to Investigational Drugs
  • FDARA Implementation
  • Pediatric PROs: Are they feasible?

Register here for in-person or online attendance


CaptureHeart Devices regulated by FDA

  • Automated external defibrillators (AEDs): Portable and automatic,  to restore normal heart rhythm
  • Cardiac ablation catheters: Long, thin flexible tubes.  to treat abnormally rapid heartbeats
  • Cardiovascular angioplasty devices: Long, thin, flexible tubes threaded into  heart vessel to open narrowed or blocked areas
  • Cardiac pacemakers: Small, battery-powered, implanted permanently, monitor heart’s electrical impulses. deliver electrical stimulation if bradycardia
  • Implantable cardioverter defibrillators (ICDs): Monitor heart rhythms and deliver shocks if dangerous tachycardia
  • Prosthetic (artificial) heart valves: Replacing diseased or dysfunctional heart valves,
  • Stents: Small, lattice-shaped, metal tubes, some with drugs,  to improve blood flow
  • Ventricular assist devices (VADs): Mechanical pumps for short-term or long term use

Warning signs and symptoms of a heart attack 


CaptureSupporting Drug Development Through Physiologically Based Pharmacokinetic (PBPK) Modeling

PBPK Models to Mechanistically Predict Drug Pharmacokinetics

  • Grounded in human physiology – describe time course of absorption, distribution, metabolism, and elimination of one or more drugs
  • Includes anatomical or physiological parameters such as blood flow, tissue composition, enzyme abundance, drug-specific values, such as tissue-to-plasma concentration ratios, metabolism and clearance
  • Make predictions on drug concentrations achieved in the absence of clinical data
  • Focus to improve accuracy of predictions and incoporate PBPK models in drug development

READ


image credit: FDA

News & Views: 2019 Opioid Agenda, Quality for Continuous Manufacturing, Task Force for Public Health Emergencies, Brain Computer Interface devices, Quantifying Oncology Patient Experience

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2019 policy and regulatory agenda for continued action to forcefully address the tragic epidemic of opioid abuse

New actions to build on 2018 efforts and also adapt to changing nature of threat

  • Reducing Misuse and Abuse of Opioid Drugs: Appropriately prescription, dose, quantity, treatment duration, disposal, REMS effectiveness
  • Support Addiction Recovery and Reduce Overdose Deaths:  OTC naloxone with model Drug Facts Labels with easy directions for use
  • Research and Innovation in Non-Addictive Pain Treatments: Non-opioid drugs, abuse-deterrent features
  • Strengthen Enforcement Against Illicit Opioids: Partnership with U.S. Customs and Border Protection

READ


CaptureQuality Considerations for Continuous Manufacturing

Continuous technology is foundation for improving  overall quality of products and availability to patients

  • Integrated process with fewer steps , shorter processing times, smaller equipment footprint, enhanced development approach e.g., quality by design (QbD) and use of process analytical technology (PAT)

Quality considerations

  • Key Concepts: Process dynamics, Defining batches for continuous manufacturing processes
  • Control Strategy: Input material, Process monitoring, Material diversion, Real Time Release, Specification, Equipment, System integration, Data processing, and Management
  • Process Validation: Stage 1 – Process  Design, Stage 2 – Process  Qualification, Stage 3 – Continued Process Verification
  • Additional Pharmaceutical Quality System Considerations: Scale-Up,  Stability, Bridging existing batch to Continuous Manufacturing
FDA requesting comments on
  • data storage and handling from process analytical technology systems
  • potential approaches for situations where direct attribute measurement is not possible (e.g., low dose compounds)
  • contract manufacturers employing continuous manufacturing
  • risk-based reporting of routine model maintenance and updates
  • statistical approaches using large samples (e.g., Large N)

DRAFT GUIDANCE


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FDA, CDC, and CMS launch task force to help facilitate rapid availability of diagnostic tests during public health emergencies

The Tri-Agency Task Force for Emergency Diagnostics (TTFED)ompsed of FDA + CDC + CMS

  • Collaborate on future emergency diagnostic response needs
  • Convene, provide timely recommendations to laboratories for rapid implementation of FDA’s Emergency Use Authorization (EUA) assays

Focus to

  • establish efficient communication channels between TTFED members
  • formalize and document interagency process for rapid implementation of EUA IVD assays in public health emergency
  • provide timely recommendations during emergencies

READ


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Implanted Brain-Computer Interface (BCI) Devices for Patients with Paralysis or Amputation – Non-clinical Testing and Clinical Considerations

Implanted BCI devices have potential to bring benefit to people with severe disabilities by increasing their ability to interact with their environment, and consequently, providing new independence in daily life

  • Implanted BCI devices are neuroprostheses that interfaces with central or peripheral nervous system to restore lost motor and/or sensory capabilities in patients with paralysis or amputation

Pre-Submission/IDE recommendations:

  • Device description
  • Software
  • Biocompatibility
  • Sterility
  • Pyrogenicity
  • Shelf life and packaging
  • Electrical safety and Electromagnetic compatibility
  • Wireless technology
  • Magnetic resonance compatibility
  • Non-clinical bench testing
  • Risk analysis
  • Electrodes
  • Leads and connectors
  • Implanted casing and electronics
  • Output simulation measurements
  • Output stimulation safety
  • Programmrrs/control unit
  • Radiofrequency transmitter and receiver
  • System level testing
  • Referencing Master Files
  • Animal testing scope
  • Clinical study considerations

READANNOUNCEMENT


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Oncology Center of Excellence — Quantifying the Patient Experience

Collaboration between FDA Centers and external stakeholders involved in patient outcomes research in cancer populations

  • Actively engaging with patients and advocacy groups
  • Fostering research into measurement of the patient experience
  • Generating science-based recommendations for regulatory policy

Goals to assess patient experience that complement existing survival and tumor information

  • Learning from Patient Experiences
  • Collaborating with Patients, Public and Private Sectors
  • Fostering Continued Engagement

READ


Image credit: CMS, FDA

News and Views: Voluntary Consensus Standards, Stopping Illicit Opioids, Device Inspection Nonbinding Feedback, Ebola Virus Pathogenesis

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Voluntary Consensus Standards to promote the adoption of innovations in drug manufacturing that can improve quality and lower drug costs

Recognizing “voluntary consensus standards” based on nationally and internationally accepted standards for drug quality

  • New draft guidance  to propose pharmaceutical quality standards for potential recognition by the FDA, providing industry with additional options for pharmaceutical development and manufacturing
  • Promote and expedite  development, streamline FDA review of drug product applications
  • Provide list of recognized standards on website; reduce regulatory uncertainty

READ


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Efforts to stop the spread of illicit opioids, further secure the U.S. drug supply chain and forcefully confront opioid epidemic

Efforts to stopping spread of illicit opioids and  securing all aspects of supply chain

  • Enforcement and interdiction of illegal shipment through US Postal Services
  • Work closely with U.S. Customs and Border Protection and U.S. Department of Justice
  • Warning Letters for illegal online marketing
  • Online Opioid Summit with appropriate stakeholders for stronger action
  • Warning letter under the Drug Supply Chain Security Act (DSCSA) McKesson Corp
  • New guidances
    • Risk/benefit framework to opioid analgesics including illicit use risks
    • Modernize development pathway for non-opioid analgesics for specific clinical conditions
    • Packaging requirements to limit number with single prescription
  • Continue work in accordance with Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act

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Nonbinding Feedback after Certain FDA Inspections of Device Establishments

Standardized method for communicating and submitting requests for nonbinding feedback and describes how FDA evaluates and responds to such requests

  • Request for nonbinding feedback submitted by device establishment to FDA regarding firm’s proposed actions to address Form 483 inspectional observations

Firm’s proposals for addressing Inspectional Observations related to

  • release of violative product that may cause death or serious injury
  • production of nonconforming, violative, and/or defective finished devices
  • release of devices likely to cause 196 death or serious injury

FDA informal feedback on whether proposals

  • address inspectional observations
  • partially adequate or inadequate with explanation
  • recommend what may be needed to be adequate

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Capture.JPGNew approach for understanding Ebola Virus Pathogenesis

Contract with Broad Institute to conduct the largest Ebola virus and host gene expression (i.e., transcriptomics) study

  • Assess how Ebola virus evolves and spreads within the body
  • Identify mechanisms and biological pathways altered in immune cells and tissues during infection
  • Inform natural history of Ebola virus disease in humans
  • Characterize nonclinical models necessary for testing
  • Utilize fordeveloping medical countermeasures (MCMs) to prevent and treat Ebola virus disease

READ


Image credit: FDA

News & Views: Patients First, Least Burdensome Provisions, Drug Supply Chain security, 510(K) exemptions

Capture.JPGFDA’s Patient Affairs Staff (PAS)-  FDA Puts Patients First

PAS works with patients, caregivers, and advocates in 2019
  • Understanding patient experience and incorporating patient feedback into FDA’s work

PAS launched several initiatives to support and connect with patients


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The Least Burdensome Provisions: Concept and Principles

Final guidance on use of least burdensome approach to medical device regulation
  • Support timely patient access to high quality, safe and effective medical devices
  • Remove or reduce unnecessary burdens throughout total product lifecycle
  • Maintaining statutory requirements for clearance and approval
  • Principles are based on sound science, intent of the law, use of alternative approaches, efficient use of resources to effectively address regulatory issues

Guiding principles

  • FDA to request minimum information necessary to adequately address regulatory question or issue at hand
  • Industry should submit material, including premarket submissions, that are least burdensome for FDA to review
  • FDA to use most efficient means to resolve regulatory questions and issues
  • Right information provided at right time (e.g., just-in-time data collection) to address right questions
  • Regulatory approaches designed to fit technology, taking into account unique innovation cycles, evidence generation needs, timely patient access
  • FDA to leverage outside US data to the extent appropriate and feasible

READ


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Improving security of Drug Supply Chain through innovations that improve tracking and tracing of medicines

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Intent to Exempt Certain Unclassified Medical Devices from Premarket Notification Requirements

Intent to exempt certain unclassified medical devices from premarket notification requirements

  • Devices are sufficiently well understood
  • Do not require premarket notification (510(k)) to assure their safety and effectiveness.

Device categories

  • Ear, Nose, and Throat
  • Gastroenterology-Urology
  • General and Plastic Surgical
  • Neurological
  • Obstetrical and Gynecological Devices
  • Physical Medicine Devices

READ


Image credit: FDA


Market Authorizations: ULTOMIRIS for paroxysmal nocturnal hemoglobinuria, Personal Genome Service (PGS) for Cervical Cancer screening

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ULTOMIRIS (ravulizumab-cwvz) injection

Alexion Pharmaceuticals
INDICATION: Treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH)
ADDRESSING UNMET NEED:
  • PNH is a rare acquired disorder that leads to the rupture or destruction of red blood cells (hemolysis)
  • Prior to this approval, treatment required every two weeks, which can be burdensome for patients and families
  • Novel formulation so patients only need treatment every eight weeks, without compromising efficacy

MECHANISM OF ACTION: Terminal complement inhibitor specifically binds to complement protein C5 with high affinity; inhibits terminal complement-mediated intravascular hemolysis in patients with PNH

EFFICACY & SAFETY:
  • First randomized clinical trial, n=246 PNH patients (treatment naïve), Ultomiris vs. eculizumab, current standard of care for PNH
  • Non-inferiority on endpoints: Transfusion avoidance and hemolysis directly measured by normalization of LDH levels
  • Second randomized trial, n=195 PNH patients clinically stable after eculizumab treatment, Ultomiris vs. continue eculizumab
  • Similarity on several clinical measures including hemolysis and avoiding transfusion
  • Common side effects: Headache, upper respiratory infection
  • Boxed Warning: Risk of life-threatening meningococcal infections and sepsis
REGULATORY PATHWAY: BLA
  • Priority Review designation, Orphan Drug designation
  • Postmarketing commitments: Data from clinical trials in patients with paroxysmal nocturnal hemoglobinuria (ALXN1210-PNH-301 and ALXN1210-PNH-302) to include the extension period of up to 2 years of follow-up

Personal Genome Service (PGS) Genetic Health Risk Report for
MUTYH-Associated Polyposis for Cervical Cancer screening

23andMe

INTENDED USE: PGS uses qualitative genotyping to detect select clinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years for the purpose of reporting and interpreting genetic health risks, including the 23andMe PGS Genetic Health Risk Report for MUTYH-Associated Polyposis (MAP)

INDICATION FOR USE: The 23andMe PGS Genetic Health Risk Report for MUTYHAssociated Polyposis is indicated for reporting of the Y179C and the G396D variants in the MUTYH gene. The report describes if a person is at increased risk of developing colorectal cancer. The two variants included in this report are most common and best studied in people of Northern European descent and may not represent the majority of the MUTYH variants found in people of other ethnicities. 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.

DESCRIPTION:

  • The core components of the PGS are unchanged from the de novo authorization for the predicate device, the PGS Genetic Health Risk Report for BRCA1/BRCA2 and also the additional de novo Authorizations of the PGS for Carrier Screening Tests for Bloom Syndrome and PGS Genetic Health Risk Reports including saliva collection kit, reagents and beadchip, instrumentation, software, test processes, procedures
  • Novel components: (a) specific variants to be reported (b) qualitative reporting of risk for MAP, as opposed to the BRCA related cancer risks

REGULATORY PATHWAY: Traditional 510(k)

  • Trade/Device Name: MUTYH-Associated Polyposis (MAP)
  • Regulation Number: 21 CFR 866.6090
  • Regulation Name: Cancer Predisposition Risk Assessment System
  • Regulatory Class: Class II
  • Product Code: QAZ

SUMMARY


Image credits: Alexion, 23andMe

News & Views: FDA opens, CDRH record-setting year, New Drug Class for Migraines

FDA Opens

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Capture.JPGCapture.JPGCDRH-Record Year for Device Innovation

Success in advancing device innovation and approval/clearance novel, safe and effective technologies

  • Approval of 106 novel devices, surpassing the 40-year record we set in 2017 of 99
  • Granted 112 Breakthrough Device Designation requests;  9 approved/cleared

Examples of innovative products

  • Automated insulin dosing system – including for those as young as age 7
  • World’s smallest heart valve for newborns
  • First blood test in the world to evaluate mild traumatic brain injury
  • First mobile medical app to help treat substance abuse disorders\
  • Artificial Intelligence to detect diabetic retinopathy in adults
  • Artificial Intelligence to detect wrist fractures
  • First artificial iris

READ


captureNew Drug Class Employs Novel Mechanism for Migraine Treatment and Prevention

Recently approved drug class targeting  calcitonin gene-related peptide (CGRP) – elevated in blood serum during migraine attacks

  • New migraine drugs block effects of CGRP
  • Specialized monoclonal antibodies cloned subclasses of immunoglobulin G (IgG)
  • Designed to have low potential to interact with other drugs
  • Metabolized differently with fewer adverse reactions
  • Aimovig (erenumab-aooe), Ajovy (fremanezumab-vfrm), Emgality (galcanezumab-gnlm)

READ


Image credit: FDA

 

 

New & Views: Shutdown snapshots, Gene Therapy policies, Sentinel safety surveillance, 510(k) modernization, Accelerated Approval labeling

Shutdown Snapshots 

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Surge of cell and gene therapy products reflecting significant scientific advancement 

  • Anticipate >200 INDs /year by 2020
  • Anticipate approving 10 1 20 cell and gene therapy products/year  by 2025

New policies to advance development and approval

  1. Expediting programs including regenerative medicine advanced therapy (RMAT) designation and accelerated approval
  2. Series of clinical guidance documents on different areas of development including neurodegenerative diseases
  3. Efficient pathways for regulatory compliance particularly to assist small sponsors, including academic investigators

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Capture.JPGThe Future of FDA’s Electronic Safety Surveillance

https://www.sentinelinitiative.org/

Sentinel is integral part of FDA’s safety monitoring efforts

  • Influential in range of outcomes including label changes, Advisory Committees meetings, safety evidence
  • Widespread use of real world evidence (RWE) to increase product development  efficiency and lower cost
  • Pursuing ways to better incorporate information from electronic health records (EHRs) into pre- and post-market surveillance

Five-year strategy

  • Enhance and expand the Sentinel System’s foundation, including data, infrastructure, operations and technology;
  • Augment Sentinel’s safety analysis capabilities using advances in data science and signal detection;
  • Use Sentinel System to accelerate access to and broaden the use of real world data for real world evidence;
  • Broaden the Sentinel System’s ecosystem of stakeholders to pursue the vision of a national resource; and
  • Disseminate knowledge and advance regulatory science to encourage innovation and meet the agency’s scientific needs.

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Capture.JPGSteps to strengthen its 510(k) pathway by promoting the use of robust performance criteria and modern predicate devices

Safety and Performance Based Pathway

  • Expands approach previously applied through Abbreviated 510(k) Program, based on conformity to FDA-recognized consensus standards
  • Show new device meets FDA-identified performance criteria reflecting current technological principles and the safety and performance of modern predicate devices
  • May request and review underlying data and testing methodologies for substantially equivalent assessment

Promoting use of more modern predicate devices

  • Make public a list of devices or manufacturers who make technologies that rely on predicates that have been on the market for more than a certain number of years (e.g., 10 years)
  • Consider using other criteria to inform our point of reference?
  • Promote use of more modern predicates
  • New authority, such as making at least some older devices ineligible as predicates

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Labeling for drugs approved under accelerated approval, reflecting the more frequent use of this pathway for drugs used in certain clinical settings

Focus on indications for drugs approved via accelerated approval based on surrogate endpoint or clinical endpoint other than survival or irreversible morbidity

Example: This indication is approved under accelerated approval based on {state effect on surrogate endpoint or intermediate clinical endpoint that supported the accelerated approval} [see Clinical Studies (14.X)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Considerations:  

  • Limitations of Usefulness and Clinical Benefit : Uncertainty, Continued Approval
  • When Clinical Benefit Has Been Verified
  • Withdrawal of an Accelerated Approved Indication: Lack of Evidence Concerning the Withdrawn Indication, Safety Information Concerning the Withdrawn Indication

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Image credit: FDA

Novel Device Market Authorizations: MIRIS Human Milk Analyzer, SEM Scanner for pressure ulcer, EyeBOX for concussion, ENLIGHT 1810 for mechanical ventilation

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MIRIS Human Milk Analyzer

Miris AB

INDICATION FOR USE: Quantitatively measures the concentration of fat, carbohydrate, and protein in human milk. The Miris HMA also provides calculated values for total solids and energy. These measurements, in conjunction with other clinical assessments, may be used to aid in the nutritional management of newborns, including preterm, and infants. This device is intended for use in healthcare by trained healthcare personnel at clinical laboratories.

ADDRESSING UNMET NEED:

  • Some infants — including those who may be born preterm or have certain health conditions — may need additional nutrients in order to support their optimal growth
  • Doctors have access to test to analyze nutrients in breast milk to aid parents and healthcare providers

DESCRIPTION: Breast Milk Macronutrients Test System

  • Intended to quantitatively measure fat, protein, and total carbohydrate content in human breast milk. These measurements, in conjunction with other clinical assessments, may be used to aid in the nutritional management of infants

SAFETY AND EFFECTIVENESS:

  • N= 112 samples of human milk; comparison of machine vs expected values
  • Device effective at determining levels of protein, fat and carbohydrate in the milk
  • However, certain medications taken by nursing mother could interfere with test’s ability

RISKS AND MITIGATIONS:

  • Incorrect test results: General controls and special controls 
  • Incorrect action based on test results: General controls and special controls 

REGULATORY PATHWAY: De Novo request

  • Regulation Number: 21 CFR 862.1493 
  • Regulation Name: Breast milk macronutrients test system
  • Regulatory Class: Class II 
  • Product Code: QEI

CLASSIFICATION ORDER


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SEM Scanner (Model 200) for Pressure Ulcers

Bruin Biometrics

INDICATION FOR USE: Intended to be used by healthcare professionals as an adjunct to standard of care when assessing the heels and sacrum of patients who are at increased risk for pressure ulcers

DESCRIPTION: Pressure ulcer management tool

  • Prescription device intended for patients at risk of developing pressure ulcers. The device provides output that supports a user’s decision to increase intervention. The device is an adjunct tool for pressure ulcer management that is not intended for detection or diagnostic purposes.
 

RISKS & MITIGATIONS:

  • Class I (general) controls provide reasonable assurance of safety and effectiveness 
  • Identified risks to health are adverse tissue reaction, transmission of infection between patients, electromagnetic interference with patient monitoring equipment, electrical shock

REGULATORY PATHWAY: De Novo request

  • Regulation Number: 21 CFR 876.2100
  • Regulation Name: Pressure ulcer management tool 
  • Regulatory Class: Class I 
  • Product Code: QEF

CLASSIFICATION ORDER


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EyeBOX

Oculogica

INDICATION FOR USE: Intended to measure and analyze eye movements as an aid in the diagnosis of concussion within one week of head injury in patients 5 through 67 years of age in conjunction with a standard neurological assessment of concussion.
A negative EyeBOX classification may correspond to eye movement that is consistent with a lack of concussion.
A positive EyeBOX classification corresponds to eye movement that may be present in both patients with or without concussion.

DESCRIPTION: Traumatic brain injury eye movement assessment aid

  • Prescription device that uses a patient’s tracked eye movements to provide an interpretation of the functional condition of the patient’s brain. This device is an assessment aid that is not intended for standalone detection or diagnostic purposes.

RISKS AND MITIGATIONS:

  • Incorrect or misinterpreted results, including: False positive (brain injury when in fact none is present), False negative (no brain injury when in fact brain injury is present): Clinical performance testing, Software verification, validation, and hazard analysis; Labeling
  • Interference with other devices: Electromagnetic compatibility (EMC) testing
    Software verification, validation, and hazard analysis 
  • Electrical shock or burn: Electrical safety testing, Software verification, validation, and hazard analysis 
  • Adverse tissue reaction: Biocompatibility evaluation
  • Eye hazard or injury: Light hazard assessment

REGULATORY PATHWAY: De Novo request

  • Regulation Number: 21 CFR 882.1455 
  • Regulation Name: Traumatic brain injury eye movement assessment aid 
  • Regulatory Class: Class II 
  • Product Code: QEA

CLASSIFICATION ORDER


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ENLIGHT 1810 Ventilatory Device

Timpel

INDICATION FOR USE:  Non-invasive, non-radiation medical device that provides information of local impedance variation within a cross-section of a patient’s thorax. This information is presented to the clinician user as an adjunctive tool to other clinical information in order to support the user’s assessment of variations in regional air content within a cross section of a patient’s lungs.
It is intended for mechanically ventilated adult patients in a hospital setting, whose thorax perimeter is within the range of 78-122 cm.

DESCRIPTION: Ventilatory electrical impedance tomograph

  • Prescription non-invasive, non-radiological ventilatory device that provides an assessment of local impedance variation within a cross-section of a patient’s thorax

RISKS AND MITIGATIONS:

  • Adverse tissue reaction: Biocompatibility evaluation 
  • Electromagnetic interference with other devices: Electromagnetic compatibility testing, Infection Reprocessing validation, Labeling 
  • Inaccurate images due to either device hardware or software failure/malfunction: Software verification, validation, hazard analysis, Non-clinical performance testing, Labeling 
  • Electrical shock injury or thermal injury: Electrical, thermal, and mechanical safety testing; Software verification, validation and hazard analysis; Non-clinical performance testing; Labeling

REGULATORY PATHWAY: De Novo request

  • 21 CFR 868.1505 
  • Regulation Name: Ventilatory electrical impedance tomograph 
  • Regulatory Class: Class II 
  • Product Code: QEB

CLASSIFICATION ORDER


Image credits: Miris, Bruin Biometrics, Oculogica, Timpel

News & Views: 2019 Shutdown and Funding Lapse, Breakthrough Devices, Safer Technologies Program, Software Precertification Program Model v1.0, Sentinel System Roadmap

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FDA 2019 Lapse in Funding Information

Agency operations continue to the extent permitted by law necessary to address imminent threats

  •  Handle and respond to emergencies
  • Mission critical surveillance for significant safety concerns with medical devices and other medical products

Activities funded by carryover user fee funds

  • NO acceptance of regulatory submissions for FY 2019 that require a fee payment and that are submitted during the lapse period

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Breakthrough Devices Program

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  • Provide timely access to patients and health care providers by speeding up development, assessment, and review (PMA, 510(k), De Novo)
  • Replaces Expedited Access Pathway and Priority Review for medical devices

Benefits

  • Efficient FDA interaction during premarket review phase
  • Prioritized review of submission

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Safer Technologies Program (STeP)

As part of Medical Device Safety Action Plan, STeP is for devices that treat less serious conditions and innovate on safety 

  • For devices that do not otherwise meet ‘breakthrough device’ criteria
  • Has the potential to be significantly safer than currently available alternative treatments or diagnostics
  • Additional details to be provided later

Substantial safety innovations could include

  • Reduce occurrence of serious adverse event or other safety issue
  • Address known device failure mode or common user error
  • Provide for significant safety advantages for users

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Capture.JPGDigital Health Software Precertification (Pre-Cert) Program: v1.0 Working Model

Objective

  • Streamlined and efficient regulatory oversight of software-based medical devices
  • Manufacturers who have demonstrated robust culture of quality and organizational excellence
  • Manufacturers who are committed to monitoring real-world post-marketing performance

Proposed key components 

  • Excellence Appraisal: Five excellence principles of patient safety, product quality, clinical responsibility, cybersecurity responsibility, and proactive culture
  • Review: De Novo classification process with review corresponding to excellence principles
  • Streamlined Review: Interactive review of  software product with special controls and TPLC approach
  • Real-world Performance: Type of information about how software product is performing with patients and emerging risks

2019 TEST PLAN

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Sentinel System – Five-Year Strategy 2019-2023

Sentinel System

  • Core feature of medical product post-market safety surveillance armamentarium
  • Proactively monitors product safety, methodological innovation, real-world evidence
  • Roadmap to focus on innovations emerging from new data science disciplines (NLP, ML), , expand access and use of EHRs

Five Strategic Aims

  • Enhance and expand foundation, including data, infrastructure, operations and technology
  • Augment safety analysis capabilities using advanced data science, signal detection
  • Accelerate access to and broaden use of real-world data  for real-world evidence
  • Broaden stakeholder ecosystem
  • Disseminate knowledge and advance regulatory science

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Image credits: FDA

Market Authorizations: VITRAKVI for NTRK cancer, FIRDAPSE for rare disease, XOSPATA for AML, reSET-O App, TRUXIMA rituximab biosimilar

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Vitrakvi (larotrectinib) capsules and oral solution

 Loxo Oncology

INDICATION: Treatment of adult and pediatric patients with solid tumors that:

  • have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation
  • are metastatic or where surgical resection is likely to result in severe morbidity
  • have no satisfactory alternative treatments or that have progressed following treatment

ADDRESSING UNMET NEED:

  • Treatment based on a common biomarker across different types of tumors rather than location of tumor
  • Treatment for cancers based on tumor genetics rather than site of origin
  • New paradigm in the development of cancer drugs that are “tissue agnostic”

MECHANISM OF ACTION: Inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, TRKC; TRK fusion proteins can act as oncogenic driver, promoting cell proliferation and survival in tumor cell lines

EFFICACY:

  • Three multicenter, open-label, single-arm clinical trials, n= 55 pediatric and adult patients with solid tumors with NTRK gene fusion with no satisfactory alternative treatments
  • Responding tumor types: Soft tissue sarcoma, salivary gland cancer, infantile fibrosarcoma, thyroid cancer and lung cancer
  • Overall response rate across different types of solid tumors: 75%
  • Response duration: 73% lasting at least six months, 39% lasting a year or more

SAFETY:

  • Common side effects: Fatigue, nausea, cough, constipation, diarrhea, dizziness, vomiting, increased AST and ALT enzyme blood levels in the liver
  • May cause harm to a developing fetus or newborn baby

REGULATORY PATHWAY: NDA

  • Accelerated approval based on specific genetic feature (biomarker); continued approval contingent upon verification and description of clinical benefit in confirmatory trials
  • Accelerated approval requirement: Verify and describe clinical benefit in adult and pediatric patients
  •  Priority Review, Breakthrough Therapy designation, Orphan Drug designation
  • Rare pediatric disease priority review voucher  denied

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FIRDAPSE (amifampridine) tablets

 Catalyst Pharmaceuticals

INDICATION: Treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults

ADDRESSING UNMET NEED:

  • First treatment for LEMS
  • Rare autoimmune disorder affecting connection between nerves and muscles
  • Causes weakness and other symptoms in affected patients

MECHANISM OF ACTION: Not fully elucidated; broad spectrum potassium channel blocker.

EFFICACY:

  • Two clinical trials, n=64 adult patients, Firdapse vs. placebo
  • Endpoint: Quantitative Myasthenia Gravis score (a 13-item physician-rated categorical scale assessing muscle weakness) and Subject Global Impression (a seven-point scale on which patients rated their overall impression of the effects of the study treatment on their physical well-being)
  • Patients receiving Firdapse experienced a greater benefit vs. placebo

SAFETY:

  • Most common side effects: Burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms
  • Seizures and  hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing

REGULATORY PATHWAY: NDA

  • Priority Review, Breakthrough Therapy designations, Orphan Drug designation

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XOSPATA (gilteritinib) tablets

Astellas

INDICATION: Treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test

ADDRESSING UNMET NEED:

  • ~ 25-30% AML patients have FLT3 gene mutation; associated with aggressive form of disease and higher risk of relapse
  • First drug to be used alone in treating patients with AML having FLT3 mutation

MECHANISM OF ACTION: Inhibits multiple receptor tyrosine kinases, including FLT3

EFFICACY:

  •  Clinical trial, n=138 patients with relapsed or refractory AML with confirmed FLT3 mutation
  • Complete remission (no evidence of disease and full recovery of blood counts) or complete remission with partial hematologic recovery (no evidence of disease and partial recovery of blood counts) : 21%
  • Of the 106 patients requiring RBC or platelet transfusions; 31% transfusion-free for at least 56 days

SAFETY:

  • Common side effects: Muscle and joint pain (myalgia/arthralgia), fatigue and elevated liver enzymes (liver transaminase)
  • Required monitoring for posterior reversible encephalopathy syndrome, prolonged QT interval, pancreatitis (inflammation in the pancreas)
  • May cause harm to a developing fetus or newborn baby.

REGULATORY PATHWAY: NDA

  •  Fast Track, Priority Review designation, Orphan Drug designation
  • Postmarketing requirements: Clinical assessment of long-term safety and risks or rare adverse events (differentiation symdrome)

LABEL


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reSET-O App

Pear Therapeutics

INDICATION FOR USE:  Prescription cognitive behavioral therapy intended to be used in addition to outpatient treatment under the care of a health care professional, in conjunction with treatment that includes buprenorphine and contingency management

ADDRESSING UNMET NEED:

  • As part of FDA efforts to address the misuse and abuse of opioids
  • New tool to help more people with opioid use disorder successfully treat their addiction

DESCRIPTION:

  • App can be downloaded directly to a patient’s mobile device
  • Used while participating in an outpatient Opioid Use Disorder (OUD) treatment program
  • For training, monitoring and reminder tool for health care providers and patients
  • Compliance reward system– such as earning special icons on a prize wheel

EFFECTIVENESS & SAFETY:

  •  Multi-site, unblinded, controlled 12-week clinical trial, n=170 patients, with or without reSET-O
  • Supervised administration of buprenorphine and urine screens; contingency management system to reward negative urine tests
  • Illicit drug use, abstinence improvement : No decrease  with reSET-O vs. buprenorphine treatment and contingency management alone
  • Retention in treatment program for 12 weeks: 82.4%  with reSET-O vs. 68.4% without reSET-O
  • Adverse events: Typical of patients with OUD – cardiovascular disease, gastrointestinal diseases, HIV, Hepatitis C, nutritional diseases, risk of overdose, depression, mania, suicidal behavior and suicidal ideation and attempts

REGULATORY PATHWAY: 510(k)

  • Predicate device, reSET App- classified via De Novo pathway in 2017
  • Regulation Number : 882.5801
  • Classification : II
  • Classification Name: Computerized Behavioral Therapy Device For Psychiatric Disorder
  • Product Code: PWE

Regulation


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Truxima (rituximab-abbs)

Celltrion Inc.

INDICATION: Non–Hodgkin’s Lymphoma (NHL). Treatment of adult patients with:

  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy

ADDRESSING UNMET NEED & REGULATORY PATHWAY:

  • First biosimilar to Rituxan (rituximab, Genentech Inc.)  
  • Approval based on a review of extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, other clinical data
  • Demonstrated that Truxima is biosimilar to Rituxan
  • Not as an interchangeable product.

LABEL


Image credit: Loxo, Catalyst, Astellas, Pear, Celltrion

 

 

 

 

 

 

 

 

 

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

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

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

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

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

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

Safety communication to hospitals and health care providers

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

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Biomarker Qualification: Evidentiary Framework

Evidentiary framework to support biomarker qualification with recommended components

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

Framework consists of 

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

Biomarker validation

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

Scope

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

Principle benefits

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

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Data Integrity and Compliance With Drug CGMP

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

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

Q & As on broad range of topics provided

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

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

  • Necessary components of drug development program

Overview:

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

NASH guidance


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Report on Non-Device Software Functions 

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

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

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

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

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

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

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Image credit: FDA

 

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

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Framework for Real-World Evidence Program

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

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

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

Women’s Health Research Roadmap

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

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

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New Steps to Advance Clinical Testing to Deliver New Cures

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FDA Recognition of Public Human Genetic Variant Databases

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

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

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

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

Establish procedures and criteria for medical device De Novo classification process

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

De Novo request granted

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

De Novo request decline

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

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Collaborative Community Toolkit

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

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

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

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

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

Selected applicants receive Breakthrough Device designation

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Steps to advance safety and accuracy of blood glucose monitors

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

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

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

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

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Patient Engagement Advisory Committee (PEAC)

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

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

FDA needs to take following steps 

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

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Image credits: FDA

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

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

Cosmo Technologies, Ltd

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

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

ADDRESSING UNMET NEED: 

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

MECHANISM OF ACTION: Antibacterial drug

EFFICACY:

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

SAFETY: 

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

REGULATORY PATHWAY: NDA

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

LABEL


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YUPELRI™ (revefenacin) inhalation solution

Theravance and Mylan

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: NDA

  • Pediatric requirements waived

LABEL


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Novimmune SA

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: BLA

  • Orphan designation, Priority Review and Breakthrough Therapy designation

LABEL


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DAURISMO (glasdegib) tablets

Pfizer

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

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: NDA

  • Orphan and Priority designations

LABEL


Image credits: Cosma, Theravance, Novimmune, Pfizer

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

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

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

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

Reliance on more modern predicate devices or objective performance criteria

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

Report on Strengthening the 510(k) program

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

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

FDA has increased its oversight through additional device inspections since 2007

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

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 Monitoring Social Media to Better Understand Drug Use Trends

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

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

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Prescription Drug-Use-Related Software

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

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

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

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

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New Efforts to Address Drug Shortages

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

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

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

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

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

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Image credits: FDA

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

Capture.JPGAdcetris (brentuximab vedotin) injection

Seattle Genetics

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

ADDRESSING UNMET NEED:

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

EFFICACY: 

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

SAFETY:

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

EXPANDED LABEL


Capture.JPGDPP Ebola Antigen System

ChemBio Diagnostic

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

ADDRESSING UNMET NEED:

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

DESCRIPTION: 

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

REGULATORY PATHWAY: Emergency Use Authorization

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CapturepicoAMH ELISA Menopause Test

Ansh Labs

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

ADDRESSING UNMET NEED: 

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

GENERIC DEVICE TYPE: Menopause test system

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

EFFECTIVENESS AND SAFETY:

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

RISKS & MITIGATIONS:

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

REGULATORY PATHWAY: De Novo request

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

CLASSIFICATION ORDER


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INNOVO 

Atlantic Therapeutics Group

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

GENERIC DEVICE TYPE: Transcutaneous electrical continence device

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

EFFECTIVENESS AND SAFETY:

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

RISKS & MITIGATIONS

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

REGULATORY PATHWAY: De Novo request

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

CLASSIFICATION ORDER


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

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

Capture.JPGFDA MyStudies app

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

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

Two versions of the app

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

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

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Asthma Management and OTC Treatment Option

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

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

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

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

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New efforts to strengthen FDA’s expanded access program

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

Steps taken for improvement

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

Additional improvements based on independent assessment

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

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

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

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

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Image credit: FDA

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

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VisuMax Femtosecond Laser

 Carl Zeiss Meditec, Inc.

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

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

DESCRIPTION

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

EFFECTIVENESS & SAFETY:

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

REGULATORY PATHWAY: PMA

  • Device Procode: OTL

LABEL


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BioMimics 3D Vascular Stent System

Veryan Medical Limited

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

DESCRIPTION:

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

EFFECTIVENESS & SAFETY:

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

REGULATORY PATHWAY: PMA

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

LABEL 


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 Personal Genome Service (PGS) Pharmacogenetic Reports

23andMe

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

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

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

ADDRESSING UNMET NEED: 

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

GENERIC DEVICE TYPE: Pharmacogenetic assessment system

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

EFFECTIVENESS & SAFETY: 

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

RISKS & MITIGATIONS:

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

REGULATORY PATHWAY: De Novo classification request

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

CLASSIFICATION ORDER


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Fluobeam 800 Clinic Imaging Device

Fluoptics

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

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

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

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

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

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

EFFECTIVENESS & SAFETY:

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

RISKS & MITIGATIONS:

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

REGULATORY PATHWAY: De Novo classification request

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

CLASSIFICATION ORDER


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

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

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

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

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

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

LABEL


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

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

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

Medical device cybersecurity is shared responsibility across the medical device ecosystem

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

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

Building strategic alliances (with MITRE, MDIC)

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

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FDA Seeking Digital Health Advisor

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

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

https://twitter.com/_bakulpatel


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Stakeholder Update: FDA’s 2018 Strategic Policy Roadmap

Update on priority areas to advance public health

Reduce the burden of addiction crises 

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

Leverage innovation and competition to improve health care and access

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

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

Dsuvia approval considerations in the context of the overall therapeutic armamentarium

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

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

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

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

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Accreditation Scheme for Conformity Assessment (ASCA)

Piloted under CDRH’s Standards and Conformity Assessment Program

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

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

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

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

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

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Image credit: FDA

Market Authorizations: ARIKAYCE, clonoSEQ Assay, XOFLUZA

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ARIKAYCE (amikacin liposome inhalation suspension) oral
inhalation  

with LAMIRA nebulizer system 

Insmed, Inc

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

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

ADDRESSING UNMET NEED: 

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

MECHANISM OF ACTION: Antibacterial drug

EFFICACY:

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

 SAFETY

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

REGULATORY PATHWAY: NDA

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

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clonoSEQ Assay

Adaptive Biotechnologies

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

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

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

ADDRESSING UNMET NEED:

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

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

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

CLINICAL VALIDITY: 

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

RISKS & MITIGATIONS:

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

REGULATORY PATHWAY: De Novo request

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

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XOFLUZA (baloxavir marboxil) tablets

Shionogi & Co, Genentech USA

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

  • Most common adverse reactions: Diarrhea and bronchitis

REGULATORY PATHWAY: NDA

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

LABEL


Image credits: Insmed, Adaptive Biotechnologies, Shionogi/Genentech

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

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

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

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

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

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

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

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Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank

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

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

Civil money penalties may be assessed for

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

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

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


Image credits: FDA, Interpol

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

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Organs-On-Chips for Radiation Countermeasures

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

Use for development of medical countermeasures (MCMs)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Two new guidances

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

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

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

DHHS/FDA List

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Image credit: FDA

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

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BOSE HEARING AID

Bose Corporation

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

ADDRESSING UNMET NEED: 

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

DEVICE DESCRIPTION:

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

EFFECTIVENESS & SAFETY:

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

REGULATORY PATHWAY: De Novo request


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

Bayer Healthcare

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

ADDRESSING UNMET NEED:

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

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

BENEFIT/RISK:

Benefits

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

Risks

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

REGULATORY PATHWAY: BLA

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LIBTAYO (cemiplimab-rwlc) injection

Regeneron Pharmaceuticals

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

ADDRESSING UNMET NEED: 

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: BLA

  • Breakthrough Therapy and Priority Review designations

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VIZIMPRO (dacomitinib) tablets

Pfizer

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: NDA

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

LABEL


Image credit: Bose, Bayer, Regeneron, Pfizer

 

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

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Medical device guidance documents intended to be published in 2019

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

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

The ‘A’ List- Final Guidances

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

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

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

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

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

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

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

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

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

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

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

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

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Antimicrobial Resistance Information from FDA

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

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

Proactively addressing complex challenges associated with growing threat of AMR by

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

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

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

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

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Image credit: FDA

 

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

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FDA Budget Matters: Advancing Innovation in Digital Health

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

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

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

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

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

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

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

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

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


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Preparations for the upcoming flu season and vaccinations

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

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

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

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FDA awards 12 grants to advance rare diseases medical products 

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

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

Grant recipients 

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

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CaptureCollaborative Communities Toolkit 

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

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

Toolkit

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

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Image credit: FDA

 

 

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

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

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

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

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Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

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

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

New requirements

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

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

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

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Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank

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

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

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Image credit: FDA

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

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ECG App

Apple

INDICATION FOR USE: 

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

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

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

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

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

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

IDENTIFIED RISKS/MITGATION MEASURES:

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

REGULATORY PATHWAY: De Novo request

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

CLASSIFICATION ORDER


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Irregular Rhythm Notification Feature

Apple

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

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

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

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

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

IDENTIFIED RISKS/MITGATION MEASURES:

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

REGULATORY PATHWAY: De Novo request

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

CLASSIFICATION ORDER


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LUMOXITI (moxetumomab pasudotox-tdfk) for injection

AstraZeneca

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: BLA

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

LABEL


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PK Papyrus System 

Biotronik

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

ADDRESSING UNMET NEED: 

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

DEVICE DESCRIPTION:

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

EFFECTIVENESS & SAFETY:

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

REGULATORY PATHWAY: Humanitarian Device Exemption

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

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AJOVY (fremanezumab-vfrm) injection

Teva

INDICATION: Preventive treatment of migraine in adults

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: BLA

LABEL


Image credit: Apple, AstraZeneca, Biotronik, Teva

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

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Agency’s commitment to studying breast implant safety

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

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

Streamlining and modernizing postmarket actions to address device safety issues 

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

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New steps to address epidemic of youth e-cigarette use

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

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

Series of compliance actions over the past year

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

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Medical Device Submissions in Electronic Format

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

  • To improve efficiency of premarket submission program

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

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

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

Overview:

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

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Image credits: FDA

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

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BRAINSWAY Deep Transcranial Magnetic Stimulation System

Brainsway Ltd.

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

ADDRESSING UNMET NEED: 

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

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

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

EFFECTIVENESS & SAFETY: 

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

IDENTIFIED RISKS & MITIGATION MEASURES:

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

REGULATORY PATHWAY: De Novo request

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

CLASSIFICATION ORDER


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Abbott RealTime IDH1

Abbott Molecular Inc.

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

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

This test is for prescription use only.

COMPONENTS:  

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

EFFECTIVENESS:

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

SAFETY:

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

REGULATORY PATHWAY: PMA, Device Procode: OWD

LABEL


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TAKHZYRO (lanadelumab-flyo) injection, for subcutaneous use

Dyax Corporation

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY: 

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

REGULATORY PATHWAY: BLA

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

LABEL


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

Dompé farmaceutici SpA.

INDICATION: Treatment of neurotrophic keratitis

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: BLA

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

LABEL


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DIACOMIT (stiripentol) capsules and powder, for oral suspension

Biocodex

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

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

ADDRESSING UNMET NEED: 
  • Treatment option for rare genetic condition leading ot seizures from first year of life

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

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

LABEL


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

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

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

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

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

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

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

Private Payor Program: Launched in 2016

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

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

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

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

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

Examples provided

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

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

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

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Image credits: FDA, CMS

 

 

 

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

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Agency’s ongoing work to forcefully address the opioid crisis

FDA addressing opioid crisis forcefully

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

Progress

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

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Complex Innovative Trial Designs Pilot Program

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

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

Goals

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

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

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

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Image credit: FDA

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

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

Need to reexamine how opioid analgesics are being prescribed

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

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

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

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

Addition of: 

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

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

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

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

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

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

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

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

Placebo-controlled design only in selected circumstances

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

Considerations: 

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

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Image credit: FDA

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

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ONPATTRO (patisiran) infusion 

Alnylam Pharmaceuticals

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: NDA

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

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NATURAL CYCLES Mobile Medical App

Natural Cycles Nordic AB.

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

ADDRESSING UNMET NEED:

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

DESCRIPTION: 

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

GENERIC DEVICE TYPE: Software application for contraception

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

EFFECTIVENESS & SAFETY: 

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

REGULATORY PATHWAY: De Novo request

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

CLASSIFICATION ORDER


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BONEBRIDGE Hearing System

MED-EL Elektromedizinische Geraete GmbH

INDICATION FOR USE:  Bone conduction hearing implant system for:

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

GENERIC TYPE OF DEVICE: Active implantable bone conduction hearing system

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

RISKS:

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

CLASSIFICATION ORDER


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GALAFOLD (migalastat) capsule

Amicus Therapeutics

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

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: NDA

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

LABEL


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

Population Council, Inc.

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

ADDRESSING UNMET NEED:

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

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

EFFICACY & SAFETY:

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

REGULATORY PATHWAY: NDA,  505(b)(2)

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

LABEL


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

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

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

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

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

READ


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

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

Blue Button


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Amazon, Google, IBM, Microsoft, Oracle, Salesforce

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

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

Potassium chloride oral solution USP

Apotex Inc

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

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

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

EFFICACY, SAFETY, QUALITY

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

READ


Image credits: JAMA, FDA. CMS

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

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Magtrace and Sentimag Magnetic Localization System

 Endomagnetics Inc.

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

ADDRESSING UNMET NEED:

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

SYSTEM DESCRIPTION:

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

EFFECTIVENESS AND SAFETY:

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

REGULATORY PATHWAY: PMA, Combination Product

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

LABEL

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Surpass Streamline Flow Diverter

Stryker 

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

DEVICE DESCRIPTION:

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

EFFECTIVENESS AND SAFETY:

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

REGULATORY PATHWAY: PMA

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

LABELING


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MolecuLight i:X

MolecuLight Inc.

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

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

For prescription use only.

GENERIC DEVICE TYPE: Wound autofluorescence imaging device

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

REGULATORY PATHWAY: De Novo request

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

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

  • No special controls

CLASSIFICATION ORDER


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POTELIGEO (mogamulizumab-kpkc) injection 

Kyowa Hakko Kirin

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: BLA

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

LABEL


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

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

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Influenza Virus Vaccine for the 2018-2019 Season

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

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

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

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

READ


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

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

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

Significant decline in prescribing of TIRF products since REMS  implemented

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

READFDA Briefing Document


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

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

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

READ


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

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

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

READ


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

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

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

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

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

READ 


Image credits: FDA, CDC

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

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ORILISSA (elogolix) Tablets

AbbVie

INDICATION: Management of moderate to severe pain associated with endometriosis

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: NDA

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

LABEL


Capture.JPGMULPLETA (lusutrombopag) Tablets

Shionogi Inc.

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

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: NDA

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

LABEL


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AZEDRA (iobenguane I 131) injection

Progenics Pharmaceuticals

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

ADDRESSING UNMET NEED:  

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: NDA

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

LABEL


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FREESTYLE LIBRE Libre 14 Day Flash Glucose Monitoring System

Abbott

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

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

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

Expanding indication to:

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

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

SYSTEM DESCRIPTION:

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

EFFECTIVENESS AND SAFETY:

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

REGULATORY PATHWAY: PMA Supplement

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

LABEL


Image credits: AbbVie, Shionogi, Progenics, Abbott

 

 

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

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

Statement from FDA Commissioner

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

Steps taken by FDA based on increased reporting to MAUDE database

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

FDA will remain vigilant in protecting patients with implanted device

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

READ

WATCH: The Bleeding Edge


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Biomarkers and Surrogate Markers

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

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

Surrogate endpoints (SEs) are  small subclass of biomarkers

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

FDA steps to enhance SE use in drug development

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

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

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

FDA providing listing of MMAs cleared or approved since 1997

READ


Image credits: Bayer, FDA

Market Authorizations: TIBSOVO + REALTIME ASSAY, KISQALI, TPOXX, XTANDI, FRENCH FREEZE DRIED PLASMA

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TIBSOVO (ivosidenib) tablets

Agios Pharmaceuticals

 RealTime IDH1 Assay  

Abbott Laboratories

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: NDA

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

LABEL


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KISQALI (ribociclib) tablets

Novartis

EXPANDED INDICATION:  KISQALI in combination with:

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

or

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

ADDRESSING UNMET NEED: 

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

EFFICACY AND SAFETY:

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

REGULATORY PATHWAY: Prior Approval Supplement utilizing two new pilot programs

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

Updated LABEL not available at this time


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TPOXX (tecovirimat) capsules

Siga Technologies 

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

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

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

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

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

LABEL


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XTANDI (enzalutamide) capsules

Astellas 

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY: sNDA

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

LABEL


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

U.S. Department of Defense (DoD)

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

ADDRESSING UNMET NEED: 

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

DESCRIPTION: 

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

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

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

REGULATORY PATHWAY: Emergency Use Authorization

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

FACT SHEET

DECLARATION


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

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

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Biosimilars Action Plan (BAP)

Focus on four key areas

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

Actions will help create competitive market, provide incentives for sponsors

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

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CDER Conversation: Treatment for Opioid Use Disorder

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

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

Use Information

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

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

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

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

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New efforts to empower consumers by advancing access to nonprescription drugs

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

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

Use of innovative technologies

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

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

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

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

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Image credits: FDA

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

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

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

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

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

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

Current initiatives

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

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Evaluating Inclusion and Exclusion Criteria in Clinical Trials

Eligibility criteria define patient population under investigation

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

Strategies to Support Better Development of Eligibility Criteria and Increase Enrollment

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

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FDA’s Efforts to Advance Development of Gene Therapies

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

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

Disease Specific Gene Therapy Guidances

Human Gene Therapy for Rare Diseases

Guidances on Manufacturing Gene Therapies

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

New policy to strike right balance between

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

New steps to aggressively confront the addiction epidemic

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

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

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

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

Content and Format

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

Other considerations

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

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FDA Regulation of Mobile Medical Apps

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

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

FDA initiatives

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

Firm-based approach based on culture of excellence and leveraging

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

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

New Drug Shortages Task Force – including CMS and VA

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

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Image credits: FDA, HHS

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

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EPIDIOLEX  (cannabidiol) oral solution

GW Pharmaceuticals

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

ADDRESSING UNMET NEED:

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

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

EFFICACY:

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

SAFETY:

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

REGULATORY PATHWAY:

FDA

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

DEA

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

LABEL


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ZEPHYR Endobronchial Valve (Zephyr Valve)

Pulmonx

INTENDED USE: Treat breathing difficulty associated with severe emphysema

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

DEVICE DESCRIPTION:

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

EFFECTIVENESS: 

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

SAFETY:

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

REGULATORY PATHWAY: PMA

  • Breakthrough designation

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Ellipsys Vascular Access System 

Avenu Medical

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

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EVERLINQ endoAVF System 

TVA Medical

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

………………..

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

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

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

CLINICAL PERFORMANCE:

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

RISKS: 

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

REGULATORY PATHWAY: De Novo request

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

CLASSIFICATION ORDER (Ellipsys)

CLASSIFICATION ORDER (everlinQ)


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DreaMed Advisor Pro decision-support software

DreaMed Diabetes, Ltd

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

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

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

DreaMed Advisor Pro does not replace clinical judgment

DEVICE TYPE: Insulin Therapy Adjustment Device

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

DESIGN VERIFICATION & VALIDATION:

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

RISKS:

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

REGULATORY PATHWAY: De Novo request

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

CLASSIFICATION ORDER


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EVERSENSE Continuous Glucose Monitoring (CGM) system

Senseonics

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

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

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