FDA News and Views: Illegal Online Drug Marketing, Patient Preferences for Devices, Digital PreCert Program Selection, Drug Patents and Exclusivities, Compounded Medications

FDA BRIEF: Week of September 25, 2017


FDA conducts major global operation to protect consumers from potentially dangerous prescription drugs sold online

Operation Pangea X, a global cooperative effort led by Interpol, to combat unlawful sale and distribution of illegal, counterfeit, substandard medical products on the internet

  • Action against > 500 websites illegally selling dangerous, unapproved versions of prescription medicines –  including opioids
  • Remove products from supply chain
  • Prevent health risks as well as credit card fraud, identity theft and computer viruses



How Patient Preferences Contribute to Regulatory Decisions for Medical Devices

Examples of using Patient Preference Initiative as part of medical device regulatory decision-making process

  • Expanded indication for home hemodialysis machine to be used without presence of care partner
  • Worked with medical device company, NxStage, to develop Patient Preference Framework
  • Enhancing safety of continuous glucose monitors – Dexcom G5 Continuous Glucose Monitoring (CGM) System and Animas Vibe System.
  • Used patient feedback to develop risk mitigation strategies such as lockout feature to prevent accidental boluses

Companies invited to discuss on patient preference information during Pre-Submission meetings



FDA selects participants for new digital health software Precertification pilot program

Selection of companies to participate in a first-of-its kind pilot program to revolutionize digital health regulation in the U.S.

  • Pre-cert pilot program is precertify software developers based on systems for software design, validation and maintenance, meeting quality standards
  • Precertified companies could potentially submit less FDA information before marketing a new digital health tool
  • >100 applicants; selection based on company size, demonstrated record of quality and organizational excellence, represent unique approaches  digital health technology development

Apple, Cupertino, California

Fitbit, San Francisco, California

Johnson & Johnson, New Brunswick, New Jersey

Pear Therapeutics, Boston, Massachusetts

Phosphorus, New York, New York

Roche, Basel, Switzerland

Samsung, Seoul, South Korea

Tidepool, Palo Alto, California

Verily, Mountain View, California


CapturePatents and Exclusivities for Generic Drug Products


  • Property right granted by US -PTO -term of 20 years from the date of filing with the PTO
  • FDA does not enforce patents, or evaluate patent validity or infringement
  • Product manufacturers submit patent information to FDA for inclusion in “Orange Book”  –  informs when a generic drug application may be approved


  • Provides limited market protection from new competition; precludes approval of certain ANDAs for prescribed periods of time – Hatch Waxman Amendments
  • Also for brand-name “orphan” drug products- Orphan Drug Act
  • Also for certain pediatric-related uses and for qualifying antibiotic drug products.
  • FDA administers exclusivities

Types of Exclusivities:

  • Five-Year New Chemical Entity
  • Three-Year New Clinical Studies
  • Orphan Drug.
  • Pediatric
  • “Generating Antibiotic Incentives Now” (GAIN)
  • 180-Day



New efforts to encourage compounding of better quality drugs 

Important for health care providers to have access to compounded drugs

  • When patient needs cannot be met by FDA-approved drugs
  • Oversight based on Drug Quality and Security Act (DQSA) to prevent manufacturing issues and associated patient risks
  • Posting  new report  on drugs that entities registered as outsourcing facilities have produced
  • Sharing guide, “Outsourcing Facility Information,” for outsourcing facilities
  • Collaboration with state partners at sixth intergovernmental meeting on drug compounding
  • Assist more compounders register as outsourcing facilities


Image credits: FDA



FDA/CMS Hurricane Relief Efforts

Hurricanes Irma and Jose

Support of the Hurricane Relief Effort

Harvey, Irma, and Maria


Address safety and shortages

  • Ensuring safety of regulated products including medicines, medical devices, food, and the blood supply
  • Priority Actions : Recommendations on food and medical products handling, assess damage and impact to industry facilities, avoid food and crop loss, identify solutions to prevent shortages of life-saving therapies



Gain access to health coverage immediately 

  • Medicare special enrollment period:  Enroll, dis-enroll or switch Medicare health or prescription drug plans
  • Federal Health Insurance Exchange special enrollment period: For individuals  unable to complete application, plan selection, and enrollment process


Image credit: FDA

FDA Adverse Events Reporting System (FAERS) Public Dashboard


FDA Adverse Events Reporting System (FAERS) Public Dashboard

Highly interactive web-based tool for FAERS data

  • Human adverse events reported to the FDA by the pharmaceutical industry, healthcare providers and consumers
  • Expand access of FAERS data to general public
  • Some limitations : Incomplete reports, uncertain causation, unverified information, unknown rates of occurrence



Image credit: FDA

FDA Opioid Action Plan

Opioids and FDA Opioid Action Plan

To address  growing epidemic of opioid abuse, dependence and overdose in the US

  • Expand use of advisory committees
  • Develop warnings and safety information for immediate-release (IR) opioid labeling
  • Strengthen postmarket requirements
  • Update Risk Evaluation and Mitigation Strategy (REMS) Program
  • Expand access to abuse-deterrent formulations (ADFs) to discourage abuse
  • Support better treatment.
  • Reassess the risk-benefit approval framework for opioid use


Image credit: FDA


Weeks of September 11 and 18, 2017


MVASI (bevacizumab-awwb) solution for intravenous infusion 

Amgen, Inc


  • Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
  • Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrmidine-oxaliplatin-based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product-containing regimen. Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
  • Non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.
  • Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate. No data is available demonstrating improvement in disease-related symptoms or survival with bevacizumab products.
  • Metastatic renal cell carcinoma, in combination with interferon alfa.
  • Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

ADDRESSING UNMET NEED: First biosimilar (to Avastin)  approved in the U.S. for the treatment of cancer

REG PATHWAY: BLA (biosimilar, not an interchangeable product)

  • Postmarketing commitments: Drug substance stability, method validation, endotoxin detection method

DESCRIPTION:  Recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems

BIOSIMILARITY: Extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and clinical safety and effectiveness data


  • 4 Studies in Metastatic Colorectal Cancer: Double blind, open label, survival improvement
  • Adjuvant Treatment of Colon Cancer: No efficacy
  • Unresectable Non–Squamous Non–Small Cell Lung Cancer:  Single, large, randomized, active-controlled, open-label, multicenter study. Higher Overall Survival
  • Glioblastoma: Open-label, multicenter, randomized, non-comparative study.Efficacy based on WHO radiographic criteria and by stable or decreasing corticosteroid use
  • Metastatic Renal Cell Carcinoma:  Multicenter, randomized, double-blind,
    international study.  Statistically significantly prolonged progression free survival
  • Persistent, Recurrent, or Metastatic Carcinoma of the Cervix: Randomized, four-arm, multi-center trial. Higher overall survival


  • Boxed Warning: Increased risk of gastrointestinal perforations; surgery and wound healing complications; severe or fatal pulmonary, gastrointestinal, central nervous system and vaginal bleeding
  • Serious expected side effects:  Perforation or fistula, arterial and venous thromboembolic events), hypertension, encephalopathy syndrome, proteinuria, ovarian failure
  • Common expected side effects: Epistaxis), headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis


Image result for solosec logo

SOLOSEC (secnidazole) oral granules

Symbiomix Therapeutics

INDICATION: Treatment of bacterial vaginosis in adult women


  • New medication for bacterial vaginosis
  • First one-dose oral regimen for most common vaginal infection in adult women


  • Qualified Infectious Disease Product (QIDP) designation
  • Fast Track designation, Priority Review
  • Deferred pediatric assessments

MECHANISM OF ACTION:  Nitroimidazole antimicrobial drug


  • Two randomized placebo-controlled clinical trials, n=144 and 189, patients with diagnosed bacterial vaginosis
  • Efficacy: Clinical outcome in 21 to 30 days, “normal” vaginal discharge, negative
    “whiff” test, and clue cells <20%
  • Statistically significantly greater % clinical outcome with Solosec


  • Most common adverse reactions: Vulvo-vaginal candidiasis, headache, nausea, diarrhea, abdominal pain, vulvovaginal pruritus


Aliqopa™ (copanlisib) Logo

ALIQOPA  (copanlisib) for injection

Bayer Healthcare Pharmaceuticals

INDICATION: Treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.


  • 72,240 people in US diagnosed with some form of non-Hodgkin lymphoma this year; approximately 20,140 patients will die from disease in 2017
  • Approval provides additional choice for treatment, filling an unmet need


  • Accelerated approval, Priority Review designation, Orphan Drug designation
  • Accelerated approval based on overall response rate; continued approval contingent upon verification of clinical benefit in confirmatory trial
  • Other postmarketing requirements: Long term safety, clinical pharmacology studie
  • Pediatric assessment exemption

MECHANISM OF ACTION:  Inhibitor of phosphatidylinositol-3-kinase with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells; induces tumor cell death


  • Single-arm, multicenter, Phase 2 clinical trial, n=142 subjects with relapsed follicular B-cell non-Hodgkin lymphoma
  • Efficacy Endpoints: Tumor response according to the IWG criteria for malignant lymphoma. Overall Response rate (ORR) by Independent Review Committee.
  • ORR: 59%, with median duration of response of 12.2 months


  • Common side effects: Hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, thrombocytopenia
  • Serious side effects: Infections, hyperglycemia, hypertension, non-infectious pneumonitis, neutropenia, severe skin reactions, harm to developing fetus or newborn baby


Image credits: Amgen, SymbiomixBayer








FDA News and Views: Radio-Frequency Wireless Coexistence Standard, Tardive Dyskinesia, Medication-Assisted Treatment, Biomarker Qualification Program 

FDA BRIEF: Week of September 18, 2017

Image result for association for the Advancement of Medical Instrumentation logoImage result for ANSI Logo

Recognized Consensus Standards: Radio-Frequency Wireless Coexistence For Medical Devices And Systems

FDA publication of standards-recognition notice (Recognition List #47) that includes

  • American National Standards Institute (ANSI) American National Standard for Evaluation of Wireless Coexistence C63
  • Association for the Advancement of Medical Instrumentation (AAMI) Technical Information Report (TIR) 69: Risk management of radio-frequency wireless coexistence for medical devices and systems.

First standard to specifically address wireless coexistence testing to assess ability of wireless equipment to coexist with other wireless equipment in its intended use environment

  • For  all medical devices that incorporate wireless technology for data transmission, communications or control
  • For 510(k), PMA, PDP, HDE, GMP, Design controls

Relevant FDA Guidances

  • Radio Frequency Wireless Technology In Medical Devices – Guidance For Industry And Food And Drug Administration Staff, Document Issued On: August 13, 2013
  • Information To Support A Claim Of Electromagnetic Compatibility (EMC) Of Electrically-Powered Medical Devices – Guidance For Industry And Food And Drug Administration Staff. Document Issued On: July 11, 2016


Spotlight on CDER Science

In Pursuit of Tardive Dyskinesia: The Breakthrough Designation and Approval of Valbenazine

Tardive dyskinesia – a side effect of taking antipsychotic medicines

  • Neurological disorder with repetitive, involuntary movements such as lip smacking or pursing, as well as tongue movements
  • Impacts the health and quality of life and is often irreversible


  • First-generation antipsychotics and second-generation antipsychotics (“atypicals”) revolutionized psychiatric care but caused tardive dyskinesia
  • May be caused by irregular dopamine signaling
  • Interest in studying tetrabenzine and valbenazine to treat involuntary movements

A Breakthrough Therapy and Expedited Approval

  • Breakthrough Therapy designation based on promising clinical results
  • Facilitated discussions between the FDA and valbenazine sponsor (Neurocrine Biosciences)
  • Priority Review and drug approval in 8 months after NDA submission



FDA’s continued efforts to promote the safe adoption of Medication-Assisted Treatment for opioid addiction

Medication-assisted treatment (MAT) – the use of medication combined with counseling and behavioral therapies

  • Major pillars of federal response to opioid epidemic

However,  significant challenges with use of MAT drugs contain methadone or buprenorphine – which are also opioids

  • Increased risk of serious side effects when combining MAT drugs with benzodiazepines – often prescribed to treat anxiety, insomnia, or other conditions
  • Strengthened labeling for MAT drug buprenorphine to emphasize indefinite treatment and continued treatment as long as it contributes to treatment goals
  • Develop treatment plan to closely monitor concomitant use of benzodiazepines and taper use while considering other treatment options


FDA Encourages New Treatments for Sickle Cell Disease

Sickle Cell Disease (SCD)

  • “Sickled” or abnormally shaped red blood cells that get stuck in small blood vessels and block the flow of blood and oxygen to major organs
  • Cause severe pain, organ damage, or even stroke
  •  Is chronic and lead to shortened lifespans

Limited Treatment Options

  • Approved 1998: Hydroxyurea- for red blood cells to stay round and flexible
  • Approved 2017: Endari (L-glutamine oral powder) to reduce acute complications of sudden, severe attacks of pain (sickle cell crises)

Encouraging New Treatment Development

  • Working with stakeholders—patients, academics and companies
  • “Fast track” designation, to bring new products to market faster
  • “Breakthrough therapy” designation if promising preliminary data
  • “Orphan status” if intended to treat rare diseases affecting < 200,000 people
  • Meeting with patients and learning the patient perspective to integrate into new product development



Biomarker Qualification Program 

Biomarker Qualification Program (BQP) encourages biomarker development

  •  For use in drug development, facilitate an efficient review process, make information publicly available
  • Qualified biomarker can be used in multiple drug development program without
    need to reconfirm suitability of  biomarker’s qualified context of use.
  • Potential to streamline drug development paradigm

Three submission stages

  • Letter of Intent
  • Qualification Plan
  • Full Qualification Package

FDA Engagement throughout the process

  • At each milestone, formal written FDA determination letter
  • Seek clarification regarding determination letter
  • Obtain additional information about qualification process



Image credits: FDA, AAMI, ANSI, Neurocrine

FDA Marketing Permit: reSET

Week of September 11, 2017



Pear Therapeutics

INDICATION FOR USE:  Provide cognitive behavioral therapy, as an adjunct to a contingency management system, for patients 18 years of age and older who are currently enrolled in outpatient treatment under the supervision of a clinician. reSET is indicated as a 12 week (90 days) prescription-only treatment for patients with substance use disorder (SUD), who are not currently on opioid replacement therapy, who do not abuse alcohol solely, or who do not abuse opioids as their primary substance of abuse. It is intended to:

 increase abstinence from a patient’s substances of abuse during treatment
 increase retention in the outpatient treatment program.


  • Alcohol, cocaine, marijuana and stimulant SUDs cause clinically and functionally significant impairments
  • Innovative digital technology to provide additional tools during their treatment

REG PATHWAY: De Novo Request

  • Regulation Number: 21 CFR 882.5801
  • Regulation Name: Computerized behavioral therapy device for psychiatric disorders
  • Regulatory Class: Class II
  • Product Code: PWE

GENERIC DEVICE TYPE:  Computerized behavioral therapy device for psychiatric disorders

Prescription only device intended to provide a computerized version of condition-specific behavioral therapy as an adjunct to clinician supervised outpatient treatment to patients with psychiatric conditions. The digital therapy is intended to provide patients access to therapy tools used during treatment sessions to improve recognized treatment outcomes.


  • Mobile medical application system: Patient application + clinician dashboard
  • Delivers cognitive behavioral therapy to teach the user skills that aid in the treatment of SUD
  • Intended to increase abstinence from substance abuse and increase retention in outpatient therapy programs
  • Used in conjunction with outpatient therapy and in addition to a contingency management system (widely-used program for treating SUD)


  • Multi-site, unblinded 12-week clinical trial, n=399, patients with alcohol, cocaine, marijuana and stimulant SUD, standard treatment + desktop-based version of reSET Vs. standard treatment
  • Statistically significant increase in adherence to abstinence : with reSET (40.3%) vs. who did not (17.6%)
  • Not effective in patients reporting opioids as their substance of abuse
  • No indication of side effects


  • Device provides ineffective treatment, leading to worsening condition: Clinical data
    Software verification, validation, and hazard analysis, Labeling
  • Device software failure, leading to delayed access: Software verification, validation, and hazard analysis
  • Use error / improper device use: Labeling


Image credit: Pear Therapeutics

FDA News and Views: Orphan Drug Act, Continuous Manufacturing, Priority Therapeutic Areas

FDA BRIEF: Week of September 11, 2017


FDA is Advancing the Goals of the Orphan Drug Act

By: Scott Gottlieb, M.D., FDA Commissioner

Orphan Drug Modernization Plan

  • eliminate a backlog of about 200 orphan drug designation requests t
  • pursue policies better advance the goals of the Orphan Drug Act (ODA).

Process improvements for review efficiency

  • Reorganization to leverage expertise across FDA’s medical product centers
  • New workflow to eliminate redundancies and delays

New policy steps for incentives

  • Hold public meeting on complex scientific and regulatory issues and appropriate orphan incentives
  • Examine aspects of granting designations to meet goals intended by Congress
  • Issue guidance documents to address loopholes for avoiding pediatric studies



 “Continuous Manufacturing” – Common Guiding Principles Can Help Ensure Progress


Priority Therapeutic Areas for Development

Standardizing study data specific to therapeutic areas (TAs) facilitate evaluation of medical products

  • Prioritization of TAs based on (1) areas of particular medical need, (2) areas with existing data standardization projects underway, and (3) areas with greater drug development pipeline activity
  • New roadmap for TAs in priority groupings
  • Collaboration of FDA, CDISC, Critical Path Institute, HL7’s Clinical Interoperability Council to define related clinical concepts


Image credits: FDA

FDA DEVICE Guidance: Advisory Committee Meetings, Small Business Qualification, Real-World Evidence, Inter-Operable Devices, Age-, Race-, and Ethnicity Data

fda guidances


Procedures for Meetings of the Medical Devices Advisory Committee

Background and Scope:

  • Provide information on  processes for Medical Devices Advisory
    Committee meetings
  • Excludes Medical Devices Dispute Resolution Panel (DRP)
  • Does not apply to Device Good Manufacturing Practice Advisory Committee,
    National Mammography Quality Assurance Advisory Committee, Technical
    Electronic Product Radiation Safety Standards Committee


  • Panel Meeting Topics
    • Advice on a Premarket Submission
    • Regulatory Issues: Classification/Reclassification, General Issues
  • Panel Expertise
    • Two or more voting members with relevant clinical expertise
    • One voting member knowledgeable about device technology
  • Preparation for Panel Meetings:
    • Premarket Submission Meetings, Briefing Material Contents, CDRH-Applicant Interactions, Regulatory Issues Meetings
  • Conduct of Panel Meetings
    • Medical Device Industry Presentations
    • CDRH Presentation
    • Open Public Hearing
    • Panel Deliberations and CDRH Questions
    • Panel Voting
  • Post Meeting Activities
  • Teleconference Panel Meetings



FY 2017 Medical Device User Fee Small Business Qualification and Certification

Background and Scope:

  • Business qualified and certified as a “small business” is eligible for a substantial reduction in most of these user fees
  • Process to request qualification and certification as a small business – US and Foreign


  • Eligibility
  • U.S. Businesses
  • Foreign Businesses
  • National Taxing Authority

Small Business Fees:




Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices

Background and Scope:

  • Real-World Data (RWD): Data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources
  • Real-World Evidence (RWE): Clinical evidence regarding the usage, and potential
    benefits or risks, of a medical product derived from analysis of RWD
  • Data derived from real world sources can be used to support regulatory decisions


  • Regulatory Context in Which RWE May be Used: General  considerations,  Application of IDE Requirements
  • Characteristics of RWD:  Relevance,  Reliability (Data accrual, Data assurance)
  • Examples Where RWE is Used
    • Expanded Indications for Use
    • Postmarket Surveillance Studies
    • Post-Approval Device Surveillance as Condition of Approval
    • Control Group
  • Supplementary Data
  • Objective Performance Criteria and Performance Goals




Design Considerations and Premarket Submission Recommendations for Interoperable Medical Devices

Background and Scope:

  • Advancing the ability of medical devices to exchange and use information safely and effectively with other medical devices as well as other technology
  • Potential to increase efficiency in patient care
  • Promote development and availability of safe and effective interoperable
    medical devices


  • Design Considerations for Interoperable Medical Devices
    • Purpose of the Electronic Interface
    • Anticipated Users.
    • Risk Management Considerations
    • Verification and Validation Considerations
    • Labeling Considerations
    • Use of Consensus Standards
  • Recommendations for Contents of Pre-market Submissions
    • Device Description
    • Risk Analysis
    • Verification and Validation
    • Labeling



Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical Studies

Background and Scope:

  • Improve data quality, consistency, transparency regarding  device performance within specific age, racial, and ethnic groups
  • Can benefit patients, clinicians, researchers, regulators, and others
  • Recommendations to overcome barriers to enrollment


  • FDASIA: Considerations for age-, race- and ethnicity-specific differences
    • Participation of subgroups in clinical trials.
  • Recommendations for Appropriate Enrollment
    • Study Design, Early Enrollment Stage
    • Premarket Submission Stage
    • Postmarket Submission Stage
  • Planning for Diverse Study Recruitment
    • Study Design, Early Enrollment Stage
    • Premarket Submission Stage
    • Postmarket Submission Stage
  • Considerations for Study Follow-Up Visits
  • Interpretation of Study Results
  • Assessing Heterogeneity Across Subgroups
  • Recommendations for Subgroup Specific Statistical Elements
  • Recommendations for Submissions to Agency



FDA Clearance: SENOGRAPHE PRISTINA with Self-Compression 

FDA BRIEF: Week of September 4, 2017

GE Healthcare, Senographe Pristina mammography system, launch, RSNA 2017, patient comfort

 Senographe Pristina with Self-Compression 

GE Healthcare

INDICATION FOR USE (based on predicate Senographe Pristina): Generates digital mammographic images that can be used for screening and in the diagnosis of breast cancer. Allows patients to increase or decrease the amount of compression applied to their own breast before the mammogram x-ray is taken.


  •  First 2D digital mammography with patient-assisted compression remote control
  • Enable patient, with the help of a technologist, to set compression that feels right for her
  • Minimize women’s perceived pain and discomfort by giving active role in the application of compression


  • Predicate Device: Senographe Pristina
  • Device Classification Name: Full Field Digital,System,X-Ray,Mammographic
  • Regulation Number: 892.1715
  • Classification Product Code: MUE


  • Senographe Pristina: Full Field Digital Mammography (FFDM) system
  • X-ray image acquisition system dedicated to breast imaging includes Cesium Iodine digital detector, x-ray tube, integrated high voltage generator, compression paddles
  • Control station for image acquisition, processing and display includes touch-screen user interface
  • Pristina Dueta: Addition of handheld wireless remote control to adjust compression force after breast positioning, guided by technologist


  • Clinical validation: Addition of remote to allow self-compression did not negatively impact image quality
  • Performing a mammogram with patient-assisted compression vs. compression solely applied by the technologist did not significantly increase time of the exam
  • IPSOS Patient satisfaction study (n=160):  Improved the comfort of exam (79%), less anxiety (54%)

510(k) Notification


Image credit: GE


FDA News and Views: Interoperability, Public Engagement in Regulatory Framework, Therapeutic Protein Products

FDA BRIEF: Week of September 2, 2017

Medical Device and Hurricane Emergencies

Hurricanes Irma and Jose

Medical Device and Hurricane Emergencies

During natural disasters medical devices may be exposed to fluctuating power, contaminants, or unusual levels of heat or humidity.

FDA provides information on using medical devices during and following emergency situations

  • Re-Use of Devices
  • Disposal of Contaminated Devices
  • Reopening Dialysis Clinics
  • Medical Devices Requiring Refrigeration
  • Medical Devices Exposed to Heat and Humidity
  • Blood Glucose Meters
  • Mammography Facilities


Image credit: FDA

Digital Health Entrepreneur-in-Residence Program


Entrepreneur-in-Residence in CDRH Digital Health team 

  • To support and help develop our Software Precertification (PreCert) Pilot Program —a critical piece of CDRH’s Digital Health Innovation Action Plan
  • Need to have experience in digital health and passionate about developing innovative solutions to complex challenges
  • Help FDA establish the most appropriate criteria for standing up a firm-based precertification program



FDA News and Views: Stem Cell Therapies Enforcement, Real -World Evidence, KEYTRUDA alert, Drug Manufacturing Oversight, AIDS Look Back,

FDA BRIEF: August 28, 2017


 FDA’s new policy steps and enforcement efforts to ensure proper oversight of stem cell therapies and regenerative medicine

Promising new field involving pathways involved in tissue damage and regeneration with potential applications across a wide range of diseases and conditions

  • However, ‘unscrupulous actors’  making corrupt, assurances to patients based on unproven and dangerous products
  • Promote unproven, illegal, expensive treatments that offer little hope, and pose significant risks to the health and safety

Stepped Up Enforcement

  • Steps in Florida and California to address troubling products being marketed
  • Will take additional actions in the coming months
  • New working group to pursue unscrupulous clinics

Efficient Regulation

  • Promote science-based policy to expedite development of innovative, scientifically proven regenerative cell therapies
  • New framework  based on current risk-based, flexible regulatory framework and provisions of the Cures Act
  • Issue compliance policy for current product developers to interact with FDA to determine marketing authorization needs


mom and child, 3 people, baby

Use of RealWorld Evidence to Support Regulatory Decision-Making for Medical Devices

Final guidance on the Use of RealWorld Evidence to Support Regulatory Decision-Making for Medical Devices

  • Clarifies how realworld data may be sufficient for use in regulatory decisions,
  • Clarifies evaluation plan to determine relevancy and reliability
  • Clarifies when Investigational Device Exemption (IDE) may be needed to collect and use realworld data

Guidance is cornerstone of strategic priority to build a national evaluation system for health technology (NEST)


Related image

FDA Alerts Healthcare Professionals and Oncology Clinical Investigators about KEYTRUDA (pembrolizumab) in Multiple Myeloma

Inform public, health care professionals, and oncology clinical investigators about risks with KEYTRUDA® (pembrolizumab)

  • In combination with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of patients with multiple myeloma
  • Based on data review from two clinical trials – KEYNOTE-183 and KEYNOTE-185
  • Interim results demonstrated an increased risk of death for patients
  • Patients on KEYTRUDA® for an approved use : Melanoma, Lung Cancer, Head and Neck Cancer, Classical Hodgkin Lymphoma, Urothelial Carcinoma, Microsatellite Instability-High (MSI-H) Cancer


New Steps To Strengthen FDA’s Inspection And Oversight Of Drug Manufacturing

CDER and the Office of Regulatory Affairs (ORA) implementing a new, concept of operations agreement

  • integrate drug review programs with facility evaluations and inspections
  • “Integrated Quality Assessment”  team for closer risk assessments for drug substance, drug product, manufacturing processes, and facilities
  •  ORA reorganized into program-aligned commodity areas mirroring FDA’s centers and industries
  • New model will cover Pre- and Post-Approval Inspections, Surveillance Inspections, and For-Cause inspections at domestic and international drug manufacturing facilities


Commemorating 20 Years AIDS poster

A Look Back: The AIDS Crisis and FDA … 30 Years Later

Office of AIDS and Special Health Issues established in 1994 at the height of the AIDS epidemic

  • Advocacy group ACTUP (AIDS Coalition to Unleash Power) functionally closed down the FDA in 1988
  • Individuals continually called up various offices of FDA complaining that no one was paying attention to AIDs
  • There were “fax attacks” – to disrupt “business as usual,”
  • FDA responded to these needs

FDA engagement with AIDS Community particularly the patients

  • Patients played an important role in AIDS drug development
  • Pushed for use of accelerated approval based on viral load – a surrogate endpoint
  • Pushed for expanded access
  • Highlighted that policy had to move in tandem with science
  • Participated in Advisory Committee Meetings

In 1996, when protease inhibitors were approved, everything turned around


Image Credit: FDA

FDA Approvals: KYMRIAH, MYLOTARG, VABOMERE, Benznidazole

FDA BRIEF: Week of August 28, 2017

FDA approved

CAR T Cell


KYMRIAH (tisagenlecleucel) suspension for intravenous infusion



INDICATION:  CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse


  • First gene therapy available in the US
  • New approach to treatment of cancer and other serious and life-threatening diseases
  • New treatment option where very limited options existed,  with promising remission and survival rates in clinical trials


  • Priority Review and Breakthrough Therapy designations
  • Coordinated, cross-agency approach
  • Clinical review : Oncology Center of Excellence
  • All other review aspects and final product approval determination: CBER

MECHANISM OF ACTION:  CD19-directed genetically modified autologous T cell immunotherapy which involves reprogramming patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. Upon binding to CD19-expressing cells, CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the KYMRIAH cells.


  • Open-label, multicenter single-arm trial, n=107, pediatric and young adults with R/R B-cell precursor ALL, lymphodepleting chemotherapy  followed by a single dose of KYMRIAH
  • Endpoints: Complete Remission (CR) within 3 mo., CR duration, proportion of patients with CR and minimal residual disease (MRD) <0.01% by flow cytometry (MRD-negative)


  • Boxed Warning: Cytokine release syndrome (CRS)  causing high fever and flu-like symptoms, and for neurological events
  • Severe side effects: Serious infections, hypotension, acute kidney injury, fever, hypoxia
  • Destruction of normal B cells that produce antibodies – increased risk of infections for a prolonged period of time



  • Modernization of current healthcare payment systems need to ensure access to new high-cost therapies
  • Innovative payment arrangements including outcome-based pricing in relation to clinical outcomes
  • Center for Medicare and Medicaid Innovation (CMMI)  to test payment and service delivery models on value-based payment arrangements
  • Issue guidance on sponsor engagement in innovative payment arrangements


Capture.JPGMYLOTARG (gemtuzumab ozogamicin) injection



  • Newly-Diagnosed CD33-positive Acute Myeloid Leukemia (AML): Treatment of newly-diagnosed CD33-positive acute myeloid leukemia in adults
  • Relapsed or Refractory CD33-positive AML: Treatment of relapsed or refractory CD33-positive acute myeloid leukemia in adults and in pediatric patients 2 years and older


  • AML is rapidly progressing cancer, forms in bone marrow, results in increased white blood cell
  • ~21,380 diagnosed this year in US,  10,590 will die of disease
  • Importance of examining alternative dosing, scheduling, and administration of therapies

REG PATHWAY: BLA, Orphan Drug Designation

  • Accelerated Approval  in 2000 at higher dose for stand-alone treatment for older patients with CD33-positive AML who had experienced a relapse
  • Voluntary withdrawal in 2010 after confirmatory trial failed to show clinical benefit and higher rate of fatal toxicity
  • This approval includes a lower recommended dose, a different schedule in combination with chemotherapy or on its own, and a new patient population

MECHANISM OF ACTION: CD33-directed antibody-drug conjugate (ADC), small molecule  N-acetyl gamma calicheamicin, is a cytotoxic agent covalently attached to antibody. Activity due to binding of ADC to CD33-expressing tumor cells, internalization of ADC-CD33 complex, intracellular release of small molecule


  • Two, separate trials
  • First trial:  newly diagnosed AML, n=237,  MYLOTARG vs. best supportive care
  • Median Overall Survival: 4.9 months vs. 3.6 months
  • Second trial: Single-arm study,  CD33-positive AML, n=57,  single course of MYLOTARG
  • Complete Remission.  26% that lasted a median 11.6 months


  • Boxed Warning: Hepatotoxicity, veno-occlusive disease or sinusoidal obstruction syndrome
  • Severe side effects: Low blood counts, infections, liver damage, hepatic veno-occlusive disease, infusion-related reactions, hemorrhage
  • Common side effects: Pyrexia, nausea, infection, vomiting, bleeding, thrombocytopenia, stomatitis, constipation, rash, headache, elevated liver function tests, neutropenia


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VABOMERE™ (meropenem and vaborbactam) for injection

Rempex Pharmaceuticals (The Medicines Company)

INDICATION: Treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex


  • Antibacterial product to treat serious or life-threatening infections
  • Additional treatment option for patients with cUTI

REG PATHWAY: NDA, Priority Review

  • Designated as a qualified infectious disease product (QIDP) under Generating Antibiotic Incentives Now (GAIN)
  • Postmarketing Requirements/Commitments:   Surveillance study for drug resistance, extractable/leachable studies

MECHANISM OF ACTION: Penem antibacterial drug that inhibits cell wall synthesis in most gram-positive and gram-negative bacteria


  • Double-blind, double dummy, multi-center trial,  N=545 adults with cUTI, including pyelonephritis, VABOMERE vs.  piperacillin/tazobactam
  • Clinical and microbiological response at the end of IV treatment (EOIVT): Clinical outcome of cure or improvement + microbiologic outcome of eradication
  • Clinical and microbiological response at Test of Cure (TOC) visit at 7 d
  • Cure/improvement in symptoms + negative urine culture test: 98% vs 94%
  • TOC with resolved symptoms + negative urine culture: 77% vs 73%


  • Most common adverse reactions: Headache, infusion site reactions and diarrhea
  • Serious risks : Allergic reactions,  seizures


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BENZNIDAZOLE tablets, for oral use

Exeltis USA

INDICATION:   Indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi


  • First approved treatment approved in US
  • There may be ~  300,000 US patients
  • Granted tropical disease priority review voucher under section 524 of FDCA
  • Voucher entitles designation of a human drug/biologic application as qualifying for a priority review
  • Accelerated Approval: Based on negative Immunoglobulin G (IgG) antibody  test
  • Accelerated Approval Requirement:  Prospective, single-arm, multicenter trial, with historical controls, to evaluate safety, efficacy and pharmacokinetics in children
  • Postmarketing Requirements: ADME study, Fertility toxicity study

MECHANISM OF ACTION: Inhibits synthesis of DNA, RNA, and proteins within parasite


  • Two adequate and well-controlled trials
  • Trial 1 (Argentina): Randomized, double-blind, placebo-controlled trial, children 6-12 yr with chronic indeterminate Chagas disease, n=106, benznidazole vs placebo, followed for 4 years
  • Trial 2 (Brazil): Randomized, double-blind, placebo-controlled trial, children 7 -12 yr with chronic indeterminate Chagas disease, n=129, benznidazole vs placebo
  • Endpoint: Antibodies measured by conventional and nonconventional assays
  • Benznidazole treatment resulted in significantly higher percentage of seronegative patients: 55-60% vs  5-14%


  • Most common adverse reactions: Stomach pain, rash, decreased weight, headache, nausea, vomiting, abnormal white blood cell count, urticaria, pruritus, decreased appetite
  • Serious risks: Serious skin reactions, nervous system effects and bone marrow depression
  • Based on animal findings: Could cause fetal harm when administered to pregnant woman


Image credits: FDA, CDC, Pfizer, Medicines Company