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

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


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

Antimicrobial resistance one of  most pressing public health challenges

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

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

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


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

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

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

IDEs submitted for EFS has more than doubled

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

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


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

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

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

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

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

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

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

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

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


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

Certain drug issues need additional evaluation after approval

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

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

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



Advancing Policies to Promote Safe, Effective MedTech Innovation

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

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

Make review process more benefit-risk based

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

New Steps to Reform, Modernize 510(k) Review

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


FDA's Toxicology Roadmap

Predictive Toxicology Roadmap to Enable Advances in Toxicity Testing

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

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

FDA’s Predictive Toxicology Roadmap

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




 Promise and Potential of 3D Printed Pharmaceuticals

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

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

Addressing 3D Printing Questions Through Research

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


Artificial Pancreas Diagram


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

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

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


Image credits: FDA


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

CaptureTechnical Considerations for Additive Manufactured Medical Devices

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

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


Design and Manufacturing Process Considerations

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

Device Testing Considerations

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


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


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

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

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

FDA Interpretation of Medicare Coverage Categories A and B

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

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

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


CaptureClinical and Patient Decision Support Software

FDA’s regulatory oversight of:

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

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

Scope of FDA oversight of CDS/PDS software:

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

FDA Definitions:

CDS: Software functions that are considered as device:

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

Function excluded from the definition of device with additional criterion

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

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

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

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

Examples provided


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

Global regulatory framework and principles for SaMD

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

Clinical Evaluation of SaMD 

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


General Principles and Context of Clinical Evaluation Process 

  • Definition Statement and Category
  • Clinical Evaluation Processes

Clinical Evaluation Process Flow Chart 

  • Considerations for Generating and Assessing Evidence

Importance of Independent Review of Clinical Evaluation 

Continuous Learning Leveraging Real World Performance Data



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

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

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

Level 2 updates to be made to following guidance documents:

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

Withdrawing following guidance document:

  • Submission of Premarket Notifications for Medical Image Management Devices

Interpretation of Cures Act and modifications to existing guidances:

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



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

FDA BRIEF: Week of November 27, 2017

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

Foundation Medicine

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


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


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


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


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

REIMBURSEMENT PATHWAY:  National Coverage Determination (NCD)

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


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

Federal Register: Program for Parallel Review of Medical Devices

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

Teoxane SA



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


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


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


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


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


CaptureTRIVISC (Sodium Hyaluronate ) injection


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



  • Product Code: MOZ


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


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


Image Credits: Foundation Medicine, Teoxane, OrthogenRx 


FDA BRIEF: Week of Nov 27, 2017

FDA approved

OGIVRI (trastuzumab-dkst) injection



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

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


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


CaptureSUBLOCADE ( buprenorphine ) monthly subcutaneous injection


 Indivior Inc.

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


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


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

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

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


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


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


Image credits: Mylan, Indivior



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

Week of Nov 27, 2017


CDER Conversation: The FDA’s Sentinel Initiative

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

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

Sentinel System different from other systems 

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




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

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

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

FDA presentations

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



PEPFAR: FDA Approves 200th HIV/AIDS Therapy

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

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

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

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



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

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

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

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

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

Providing comprehensive policy framework to manufacturers

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


Image credits: FDA, PEPFAR



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



NUCLUES COCHLEAR IMPLANT telemedicine platform

Cochlear Americas

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


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


  • Product Code : MCM


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


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




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

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

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


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


  • Product Code: PZK


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


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

IMPACT tumor profiling test 

Memorial Sloan Kettering Cancer Center

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


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


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

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

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


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



JULUCA (dolutegravir and rilpivirine) tablets

GlaxoSmithKline (ViiV)

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


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


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


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


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


Image result for hemlibra logoHEMLIBRA (emicizumab-kxwh) injection

Genentech, Inc.

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


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


  • Priority Review, Breakthrough Therapy designation, Orphan Drug designation

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


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


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


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




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

FDA BRIEF: Weeks of November 13 and 20, 2017

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

Marketing authorization of two tumor profiling NGS tests

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

Three-Tiered approach for reporting biomarkers

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


Capture.JPGBig Day for Regenerative Therapy

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

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

Two final guidance documents and Two draft guidance documents


CaptureFDA Workforce and Diversity Plan

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

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

FDA Hiring Initiative

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

FDA Diversity and Inclusion Strategic Plan

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



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

 Office of Criminal Investigations’s (OCI) nationwide presence

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

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

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

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

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



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

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

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

FDA plans to permanently transition older formulations to ADFs

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


Image credit: FDA

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

Capture.JPGXW-100 Automated Hematology Analyzer

Sysmex America, Inc.

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

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

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

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

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


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


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

Capture.JPGABILIFY MYCITE (aripiprazole with sensor) tablets

Otsuka Pharmaceuticals, Proteus Digital Health


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

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


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


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


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


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


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


Capture.JPGNSS-2 BRIDGE Neurostimulation System

Innovative Health Solutions, Inc.

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


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

REGULATORY PATHWAY: De Novo Request, to expand use

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


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


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


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

Image credit: Sysmex, Otsuka, Innovative Health Solutions


FDA approved

Capture.JPGZELBORAF (vemurafenib) Tablet

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

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


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


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


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


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


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


Capture.JPG ALECENSA (alectinib)


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

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

REGULATORY PATHWAY: sNDA, Fulfillment of postmarketing requirement

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


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


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


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


Capture.JPGPREVYMIS (letermovir) tablets and injection


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


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


  • Breakthrough Therapy and Orphan Drug designation

MECHANISM OF ACTION: Antiviral drug against CMV


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


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


CaptureADCETRIS (brentuximab vedotin)

Seattle Genetics

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


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


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


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

 CaptureMEPSEVII (vestronidase alfa-vjbk) injection

Ultragenyx Pharmaceutical, Inc.

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


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


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


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

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


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

fda guidances


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

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

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

Guiding Principles

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


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



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

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

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

Guiding Principles

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

Additional guidance

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



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

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

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

Goals of studies to determine

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


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


Capture.JPGBreakthrough Devices Program

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


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


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



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

Patients play an active role in their own healthcare

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

Categories of patient-specific information for sharing

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



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

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

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



Acceptance Review for De Novo Classification Requests

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

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

De Novo Acceptance Review Policies and Procedures

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

Checklist Acceptance Review

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

Recommended Content Checklist

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


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



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

FDA BRIEF: Week of November 6, 2017


FDA Awards Funding to Support Pediatric Clinical Trials Research

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

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

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

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


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

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

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

GHR Testing has its own risks

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

Flexible approach for regulating novel medical advances such as GHR

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

READ23andMe label

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

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

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

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

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


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

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

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


Image credit: FDA, 23andMe, IACT


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


Image of the device.

HEARTMATE 3™ Left Ventricular Assist System (LVAS)

Thoratec Corporation

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



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


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



Capture.JPGCALQUENCE (acalabrutinib) capsule

AstraZeneca Pharmaceuticals 

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


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


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

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


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


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


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


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


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


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


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


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


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


  • No public information for new indication


Image credit: Thoratec, Astra Zeneca, Alexion















































































































































































































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







PD-L1 IHC 22C3 pharmDx – P150013/S006

Image of PD-L1 IHC 22C3 pharmDx









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

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

FDA BRIEF: Week of October 30, 2017


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

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

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

Packaging innovations

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

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


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

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

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

prevalent myths concerning FDA


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

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

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

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

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



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

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

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

Warning letters to four companies for unsubstantiated claims

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


Health Literacy: Getting the Info You Need

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

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

FDA Promotes Health Literacy

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


Image credits: FDA, EMA



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

FDA BRIEF: Week of October 23, 2017


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

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

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


Biosimilars Education Campaign

Biosimilars are Potentially Cost-Saving Options

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

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

Several approved biosimilars (reference product)

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

FDA has developed educational materials   for health care providers


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

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

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


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

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

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

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

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

MDDT Webpage


Zineh_Issam_Drug_InteractionsCDER Conversation: Evaluating the Risk of Drug-Drug Interactions

What is a drug-drug interaction? 

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

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

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

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

When and how to evaluate drug-drug interactions? 

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

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

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

New draft guidances. Federal Register Notice


Image credits: FDA



Drug and Device Approvals: YESCARTA, IMPELLA RP

Week of October 16, 2017


YESCARTA™ (axicabtagene ciloleucel) suspension for intravenous infusion

Kite Pharma, Inc. (Gilead company)

INDICATION: Treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

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


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


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

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

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


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


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


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





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

ADDRESSING UNMET NEED: Smallest heart pump for right heart failure


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

DESCRIPTION: Comprised of three components

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


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


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


Image Credits: Kite, Abiomed



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

FDA BRIEF: Week of October 16, 2017


Clinical Trials & Medical Devices

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

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

2016-2017 CDRH Strategic Priority: Partner with patients

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

Culture of Patient Engagement



Patient Engagement Advisory Committee (PEAC) Summary

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

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

The future topics

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

meeting materials



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

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

FDA Final RWE Guidance describes:

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


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

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

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

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

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


Image credits: FDA




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

Flexion Therapeutics, Inc.

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

ADDRESSING UNMET NEED: Non-opioid therapy for pain


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


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


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



SENHANCE Surgical Robotic System

TransEnterix Surgical Inc

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


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


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


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


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


Siemens Medical Solutions Inc.

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


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


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


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

Image credits: Flexion, TransEnterix, Siemens



Guidance: ANDA vs 505b(2) Pathway


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

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

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

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

  • Duplicates
  • Petitioned ANDAs
  • Bundling

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

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



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

FDA BRIEF: Week of October 9, 2017

Hurricanes Irma and Jose

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

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

  • Facility closings and potential for shortages

FDA maintaining close watch on the most critical medical products

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


FDA Patient Representative Program

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

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

Recruit Patient Representatives on an as-needed basis to 

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

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

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



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

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

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

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

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

Integrate real world evidence into regulatory decision making process

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

Parameters for rigorous, systematically gathered patient preference information

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


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

Opioid formulation with “properties designed to deter abuse”

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

Testing and approval of abuse deterrent formulations (ADF)

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

Challenges associated with ADF evaluation

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

July 2017 workshop

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


Image credits: FDA


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

FDA BRIEF: Week of October 2, 2017

National CyberSecurity Awareness Month

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


Expanded Access: FDA Describes Efforts to Ease Application Process

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

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

Lifting another potential burden for applications

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

Addressing uncertainty about assessment of  adverse event data from expanded access

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

Other activities

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



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


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

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

Grants awarded for

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



Awarded 6 grants for natural history studies in rare diseases totaling $6.3 million 

  • First time to fund through Orphan Products Grants Program for natural history studies
  • Inform medical product development by better understanding diseases progression
  • More than 80 grant applications reviewed by more than 60 rare disease and natural history experts

Grants awarded for

  • Friedreich’s ataxia, pregnancy and lactation-associated osteoporosis, sarcoidosis, chronic kidney disease, Angelman syndrome, Myotonic Dystrophy Type 1

Photos of Mammography devices

Good News for Public Health: Most Mammography Facilities are in Full Compliance with MQSA Regulations

Mammography Quality Standards Act (MQSA) established in 1992

  • Facilities must meet specific standards and abide by FDA regulations
  • Services must be accredited by FDA- approved accrediting body
  • Facility must hold an active MQSA certificate

> 87% of mammography facilities have no MQSA violations

  • 8,700 MQSA certified mammography facilities, perform > 39 million mammograms/year, using ~ 18,000 mammography units
  • MQSA inspection includes performance, quality assurance records, quality control testing, personnel qualifications, medical records, and medical audit and outcome analysis records
  • Certified MQSA inspectors have performed > 175,000 MQSA inspections

Laptop, gavel and stethoscope, representing medical product-related legislation

Priority Review Vouchers 

Priority Review Vouchers (PRVs) can be used to obtain priority review designation for a subsequent application that does not itself qualify for priority review 

  • May be transferred (including by sale) the entitlement;  no limit on the number of transfers
  • Application for drug/biological product must contain no previously approved active ingredient (including salt/ester)

Tropical Disease PRV: Application for the prevention or treatment of a “tropical disease”

Rare Pediatric Disease PRV: Application for “rare pediatric disease”  that is serious or life-threatening,  affecting individuals aged from birth to 18 years, including age groups often called neonates, infants, children, and adolescents

Medical Countermeasure PRV:  Application intended to prevent or treat harm from a biological, chemical, radiological, or nuclear agent


 Opioid Policy Steering Committee

Opioid Policy Steering Committee (OPSC) proposed

  • To address opioid addiction and the resulting overdoses and deaths
  • FDA seeking public input on how use of its authorities to address crisis

Seeking public input on 3 key areas

  • What more can FDA do to ensure that the full range of available
    information, including about possible public health effects, is considered
    when making opioid-related regulatory decisions
  • What steps can FDA take with respect to dispensing and packaging
    to facilitate consistency of and promote appropriate prescribing practice
  • Should FDA require some form of mandatory education for health care professionals who prescribe opioid drug products, and if so, how should such a system be implemented


Image of a hand reaching for a pill bottle in a medicine cabinet

Reducing the Hurdles for Complex Generic Drug Development

Drug Competition Action Plan to advance new policies aimed at bringing more competition to the drug market

  • Improve the efficiency of the generic drug approval process
  • Closing loopholes that allow branded drug companies to game FDA rules to forestall generic competition
  • Facilitate generic competition to complex drugs

Complex drugs

  • Such as metered dose inhalers used to treat asthma, injectable drugs
  • Have feature(s) difficult to “genericize”
  • Have lost exclusivity, but have no generic competition
  • Can be a high-value opportunity for a generic drug maker

Provide scientific and regulatory clarity with respect to complex generic drugs

  • Adopt more rigorous and sophisticated science, including sophisticated quantitative methods and computational modeling, in drug development, evaluation, and review
  • Draft guidance on pre-ANDA meeting requests to discuss regulatory strategy
  • Draft guidance  on ANDAs for peptides manufactured using recombinant DNA technology such as namely, glucagon, liraglutide, nesiritide, teriparatide, teduglutide

Other Initiatives

  • Address challenges with bioequivalence testing
  • Identify gaps in the science and develop more tools, methods, and efficient alternatives to clinical endpoint testing
  • Workshops on  quantitative modeling approaches,  new analytical tools  for  demonstrating active ingredient sameness in complex products


Image credits: FDA

Device Approvals: COBAS ZIKA, REMEDE

FDA BRIEF: Week of October 2, 2017



Roche Molecular Systems, Inc.

INTENDED USE: Qualitative in vitro nucleic acid screening test for the direct detection of Zika virus RNA in human plasma. Intended for use to screen donor samples for Zika virus RNA in plasma samples from individual human donors, including donors of whole blood and blood components, and other living donors.

Also intended for use to screen organ and tissue donors when donor samples are obtained while the donor’s heart is still beating. Plasma from all donors should be screened as individual samples.

Not intended for use as an aid in diagnosis of Zika virus infection, on samples of other body fluids, on samples of cord blood.


  •  First approval of a Zika virus detection test for use with screening the nation’s  blood supply
  • Critical to preventing infected donations from entering the U.S. blood supply


  • Collaboration between FDA, manufacturer and blood collection industry
    • 2016 FDA guidance recommending screening whole blood and components with cobas Zika test available under IND
    • Several blood collection establishments used test providing data
    • Additional studies by manufacturer to demonstrate effectiveness


  • Fully automated sample preparation (nucleic acid extraction and purification) followed by PCR amplification and detection
  • For use on the fully automated cobas 6800 and cobas 8800 systems
  • Systems consist of the sample supply module, the transfer module, the processing module, and the analytic module
  • Automated data management is performed by software which assigns test results for all tests as non-reactive, reactive, or invalid
  • Results reviewed directly on system screen and printed as report


  • Reproducibility: Testing twelve member panel of three negative plasma samples and three positive;  reproducible performance across variables assessed for detecting Zika
  • Specificity: Testing individual samples from blood donations (n= 358,038 ) at five external laboratories;  clinical specificity was 99.997%
  • Sensitivity: Using 25 confirmed Zika-positive clinical samples at an internal testing site; detected 100%


the-remede-system-productRemedē System

Respicardia Inc.

USE:  Implantable stimulation device designed to improve cardiovascular health by  restoring natural breathing at night.

Includes wires for sensing and stimulation, a neurostimulation device, and a portable tablet programmer.

Designed to replace inappropriate signal from the brain that delivers electrical pulses at night, during sleep, to restore a more normal breathing pattern and improve  cardiovascular health in patients with Central Sleep Apnea


  • Central sleep apnea can lead to poor sleep quality and may result in increased risk for high blood pressure, heart attack, heart failure, stroke, obesity, and diabetes
  • Implantable device offers patients another treatment option for central sleep apnea



  • Battery pack surgically placed under the skin in the upper chest area
  • Small, thin wires inserted into blood vessels in chest near phrenic nerve that stimulates breathing
  • System monitors patient’s respiratory signals during sleep, delivers a small electrical stimulus to phrenic to move diaphragm and restore normal breathing
  • Has 2 modes – generate pulses at a fixed rate (asynchronous therapy) or deliver a pulse only when it detects a pause in breathing (synchronous therapy)
  • Physician sets stimulator to deliver most appropriate therapy
  • Has safeguards to make sure that therapy is only delivered during sleep


  • Study on 141 patients to assess reduction in apnea hypopnea index (AHI), a measure of the frequency and severity of apnea episodes, after 6 months
  • Reduced by 50%  or more in 51% patients vs. 11% reduction with in patients without the system
  • Most common adverse events: Concomitant device interaction, implant site infection, swelling and local tissue damage or pocket erosion

Image credits: Roche, Respicardia


Compounding Risk Alert

Compounding Risk Alert

To alert health care professionals of adverse event reports related to compounded drugs

  • Protect patients from unsafe, ineffective, and poor quality compounded drugs

Recent posts

  • Hemorrhagic Occlusive Retinal Vasculitis (HORV) Following Intraocular Injections of a Compounded Triamcinolone, Moxifloxacin, and Vancomycin Formulation
  • Adverse Events associated with Guardian’s compounded triamcinolone and moxifloxacin product for intravitreal injection
  • Two serious adverse events associated with ImprimisRx’s compounded curcumin emulsion product for injection


Image credit: FDA

FDA Guidances: IRB Minutes, REMS Counseling, Emerging Technology Submissions, Drug vs Device Classification, De Novo and MDUFA IV, Organ Preservation Devices

fda guidances


Minutes of Institutional Review Board (IRB) Meetings

IRBs have been cited in Office for Human Research Protections and  FDA Warning Letters for failing to prepare and maintain adequate minutes

  • Minutes are missing
  • Minutes reflect an inaccurate account of meeting attendance
  • Minutes lack sufficient detail to show vote on actions
  • Minutes are incomplete and only describe voting actions as “passed unanimously.”
  • Minutes do not clearly indicate IRB approvals
  • Minutes fail to include  discussion of controverted issues

Minutes need to include:

  • Attendance
  • Actions taken
  • Vote on Actions-for, against, abstaining
  • Requiring changes or disapproving research
  • Controverted issues and resolution



A Framework for Benefit-Risk Counseling to Patients About Drugs with a REMS

Additional risk management steps are required for certain prescription drugs with serious risks, to ensure that the benefits outweigh the risks

  • Part of Risk Evaluation and Mitigation Strategy – REMS
  • Additional steps include  risk communications, patient‒provider agreements, patient counseling tools
  • Warrant higher level of understanding of risks, greater degree of vigilance, activities to ensure benefits outweigh risks
  • Require individualized and collaborative counseling approach

Proposed 4-E Framework 

  1.  Evaluate (and continuously re-evaluate): Individualized health profile, treatment goals, and counseling needs
  2. Educate: Treatment needs and options, potential risks and benefits, importance of  adhering to REMS
  3. Engage: Patient participation in health care decisions and ensuring safe drug use
  4. Ensure: Patient counseling on key risk information and mitigation



Emerging Technology Program : Submission of chemistry, manufacturing, and controls (CMC) information containing emerging technology to FDA

  • Support and enable pharmaceutical innovation and modernization
  • Support flexible approaches  to advance product design, modernize pharmaceutical manufacturing, improve quality
  • Adopt innovative approaches by leveraging existing FDA resources to facilitate  regulatory assessment of novel technology submissions

Discussion of Scope and Process




Classification of Products as Drugs and Devices & Additional Product Classification Issues

To address Requests for Designation (RFDs)  whether a product should be classified as either a drug or a device

  • RFD guidance on obtaining formal determination of product’s classification
  • FDA’s decision-making process for classification determinations

Statutory Definitions

  • Drug
  • Device

Key provisions of Device definition

  • “Similar or related article”
  • “Primary intended purposes”
  • “Chemical action”
  • “Within or on the body”
  • Illustrative Examples



FDA and Industry Actions on De Novo Classification Requests: Effect on FDA Review Clock and Goals

MDUFA IV authorizes user fees for De Novo classification requests

  • Additional funds  to improve the device review process
  • Meet certain performance goals
  • Implement improvements for device review process

FDA Actions 

  •  Issue an Order Granting the Request to Classify the Device
  • Issue an Order Declining the Request
  • Request Additional Information (AI)
  • Issue a Notice of Withdrawal

De Novo Performance Goals for MDUFA IV

  • Submission
  • FDA Review
  • MDUFA IV Goals
  • Missed MDUFA Decision Communication

Requester Actions 

  • Response to an AI Request
  • Request for Withdrawal of the De Novo Request





Shortage of organs available for transplants has propelled innovation in organ preservation technologies

  • Best practices for utilizing animal studies for the evaluation of organ preservation devices
  • To support IDE, PMA, HDE, 510(k), De Novo applications/requests

Overview and General Study Design Considerations

  • Procedure Duration
  • Contamination
  • Transportability

Reperfusion Models

  • Ex Vivo Models
  • In Vivo Models

Sample Panel of Biomarkers in Liver

  • Liver Injury Biomarkers
  • Liver Function Biomarkers


Image credit: FDA



FDA BRIEF: Week of September 25, 2017

PENTAX ED34-i10T Duodenoscope 


INTENDED USE: Provide visualization and access to the upper gastrointestinal (GI) tract to treat bile duct disorders and other upper GI problems.


  • First duodenoscope with a disposable distal cap, a new feature that will improve access for cleaning and reprocessing
  • Lowering the risk of future infections associated with these devices


  • Regulation Name: 876.1500
  • Classification Code: FDA
  • Classification Name: Duodenoscope And Accessories, Flexible/Rigid


  • Lightweight, ergonomically-designed control body to minimize hand fatigue during prolonged procedures
  • Redesigned elevator improves device control
  • New detachable distal-end cap may improve reprocessing efficiency
  • HD+ imaging for enhanced visualization of mucosal detail to help improve accuracy during mucosal assessment
  • Combined with i-scan image enhancement, clearly visualizes the mucosa in fine detail and may help physicians locate minor papillae
  • Redesigned to improve stability for better device control, which may facilitate cannulation
  • Newly designed distal end with detachable cap to provide improved access for cleaning and reprocessing post-procedure

FreeStyle Libre Flash Glucose Monitoring System

Abbott Diabetes Care Inc.

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

The System detects trends and tracks patterns aiding in the detection of episodes of hyperglycemia and hypoglycemia, facilitating both acute and long-term therapy adjustments. Interpretation of the System readings should be based on the glucose trends and several sequential readings over time. The System is intended for single patient use and requires a prescription.


  • New technology  to help care of people living with chronic conditions, such as diabetes, easier and more manageable
  • System allows diabetics avoid additional step of fingerstick calibration—with a wave of the mobile reader


  • Generic Name: Sensor, glucose, invasive, non-adjunctive, factory-calibrated,
  • Procode: PZE
  • Post Approval Study (PAS) required for confirmatory evaluation of safety and effectiveness in intended use population


  • Uses an electrochemical sensor to monitor glucose levels in interstitial fluid (ISF)
  • Sensor held in place by an adhesive and incorporates both subcutaneously implanted sensor and associated electronics\
  • Sensor uses glucose oxidase enzyme to oxidize glucose and transfer electrons to a metal electrode, producing a current
  • Strength of current is proportional to the amount of glucose present in the subcutaneous space.
  • System converts electrical current signal to a glucose value for display to the user on a handheld Reader
  • 3 primary components: Sensor, Sensor Insertion Device, Reader


  • Primary effectiveness measurements based on performance evaluation of the System compared to the blood glucose values measured by a laboratory glucose analyzer during in-clinic sessions that spanned the wear period of the device (days 1, 4, 7 and 10)
  • Accuracy established across claimed measuring range (40 to 500 mg/dL glucose), precision, 10 day wear period (following the warm-up period) for sensor,  notifications (Glucose Messages), and number of readings displayed during wear period
  • Risks: Hypoglycemia or hyperglycemia for inaccurate readings and treatment decisions, mild skin irritations


  • Coverage limited to patients for whom professional CGM is medically necessary
  • Medicare does not have National Coverage Determination for professional CGM
  • Most local contractors do not have a policy limiting professional CGM


SOFIA 2 Fluorescent Immunoassay Analyzer


INTENDED USE: Bench top analyzer intended to be used with Cassette-based  Immunofluorescent in vitro diagnostic assays for professional and laboratory use

  • Measurand (analyte): Respiratory Syncytial Virus (RSV) A and B nucleoprotein antigens



  • Lateral flow immunoassay with sandwich design to qualitatively detect RSV A and RSV B nucleoprotein from nasopharyngeal (NP) swab and nasopharyngeal aspirate/wash (NA/W) specimens collected from pediatric patients
  • Four main components: (1) sample pad for receiving specimen (2) label pad containing dried, fluorescently dyed microparticles coated with RSV-specific monoclonal antibodies (3) nitrocellulose test strip for the capture of RSV analyte (4) absorbent pad to drive capillary flow


  • Demonstrating “Simple”: Designed to be simple and easy to use by incorporating the several following features
  • Demonstrating “Insignificant Risk of an Erroneous Result”-Failure Alerts and FailSafe Mechanisms
  • Demonstrating “Accuracy”
  • Proposed Labeling
  • Operator Questionnaire Results

REIMBURSEMENT: Appropriate CPT and ICD-9-CM codes to accurately reflect patient condition(s) and testing procedure(s)

User manual

Capture.JPGVERZENIO (abemaciclib) Tablet

Eli Lilly


  • in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy
    • as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting


  • New targeted treatment option for certain patients with breast cancer who are not responding to treatment
  • Can be given as a stand-alone treatment to patients


  • Priority Review and Breakthrough Therapy designations
  • Postmarketing Requuirement:  Clinical trial to evaluate effect of severe diarrhea
  • Postmarketing Commitment: Overall Survival data, Physiologically based Pharmacokinetic modeling (PBPK) analysis

MECHANISM OF ACTION:  Inhibitor of cyclin-dependent kinases 4 and 6; impacts cell cycle progression, and cell proliferation in estrogen receptor-positive (ER+) breast cancer cell lines


  • Randomized, placebo-controlled, multicenter study in women (n=669) with HR-positive, HER2-negative metastatic breast cancer,  in combination with fulvestrant, VERZENIO vs. placebo
  • % Number of patients with an event: 49.8% Vs. 70.4%, p<0.0001
  • Median months: 16.4 vs. 9.3
  • % Objective response rate: 48.1 vs. 21.3


  • Serious side effects: Diarrhea, neutropenia, elevated liver blood tests, deep venous thrombosis/pulmonary embolism, harm to developing fetus
  • Common side effects: Diarrhea, neutropenia and leukopenia, nausea, abdominal pain, infections, fatigue, anemia, decreased appetite, vomiting and headache


Image credit: Pentax, Abbott, Quidel, Lilly

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

FDA BRIEF: Week of September 25, 2017


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

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

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



How Patient Preferences Contribute to Regulatory Decisions for Medical Devices

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

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

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



FDA selects participants for new digital health software Precertification pilot program

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

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

Apple, Cupertino, California

Fitbit, San Francisco, California

Johnson & Johnson, New Brunswick, New Jersey

Pear Therapeutics, Boston, Massachusetts

Phosphorus, New York, New York

Roche, Basel, Switzerland

Samsung, Seoul, South Korea

Tidepool, Palo Alto, California

Verily, Mountain View, California


CapturePatents and Exclusivities for Generic Drug Products


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


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

Types of Exclusivities:

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



New efforts to encourage compounding of better quality drugs 

Important for health care providers to have access to compounded drugs

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


Image credits: FDA




Weeks of September 11 and 18, 2017


MVASI (bevacizumab-awwb) solution for intravenous infusion 

Amgen, Inc


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

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

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

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

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

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


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


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


Image result for solosec logo

SOLOSEC (secnidazole) oral granules

Symbiomix Therapeutics

INDICATION: Treatment of bacterial vaginosis in adult women


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


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

MECHANISM OF ACTION:  Nitroimidazole antimicrobial drug


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


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


Aliqopa™ (copanlisib) Logo

ALIQOPA  (copanlisib) for injection

Bayer Healthcare Pharmaceuticals

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


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


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

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


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


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


Image credits: Amgen, SymbiomixBayer








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

FDA BRIEF: Week of September 18, 2017

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

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

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

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

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

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

Relevant FDA Guidances

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


Spotlight on CDER Science

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

Tardive dyskinesia – a side effect of taking antipsychotic medicines

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


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

A Breakthrough Therapy and Expedited Approval

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



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

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

  • Major pillars of federal response to opioid epidemic

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

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


FDA Encourages New Treatments for Sickle Cell Disease

Sickle Cell Disease (SCD)

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

Limited Treatment Options

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

Encouraging New Treatment Development

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



Biomarker Qualification Program 

Biomarker Qualification Program (BQP) encourages biomarker development

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

Three submission stages

  • Letter of Intent
  • Qualification Plan
  • Full Qualification Package

FDA Engagement throughout the process

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



Image credits: FDA, AAMI, ANSI, Neurocrine

FDA Marketing Permit: reSET

Week of September 11, 2017



Pear Therapeutics

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

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


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

REG PATHWAY: De Novo Request

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

GENERIC DEVICE TYPE:  Computerized behavioral therapy device for psychiatric disorders

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


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


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


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


Image credit: Pear Therapeutics

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

FDA BRIEF: Week of September 11, 2017


FDA is Advancing the Goals of the Orphan Drug Act

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

Orphan Drug Modernization Plan

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

Process improvements for review efficiency

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

New policy steps for incentives

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



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


Priority Therapeutic Areas for Development

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

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


Image credits: FDA

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

fda guidances


Procedures for Meetings of the Medical Devices Advisory Committee

Background and Scope:

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


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



FY 2017 Medical Device User Fee Small Business Qualification and Certification

Background and Scope:

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


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

Small Business Fees:




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

Background and Scope:

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


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




Design Considerations and Premarket Submission Recommendations for Interoperable Medical Devices

Background and Scope:

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


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



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

Background and Scope:

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


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



FDA Clearance: SENOGRAPHE PRISTINA with Self-Compression 

FDA BRIEF: Week of September 4, 2017

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

 Senographe Pristina with Self-Compression 

GE Healthcare

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


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


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


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


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

510(k) Notification


Image credit: GE


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

FDA BRIEF: Week of September 2, 2017

Medical Device and Hurricane Emergencies

Hurricanes Irma and Jose

Medical Device and Hurricane Emergencies

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

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

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


Image credit: FDA

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

FDA BRIEF: August 28, 2017


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

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

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

Stepped Up Enforcement

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

Efficient Regulation

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


mom and child, 3 people, baby

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

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

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

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


Related image

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

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

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


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

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

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


Commemorating 20 Years AIDS poster

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

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

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

FDA engagement with AIDS Community particularly the patients

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

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


Image Credit: FDA

FDA Approvals: KYMRIAH, MYLOTARG, VABOMERE, Benznidazole

FDA BRIEF: Week of August 28, 2017

FDA approved

CAR T Cell


KYMRIAH (tisagenlecleucel) suspension for intravenous infusion



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


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


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

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


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


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



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


Capture.JPGMYLOTARG (gemtuzumab ozogamicin) injection



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


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

REG PATHWAY: BLA, Orphan Drug Designation

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

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


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


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


Image result for vabomere logo

VABOMERE™ (meropenem and vaborbactam) for injection

Rempex Pharmaceuticals (The Medicines Company)

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


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

REG PATHWAY: NDA, Priority Review

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

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


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


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


Image result for chagas disease

BENZNIDAZOLE tablets, for oral use

Exeltis USA

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


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

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


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


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


Image credits: FDA, CDC, Pfizer, Medicines Company

FDA Approvals: CYLTEZO

FDA BRIEF: Week of August 21, 2017

FDA approved

Image result for CYLTEZO logo

CYLTEZO (adalimumab-adbm)

Boehringer Ingelheim Pharmaceuticals, Inc.


  • Rheumatoid Arthritis (RA): reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis.
  • Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older.
  • Psoriatic Arthritis (PsA): reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.
  • Ankylosing Spondylitis (AS): reducing signs and symptoms in adult patients with active ankylosing spondylitis.
  • Adult Crohn’s Disease (CD): reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.
  • Ulcerative Colitis (UC): inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP).
  • Plaque Psoriasis (Ps): the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.


  • Second Biosimilar to Humira
  • Highly similar to reference product (Humira) with no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products
  • Several deferred pediatric asessments

Information on Biosimilars


Image Credit: Boehringer Ingelheim



FDA News and Views: Early Feasibility Studies, Pediatric Opioid Medications for Cough, Medication Use during Pregnancy

FDA Brief: Week of August 21, 2017


Early Feasibility Studies and Investigation Device Exemption

Early Feasibility Studies (EFS) Program provides opportunities to gain early clinical experience with innovative technology

  • enrolls small number of subjects
  • is used to evaluate the device design concept with respect to initial clinical safety and device functionality
  • may guide device modifications

CDRH’s  efforts to streamline the clinical trial initiative


Have a Baby or Young Child With a Cold? Most Don't Need Medicines

 FDA is carefully evaluating prescription opioid medications approved to treat cough in children

Vital to understand potential complications in children using opioid-containing medications, even according to labeled instruction

  • Added contraindication to drug labels alerting that codeine should not be used for any reason, including treatment of cough, in children younger than 12 years

Pediatric Advisory Committee scheduled on Sep 11th will focus on

  • use of prescription opioid products containing hydrocodone or codeine for the treatment of cough in pediatric patients
  • current treatment practices
  • benefit-risk considerations
  • help inform Agency’s decision-making processes related to these medications

Additional efforts:

  • tips for consumers on how to safely treat a child’s cold
  • funding research to develop comprehensive, consumer-centered approaches on best practices for the safe use of pediatric cough and cold medications


Pregnancy Research

Working to Improve Information on Medication Use during Pregnancy

Very few prescription medications specifically approved for use during pregnancy

  • About half of the 6.3 million preganant women/year take at least one medication

Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC)

  • Established by the 21st Century Cures Act
  • Research aimed at optimizing therapies for pregnant women and nursing mothers
  • Led by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Labeling requirements for the pregnancy and lactation subsections

  • Implemented in 2015
  • Provided framework for clearly communicating benefits/risks
  • Removed the decades-old pregnancy category letter system

Pregnancy research initiatives

  • Led by Office of Women’s Health
  • Using predictive modeling to anticipate response to drug
  • Understand safety, efficacy and effects of products e.g.  vaccine safety, MRI effects, drug toxicity

Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP)

  • Research collaboration between FDA, academia and health insurers
  • Learn  about medication effects by linking healthcare records for moms and babies
  • Epidemiologic study to evaluate effect of prescription opioids

Real-World Research and Safety Monitoring

  • Pregnancy Registry
  • Pregnancy outreach activities


Image credit: FDA



FDA BRIEF: Week of  August 14, 2017

FDA approved

Lynparza logo

LYNPARZA (olaparib) tablets


INDICATION FOR USE: Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy

ADDRESSING UNMET NEED: Addition of new indication and new formulation (tablet)


  • Initial approval of capsule formulation in 2014 for the treatment of BRCA-mutated advanced ovarian cancer
  • New tablet formulation also approved for this indicaiton and new indication
  • Tablets and capsules are not interchangeable; capsules will be phased out of market and will be available only through Lynparza Specialty Pharmacy Network
  • Postmarketing commitments:  progression-free survival (PFS) and molecular characteristics,  overall response rate (ORR) and duration of response (DOR) from ongoing clinical studies 

MECHANISM OF ACTION: Inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes that are involved in DNA transcription and DNA repair


  • Two randomized, placebo-controlled, double-blind, multicenter studies, n=295, 265, patients with recurrent ovarian cancers who were in response to platinum-based therapy
  • Major efficacy outcome: Investigator-assessed PFS evaluated according to RECIST, version 1.1.
  • Study 1 (recurrent germline BRCA-mutated cancer): Estimated median PFS was 19.1 vs. 5.5 months (olaparib vs. placebo),  p<0.0001)
  • Study 2 (regardless of BRCA status):  Median PFS was 8.4 months vs. 4.8 months, p<0.0001


  • Most common adverse reactions: Anemia, nausea, fatigue (including asthenia), vomiting, nasopharyngitis, diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, and stomatitis
  • Most common laboratory abnormalities: Decrease in hemoglobin, increase in mean corpuscular volume, decrease in lymphocytes, decrease in leukocytes, decrease in absolute neutrophil count, increase in serum creatinine, and decrease in platelets


Image for trademark with serial number 86916876

BESPONSA (inotuzumab ozogamicin) for injection


INDICATION:  Treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)


  • 5,970 in United States will be diagnosed with ALL in 2017; ~1,440 will die from disease
  • Low life expectancy for B-cell ALL patients with nonresponsive / relapsed cancer
  • New, targeted treatment option

REG PATHWAY: BLA, Orphan drug designation, Priority Review, Breakthrough Therapy

  • Postmarketing requirements: Characterize toxicity after hematopoietic stem cell transplantation (HSCT) in adult and pediatric patients, randomized trial in patients with relapsed or refractory acute lymphoblastic leukemia, Bioburden and endotoxin test method qualification

MECHANISM OF ACTION:  CD22-directed antibody-drug conjugate (ADC), is a cytotoxic agent covalently attached to antibody via linker. Anticancer activity due to binding of the ADC to CD22-expressing tumor cells


  • Randomized (1:1), open-label, international, multicenter study in patients with relapsed or refractory ALL, n= 326, BESPONSA vs.  Investigator’s choice of chemotherapy
  • Efficacy: Complete Response (CR), duration of remission (DoR) and Overall Survival



  • Boxed warning: Severe liver damage (hepatotoxicity), including blockage of veins in the liver
  • Other serious side effects: Myelosuppression, infusion-related reactions, QT interval prolongation, reproductive toxicity
  • Common side effects:  Thrombocytopenia, neutropenia, leukopenia, infection, anemia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, liver damage, abdominal pain, hyperbilirubinemia


Image credit: AstraZeneca, Pfizer

FDA News and Views: Prescription Drug Advertising, Tools for Zika

FDA BRIEF: Week of August 14, 2017

Be Smart About Prescription Drug Advertising: A Guide for Consumers

Content of Risk Information in the Major Statement in Prescription Drug Direct-to-Consumer Broadcast Advertisements

Prescription Drug Advertising regulations require direct-to-consumer (DTC) advertisements with product claims include information on  major side effects and contraindications

  • Called the major statement
  • Also provide adequate provision for dissemination of approved package labeling
  • FDA issued Guidance

FDA interested in ensuring advertisements provide clear and useful information

  • Concern that major statement not fulfilling purpose
  • Too long, minimization of important risk information, therapeutic noncompliance caused by fear of side effects

Office of Prescription Drug Promotion (OPDP), CDER,  investigating effectiveness of a limited risks plus disclosure strategy

  • Limiting  major statement to those that are severe (life-threatening), serious, or actionable
  • Disclosure that  other product risks not included in the advertisement
  • Present fair balance of risk information and avoid misleading presentation on  risk-benefit profile
  • Requesting comments on Federal Register notice

Federal Register notice

FDA In Brief

ZikaNew FDA tools for development and proper evaluation of tests for detecting Zika virus infection

FDA has made available a panel of human plasma samples for regulatory evaluation of serological tests to detect recent Zika virus infection

  • FDA worked with manufacturers to encourage development of diagnostic tests
  • Ensure they were available using Emergency Use Authorization (EUA)

Two primary blood diagnostic tests

  • Nucleic acid tests: Identify infection by confirming  virus’ RNA
  • Serological tests: Identify antibodies produced by body’s immune system upon Zika detection
  • Development of tests challenging because Zika antibodies produced by the body difficult to differentiate from other related virus antibodies (dengue, West Nile)

FDA’s sample panel

  • Plasma samples from individuals infected with Zika, West Nile, or dengue
  • Diagnostic developers use to check if test can distinguish Zika vs. others
  • Also use to compare test vs. other Zika tests approved via EUA
  • Available to developers who have interacted with the FDA through the pre-EUA process and have devices in final stages of validation


Image credit: FDA












FDA News and Views: Software PreCert Pilot, Medical Device Tool Development, GUDID Data Quality, China joins ICH

FDA BRIEF: Week of August 7, 2017

Software Precertification Pilot program

Part of Digital Health Innovation Acton Plan,  conforming to software
provisions of the 21st Century Cures legislation

  • Voluntary program for medical device software manufacturers
  • Need to demonstrate Culture of Quality and Organizational Excellence (CQOE)

Pre-Cert status allows

  • Ability to get software to market faster
  • Iterate based on real world experience
  • Have regulatory predictability

FDA Goals

  • Modern and efficient regulatory framework
  • Easy to obtain and maintain FDA Pre-Cert
  • High quality, safe and effective software throughout product life
  • Enable companies to demonstrate CQOE and measure Key Performance Indicators
  • Enable scalability, variation and evolution of software development
  • Learn and adapt based on program effectiveness


Collage; 1st picture is cross section of a human head; 2nd is a body with skeleton showing; 3rd is hand holding a blood pressure meterMedical Device Tool Development (MDDT)

MDDT program for qualification of tools for medical device sponsors in the development and evaluation of medical devices

  • Promotes innovation in medical device development
  • Bridge gap between research of devices and the delivery of devices to patients

‘Qualification’ based on FDA evaluation of  evidence that

  • tool produces scientifically-plausible measurements
  • works as intended within the specified context of use

Context of Use

  • tool or product area
  • specific output or measure
  • role in device development
  • applicable phases of device development


  • Clinical outcome assessment
  • Biomarker test
  • Nonclinical assessment model


Final Guidance

Optimizing GUDID Data Quality

The Global Unique Device Identification Database (GUDID)

  • FDA database to serve as a reference device catalog device with an identifier
  • Labeler of each medical device labeled with a unique device identifier (UDI) must submit information concerning that device to the GUDID
  • UDI integration from manufacturing through supply chain to patients,electronic health records (EHRs) and registries

FDA’s Focus on GUDID Data

  • Acceptable quality to realize public health benefits
  • Accuracy and completeness of data
  • Engage with stakeholders to optimize data quality and utility


Group photo from trip to China


China Joins ICH in Pursuit of Global Harmonization of Drug Development Standards

By: Theresa M. Mullin, Ph.D., Director of FDA’s Office of Strategic Programs, CDER

Drug development is a global endeavor

  • Requires consistent standards adopted and adhered to global drug makers and regulatory authorities

FDA meeting with China Food and Drug Administration (CFDA)

  • CFDA joins the existing International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
  • Currently includes eight regulatory authorities and six industry associations from across the globe

Steps taken by CFDA

  • Implemented reforms to align China’s regulations with global standards
  • Reformed drug review system, dedicated additional resources, implemented ICH Guidelines
  • Will visit FDA to continue conversation on regulatory modernization


Image credit: FDA



FDA BRIEF: Week of July 31, 2017




Safe Obstetrics Systems, Ltd

INDICATION FOR USE: To elevate the fetal head and facilitate delivery of the fetus in
women requiring a Caesarean Section at full dilation or those requiring a Caesarean
Section after a failed instrumental vaginal delivery. Fetal Pillow is indicated for use at a
gestational age ≥37 weeks.

REG PATHWAY: De Novo request

  • Regulation Number: 21 CFR 884.4350
  • Regulation Name: Fetal head elevator
  • Regulatory Classification: Class II
  • Product Code: PWB

GENERIC DEVICE TYPE: Fetal head elevator

  • prescription device consisting of a mechanism that elevates the fetal head to facilitate delivery during a Caesarean section


  • Adverse tissue reaction: Biocompatibility evaluation
  • Infection: Sterilization validation, Shelf life testing, Labeling
  • Fetal injury due to device failure: Non-clinical performance testing, Shelf life testing, Labeling
  • Maternal injury due to device failure: Non-clinical performance testing, Shelf life testing, Labeling
  • Use error: Labeling


  • Biocompatibility, Performance data, Non-clinical performance data, Labeling



Quantitation of Organophosphate Metabolites in Urine by LC/MS/MS

Centers for Disease Control and Prevention (CDC)

INTENDED USE/INDICATION FOR USE: Quantitation of specific organophosphate metabolites by LC/MS/MS. The device system includes organophosphate metabolite calibrators to calibrate the system and organophosphate metabolite controls for quality control monitoring of the system. This device is intended for use in a single laboratory to detect and measure the concentration of specific
organophosphate metabolites in human urine from individuals who have signs and
symptoms consistent with cholinesterase poisoning. The data obtained by this
device will be used following an exposure or suspected exposure event to confirm
exposure, identify the causative agent, and distinguish exposed from the
unexposed patients.

REG PATHWAY: De Novo request

  • Regulation Number: 21 CFR 862.3652
  • Regulation Name: Organophosphate Test System\
  • Regulatory Classification: Class II (special controls)
  • Product Code: PDY

GENERIC DEVICE TYPE:  Organophosphate test system

  • intended to measure organophosphate metabolites quantitatively in human urine from individuals who have signs and symptoms consistent with cholinesterase poisoning. The data obtained by this device is intended to aid in the confirmation and investigation of organophosphate exposure


  • Internal standards for calibrators and quality control materials
  • Solid phase extraction cartridge initially used to extract metabolites
  • Separation and analysis on a tandem mass spectrometer and HPLC system


  • Analytical Performance: Precision/Reproducibility, Linearity/assay reportable range, Traceability, Stability, Expected values, Detection limit, Analytical specificity


  • False Positive, False Negative, Public Health Risk from Incorrect Test Results: Limited distribution, analytical testing


  • Limited distribution to laboratories with experienced personnel
  • Analytical testing for performance characteristics


FDA approved

STELLAREX 0.035” OTW Drug-Coated Angioplasty Balloon

Spectranetics Corporation

INDICATION FOR USE: For percutaneous transluminal angioplasty (PTA), after appropriate vessel preparation, of de novo or restenotic lesions up to 180 mm in length in native superficial femoral or popliteal arteries with reference vessel diameters of 4-6 mm


  • Classification: III
  • Device Procode: ONU


  • Sterile, single-use, over-the-wire (OTW) device/drug combination product
  • Base PTA Catheter: Percutaneous transluminal angioplasty balloon catheter uses mechanical force of balloon expansion across a lesion to establish patency
  • Drug Coating: Paclitaxel incorporated in an excipient, to serve as an adjunct to the mechanical action of balloon angioplasty and assist in maintaining long term vessel patency post-procedure


  • Prospective, randomized, multi-center, singleblind study, Stellarex 035 DCB vs. standard balloon angioplasty (PTA)
  • Primary effectiveness endpoint: Primary patency at 12 months
  • 76.3% in the DCB group vs. 57.6% in the PTA group (p=0.003)
  • Secondary effectiveness endpoints, including target lesion revascularization (TLR) showed favorable results


  • Primary Safety Composite: 12-month freedom 92.1% (DCB) vs. 83.2% (PTA), p=0.0246
  • No significant safety signal on rare or long-term adverse device or drug effects.



TaqPath™ Zika Virus Kit (ZIKV)

Thermo Fisher Scientific


Real-time RT-PCR test intended for the qualitative detection of RNA from the Zika virus in serum and urine (collected alongside a patient-matched serum specimen) from individuals meeting CDC Zika virus clinical criteria (e.g., clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (e.g., history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiologic criteria for which Zika virus testing may be indicated), by laboratories in the US  certified under CLIA

REG PATHWAY: Emergency Use Authorization

DEVICE DESCRIPTION: Lyophilized real-time reverse transcription polymerase chain reaction (rRT-PCR) assay for the qualitative detection of RNA from Zika virus in human
serum, urine (collected alongside a patient-matched serum specimen), and other authorized specimen types


Image Credit: Safe Obstetrics Systems, CDC, Spectranetics




FDA BRIEF: Week of July 31, 2017

FDA approved

IDHIFA (enasidenib)

Celgene Corp

Abbott RealTime IDH2

Abbott Molecular Inc.

INDICATION: Treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test.

Approved for use with a companion diagnostic, the RealTime IDH2 Assay, to detect specific mutations in the IDH2 gene in patients with AML.


  • Orphan Drug Designation, Priority Review
  • Postmaketing requirements: Characterization of long-term safety in AML, Cllinical PK studies for CYP interaction, hepatic impairment
  • Companion Diagnostic: Somatic Gene Mutation Detection System

MECHANISM OF ACTION:  Inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme, decreasing 2-hydroxyglutarate (2-HG) levels, reduced blast counts and increased percentages of mature myeloid cells


  • Open-label, single-arm, multicenter, two-cohort clinical trial, n= 199,  patients with relapsed or refractory AML and IDH2 mutation (confirmed by RealTime IDH2 Diagnostic)
  • Endpoint: Rate of complete response (CR)/complete response with
    partial hematologic recovery (CRh), duration of response (DOR), rate of conversion from transfusion dependence to transfusion independence


  • Boxed Warning: Differentiation syndrome-can be fatal if not treated
  • Common side effects: Nausea, vomiting, diarrhea, increased levels of bilirubin (substance found in bile) and decreased appetite. Women who are pregnant or breastfeeding should not take Idhifa because it may cause harm to a developing fetus or a newborn baby



VYXEOS (liposome-encapsulated combination of daunorubicin and cytarabine)

 Jazz Pharmaceuticals, Inc.

INDICATION: Treatment of adults with newly-diagnosed therapy-related acute
myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC)

ADDRESSING UNMET NEED:  First FDA-approved treatment specifically for patients with t-AML or AML-MRC.

REG PATHWAY: NDA,  505(b)(2) pathway

  • Orphan designation, Priority review
  • Postmarketing requirements: Characterize nature, incidence, severity of infusion-related reactions,  determine appropriate in patients with renal impairment

MECHANISM OF ACTION:  Daunorubicin has antimitotic and cytotoxic activity and  Cytarabine is a cell cycle phase-specific antineoplastic agent


  • Randomized, multicenter, open-label, active-controlled study, n=309,  VYXEOS to a standard combination of cytarabine and daunorubicin (7+3), patients  with newly diagnosed t-AML or AML-MRC
  • Endpoint:  Overall survival from the date of randomization to death
    from any cause
  • 9.6 months vs. 5.9 months, p=0.005


  • Most common adverse reactions:  Hemorrhage events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders and vomiting


IMBRUVICA (ibrutinib) capsules

 Pharmacyclics LLC

EXPANDED INDICATION:  Treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy


  • cGVHD is life-threatening;  occurs in 30-70% patients who receive HSCT
  • This is the first FDA-approved therapy for the treatment of cGVHD


  • Priority Review,  Breakthrough Therapy, Orphan Drug Designation
  • Previously approved for certain indications in treating chronic lymphocytic leukemia, Waldenström’s macroglobulinemia and marginal zone lymphoma, as well as under accelerated approval status for mantle cell lymphoma


  • Open-label, multi-center, single-arm trial, n=42, patients with cGVHD after failure of first line corticosteroid therapy and requiring additional therapy
  • Endpoint: Best Overall Response Rate (ORR) and Sustained Response Rate based on Investigator Assessment
  • ORR: 28 (67%), Sustained Response Rate 20 (48%)


  • Serious side effects: Severe hemorrhage, infections, cytopenia, atrial fibrillation, hypertension, second primary malignancies, tumor lysis syndrome. May harm developing fetus or newborn
  • Common side effects: Fatigue, bruising, diarrhea, thrombocytopenia, muscle spasms, stomatitis, nausea, hemorrhage, anemia and pneumonia


MAVYRET (glecaprevir and pibrentasvir) tablet

AbbVie Inc.


  • Treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A)
  • Treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both


  • 2.7 to 3.9 million people in US have chronic HCV
  • First eight week treatment duration; provides a shorter treatment duration for many patients
  • Treatment option for certain patients with genotype 1 infection, the most common HCV genotype in US


  • Required pediatric assessment
  • Postmarketing commitments: Reports form ongoing studies, study in  HCV
    genotype 1,  phenotypic effect of the NS3/4A or NS5A substitutions

MECHANISM OF ACTION:   Fixed-dose combination of glecaprevir and pibrentasvir, which are direct-acting antiviral agents against  HCV


  • Several clinical trials, n=2,300 adults with genotype 1, 2, 3, 4, 5 or 6 HCV infection without cirrhosis or with mild cirrhosis, 12 or 16 weeks
  • Serum HCV RNA values were measured during the clinical trials using the Roche COBAS AmpliPrep/COBAS Taqman HCV test
  •  92-100% with no virus detected in blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured


  • Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients
  • Not recommended in patients with moderate cirrhosis and contraindicated in patients with severe cirrhosis. It is also contraindicated in patients taking the drugs atazanavir and rifampin.
  • Most common adverse reactions: Headache, fatigue and nausea


Image Credit: Celgene, Jazz, Janssen, AbbVie












FDA News and Views: FDARA, FDA Import Decisions

FDA BRIEF: Week of July 31, 2017

FDA Reauthorization Act (FDARA)

Congress passed the FDA Reauthorization Act (FDARA) of 2017

  • Reauthorizes user fee programs necessary for pre-market evaluation of prescription drugs (PDUFA), medical devices (MDUFA), generic drugs (GDUFA), and biosimilar (BsUFA) products
  • Ensures continuity for medical product review programs


ACE bar graph

New System Speeds FDA Import Decisions

by: Douglas Stearn, Program Director, Office of Enforcement and Import Operations, Office of Regulatory Affairs

Automated Commercial Environment (ACE), piloted in 2015  

  • for determining whether FDA-regulated products can enter the US
  • uses to determine the admissibility of imports
  • tools include inspections of manufacturing plants abroad, physical inspection of goods, import alerts
  • better automation of admissibility process with lower-risk products

Improvements under ACE

  • automated messages that an import “may proceed” into U.S. without manual review
  • less need to request additional information from the importers
  • improved processing times-  average within 1 minute and 36 seconds
  • improvements for products that require manual processing



FDA Guidances: Antibacterial Therapies, Child-Resistant Packaging

FDA BRIEF: Week of July 31, 2017

fda guidances

Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases


  • streamlined development programs for antibacterial drugs to treat serious bacterial diseases
  • unmet medical need – serious bacterial disease for which effective antibacterial drugs are limited or lacking
  •  may also be candidates for LPAD, per section 3042 of the 21st Century Cures Act


  • types of antibacterial drugs appropriate for streamlined development program
  • drug that treats a single species of bacteria be a candidate
  • important nonclinical considerations
  • clinical trial design considerations
  • noninferiority clinical trials
  • nested noninferiority/superiority clinical trials
  • statistical approaches or randomization strategies
  • importance of PK/PD (exposure-response) data
  • size of the premarketing safety database


Child-Resistant Packaging Statements in Drug Product Labeling


  • assist applicants, manufacturers, packagers, and distributors on
    child-resistant packaging (CRP)
  • what information should be included to support CRP statements in labeling
  • for NDAs, ANDAs, BLAs, and supplement
  • also labeling for nonprescription and Over-the-Counter drug products


  • Prescribing Information: child-resistant cap, child-resistant sachets
  • Patient Information: child-resistant package, sealed child-resistant foil pouch
  • Carton Labeling and Container Labels: Keep out of reach of children



FDA Clearance, Classification: EMBRACE MRI, QUANTX

FDA BRIEF: Week of July 24, 2017

EMBRACE Neonatal MRI System

Aspect Imaging Ltd.


Used on neonates with a head circumference up to 38 centimeters and weight between 1 and 4.5 kilograms. The system has a temperature-controlled incubator placed directly into the MRI system, minimizing movement of the baby. If urgent access to the baby is necessary during the imaging process, the baby can typically be removed from the system in less than 30 seconds.


  • First magnetic resonance imaging (MRI) device specifically for neonatal brain and head imaging in neonatal intensive care units (NICU)
  • No need to take babies out of the NICU
  • Safer imaging


  • Device Classification Name: Nuclear MRI System
  • Regulation Number: 892.100
  • Classification Product Code: LNH
  • Subsequent Product Code: MOS


  • Does not require a safety zone or a radiofrequency shielded room
  • Fully enclosed, medical device implants in close proximity to the system are not required to be “MR Conditional” or “MR Safe.”
  • Contraindicated for patients weighing more than 4.5 kilograms or with a head circumference of more than 38 centimeters
  • Contraindicated for all infants with metallic or electronically active implants since the MRI may cause tissue near the implant to heat or the implant to malfunction


  • Efficacy: Non-clinical testing including images of phantoms simulating an infant brain- of sufficient quality for use by an independent board-certified radiologist
  • Safety: Performance testing – electrical and mechanical safety measures


Quantitative Insights, Inc


Computer-aided diagnosis (CADx) software device used to assist radiologists in the assessment and characterization of breast abnormalities using MR image data. The software automatically registers images, and segments and analyzes user-selected regions of interest (ROI). QuantX extracts image data from the ROI to provide volumetric analysis and computer analytics based on morphological and enhancement characteristics. These imaging (or radiomic) features are then synthesized by an artificial intelligence algorithm into a single value, the QI score, which is analyzed relative to a database of reference abnormalities with known ground truth.

QuantX is indicated for evaluation of patients presenting for high-risk screening, diagnostic imaging workup, or evaluation of extent of known disease. Extent of known disease refers to both the assessment of the boundary of a particular abnormality as well as the assessment of the total disease burden in a particular patient. In cases where multiple abnormalities are present, QuantX can be used to assess each abnormality independently.

This device provides information that may be useful in the characterization of breast abnormalities during image interpretation. For the QI score and component radiomic features, the QuantX device provides comparative analysis to lesions with known outcomes using an image atlas and histogram display format.

QuantX may also be used as an image viewer of multi-modality digital images, including ultrasound and mammography. The software also includes tools that allow  users to measure and document images, and output in a structured report.

Limitations: QuantX is not intended for primary interpretation of digital mammography images.

REG PATHWAY: De Novo request

  • Regulation Number: 21 CFR 892.2060
  • Regulation Name: Radiological computer-assisted diagnostic (CADx) software for lesions suspicious for cancer
  • Regulatory Class: Class II
  • Product Code: POK

GENERIC DEVICE TYPE: Radiological computer-assisted diagnostic (CADx) software for lesions suspicious for cancer.

  •  image processing device intended to aid in the characterization of lesions as suspicious for cancer identified on acquired medical images such as magnetic resonance, mammography, radiography, or computed tomography
  • characterizes lesions based on features or information extracted from the images and provides information about the lesion(s) to the user
  • diagnostic and patient management decisions are made by the clinical user


  • Incorrect lesion(s) characterization leading to false positive results
  • Incorrect lesion(s) characterization leading to false negative results
  • Misused to analyze images from an unintended patient population or on images acquired with incompatible imaging hardware
  • Device failure could lead to the absence of results, delay of results or incorrect results


  • General Controls and Special Controls

Image Credits: Aspect Imaging, Quantitative Insights

FDA News and Views: Patient Engagement Advisory Committee, Generic Drug Competition, Advancing Digital Healthcare, Supply Chain Security Toolkit, OTC Drugs & Dietary Supplements Misbranding

FDA BRIEF: Week of July 24, 2017

Meeting Image

FDA Sets Inaugural Meeting of First-Ever Patient Engagement Advisory Committee

New Patient Engagement Advisory Committee (PEAC)

  • PEAC is a forum for the voice of patients
  • Inaugural Meeting: On Oct. 11-12, 2017
  • Topic: Challenges of clinical trial design, conduct, and reporting identified by patients

Committee Members

  • Nine core voting members, chair and consumer representative
  • All have direct experience as a patient or as a care-partner for a patient
  • American Association of Kidney Patients
  • Consumer Representative – Retired from the University of Pittsburgh
  • National Mammography Quality Assurance
  •  Health Motivations
  • Emory Alzheimer’s Disease Research Center
  • Veterans Administration
  • Diabetes association
  • American Cancer Society and the Cancer Action Network
  • Arthritis Foundation


generic medications

Opening Remarks by Dr. Gottlieb for Public Meeting on Generic Drug Competition

FDA doesn’t have a direct role in how drugs are priced but play a  role in the eventual cost of medicines

  • impact on cost of drug development
  • impact on drug pricing
  • cost of scientific and regulatory risk, time for development and approval, failures
  • can impact drug costs by encouraging competition with focus on generic drugs

Concern with branded companies “gaming” FDA system

  • taking advantage of rules to deliberately forestall generic entry
  • making it hard for generic drug makers to purchase branded drug  for testing
  • raising scientific objections timed to delay approval of ANDA
  • gratuitous price increases on niche products

FDA wants to hear from the public

  • ways to benefiting consumers
  • ways to balance access and innovation
  • market-based incentives to attract entrepreneurship to support new innovation

FDA undertaken “Drug Competition Action Plan” with 3 major elements

  • Identify sources of ‘gaming’ and change rules e.g. REMS
  • Identify scientific and regulatory obstacles to generic entry of generic medicines e.g. improve regulatory framework
  • Focus on the efficiency and throughput of overall generic drug program e.g. review efficiencies, improve scientific knowledge, enhance communication

GDUFA II proposal, currently pending before Congress

  • designed to reduce the number of ANDA review cycles
  • expand frequency and scope of communications between FDA and ANDA filers,  more opportunities to cure deficiencies,  get quick approvals
  • create pre-ANDA program, with a special focus on complex generics
  • issue “Good ANDA Assessment Practices” MAPP for internal policies
  • issue  “Good ANDA Submission Practices” guidance

Continued efforts on Drug Competition Action Plan and ongoing implementation of the Hatch-Waxman Amendments


Classifying Over-the-Counter Drugs as Generally Recognized as Safe and Effective and Not Misbranded

Additional criteria and procedures for classifying over-the-counter (OTC) drugs as generally recognized as safe and effective (GRASE) and not misbranded

  • OTC drug products without any US marketing experience can be evaluated under the monograph process if active ingredients meet certain “time and extent” criteria
  • If eligible, parties can submit safety and effectiveness information

FDA inviting comments on

  • Necessity of proposed collection of information for proper FDA performance
  • Accuracy of FDA’s estimate of burden of  proposed collection of information
  • Ways to enhance quality, utility, and clarity of information to be collected
  • Ways to minimize burden of collection of information on respondents


APEC Toolkit diagramKeeping the U.S. Prescription Drug Supply Chain Among the Safest in the World

By: Ilisa Bernstein, Pharm.D., J.D. Deputy Director,  Office of Compliance, CDER

Challenging yo keep U.S. prescription drug supply safest in the world

  • 4 billion prescriptions filled last year
  • moving through the U.S. supply chain
  • large percentage made outside of US
  • substandard and falsified drugs are global problems
Supply Chain Security Toolkit for Medical Products


  • Information and resources related to track and trace, internet sales, detection technology, and much more
  • Can be used by industry stakeholders and global regulators
  • PREVENT, DETECT, and RESPOND to medical products that threaten patient health and safety


dietary supplements, bottles image

Dietary supplement concerns? Tell the FTC and FDA

By: Mary Engle, FTC, and Steven Tave, FDA

Federal Trade Commission (FTC) and FDA have enforcement programs to protect consumers from false and misleading claims
  • Oversee Labeling Claims, Content, Purity, Safety
  • Monitor truth and accuracy of advertising claims
  • Monitor claims made on websites or in other online marketing
  • Inform FDA, FTC if false advertising or safety concerns

Safety Reporting Portal

FDA Guidance: IRB Waiver, Alteration of Informed Consent


  • IRB waiving or altering informed consent requirements for certain minimal risk
    clinical investigations
  • no objection to a sponsor initiating, or an investigator conducting, a minimal risk clinical investigation for which an IRB waives or alters informed consent requirements
  • in accordance with 21st Century Cures Act

Waiver: Current Rule

  • life-threatening situations
  • emergency research
  • ‘where it is not feasible or it is contrary to the best interest of such human

Waiver Revisions: Based on 21st Century Cures Act

  • clinical investigation involves minimal risk (21 CFR 50.3(k), or 56.102(i))
  • will not adversely affect the rights and welfare of the subjects
  • clinical investigation could not practicably be carried out without the waiver
  • subjects will be provided with additional pertinent information after participation


Image credit: FDA

FDA News and Views: 2017 Reauthorization Act, FDA Workforce, STEM Education, Grapefruit Interaction, Medical Device Standard Recognition

FDA BRIEF: Week of July 17, 2017

The Committee on Energy and Commerce extended user-fee programs for prescription drugs, medical devices, generic drugs, and biosimilar biological products


  • new user fees for de novo medical device classification requests
  • pilot program to audit and certify laboratories for device conformance testing
  • flexibility to better assess device types most appropriate for third-party review
  • all device submissions in electronic format by 1 October 2021
  • risk-based inspection of medical device establishments
  • establish standards to improve predictability for scheduled inspections
  • process for issuance of foreign export certificates
  • regulations to establish category of over-the-counter hearing aids
  • ensure  quality, safety and effectiveness of services devices
  • voluntary pilot program for device manufacturers for postmarket study requirements using active surveillance
  • classification of medical device accessories based on intended use
  • approval of imaging device with use of contrast agent

Prescription Drugs

  • raises penalties for counterfeit and illegally diverting drugs
  • engage with Congress to lower the cost of prescription drugs
  • recognize foreign government auditors to improve international inspection
  • clarify qualifying criteria for neglected tropical diseases priority review voucher
  • reauthorize critical path public-private partnership for five years

FDA Authorization Act of 2017

Audience Participating in Scientific Professional Development Lecture

Building a Strong FDA Workforce to Bring Scientific Advances to Patients

By: Scott Gottlieb, M.D., Commissioner 

FDA staff must remain current with dramatic advances in science and medicine

  • need for diverse, talented, and dedicated professional workforce
  • requested comprehensive evaluation of  hiring practices and procedures
  • critical to modernize process for recruiting personnel

Piloting new hiring procedures headed by Melanie Keller, Office of Management, CDER

  • align administrative hiring procedures and scientific staffing objectives
  • reflect scientific objectives of review programs in recruitment and hiring
  • prioritize hiring into positions supported by PDUFA commitments


Dr. Rick Pazdur and Members of Summer Scholars

Leveraging FDA Resources to Encourage Students to Pursue STEM Careers

By: Richard Pazdur, M.D., Director, FDA Oncology Center of Excellence

Oncology Center of Excellence recently launched pilot Summer Scholars Program

  • to introduce high-school students to oncology drug development
  • 11 Washington, D.C., area HS students to FDA’s Silver Spring campus for six weeks
  • curriculum: basic and translational science, drug manufacturing, clinical trials, regulatory review, patient advocacy, and marketing

The OCE Summer Scholars Program could be expanded next year to high school students nationally


Grapefruit Juice Drug Overdose Info-graphic (800x237)

Grapefruit Juice Drug Under-dose Info-graphic (800x237)

Grapefruit Juice and Some Drugs Don’t Mix

Grapefruit juice interacts with some drugs:

  • statin drugs to lower cholesterol: Zocor (simvastatin), Lipitor (atorvastatin)
  • to treat high blood pressure: Procardia and Adalat CC (both nifedipine)
  • organ-transplant rejection drugs: Sandimmune and Neoral (both cyclosporine)
  • anti-anxiety drugs: buspirone
  • corticosteroids to treat Crohn’s disease or ulcerative colitis: Entocort EC and Uceris (both budesonide)
  • to treat abnormal heart rhythms: Pacerone and Nexterone (both amiodarone)
  • antihistamines: Allegra (fexofenadine)

Severity of the interaction dependent on the person, the drug, and the amount of grapefruit juice


Recognition of a Medical Device Standard

The 21st Century Cures Act of 2016 clarifies how FDA will process requests for recognition of voluntary consensus standards:

  • 60-day timeframe for FDA response to recognition requests
  • FDA response in writing
  • FDA publication of rationale for recognition of all, part, or none of standard


Image Credit: FDA



FDA Brief: Week of July 17, 2017

FDA approved

TREMFYA (guselkumab) injection

Janssen Biotech, Inc.

INDICATION: Treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy


  • Required Pediatric Assessments: PK, Safety and Efficacy Study in pediatric subjects
    6 years to < 18 years with moderate to severe plaque psoriasis
  • Postmarketing requirements: Registry-based observational exposure cohort study on maternal, fetal, and infant outcomes of exposed pregnant women, claims or electronic medical record data or a case control study to assess adverse pregnancy outcomes

MECHANISM OF ACTION: Human monoclonal IgG1λ antibody, selectively binds to p19 subunit of interleukin 23 (IL-23), inhibits its interaction with the IL-23 receptor – inhibits release of proinflammatory cytokines and chemokines


  • Three multicenter, randomized, double-blind trials, n=1443 + 268, moderate-to-severe plaque psoriasis eligible for systemic therapy or phototherapy, TREMFYA vs. placebo or adalimumab, 16 weeks
  • Study 1 &2: Co-primary endpoints- Achievement of (i) Investigator’s Global Assessment (IGA) score of 0 (“cleared”) or 1 (“minimal”) and (ii) at least a 90% reduction from baseline in Psoriasis Area and Severity Index (PASI) composite score
  • 70%-80% vs. <10% response rate, maintained and durable for 48 weeks, greater improvements on Patient Reported Outcome based on Psoriasis Symptoms and Signs Diary (PSSD)
  • Study 3: TREMFYA vs. ustekinumab treatment; greater response with TREMFYA


  • Warnings and Precautions: Infections,  Tuberculosis (TB) – Evaluate for TB prior to initiating treatment
  • Most common (≥1%) adverse reactions:  Upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea infections, herpes simplex infections


NERLYNX (neratinib maleate) Tablets

Puma Biotechnology, Inc.

INDICATION:  Extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy

ADDRESSING UNMET NEED: Personalized medicine


  • Postmarketing Requirements: Physiologically-based pharmacokinetic  modeling/simulation study on effect of repeat doses of a moderate CYP3A4 inhibitor, 2-year carcinogenicity study in the rat

MECHANISM OF ACTION: Irreversibly binds to Epidermal Growth Factor Receptor  (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4, inhibited activity of EGFR, HER2 and HER4


  • Single multicenter, randomized, double-blind, placebo-controlled trial,  n=2,840, early-stage HER2-positive breast cancer, NERLYNX vs. placebo, one year
  • Major efficacy outcome measure: Invasive disease-free survival (iDFS)  with 2 years and 28 days of follow-up; 94.2% vs. 91.9%  (HR 0.66; 95% CI: 0.49, 0.90, p=0.008)


  • Common adverse reaction leading to discontinuation: Diarrhea, Hepatotoxicity or increases in liver transaminases
  • Most common adverse reactions: Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight loss, and urinary tract infection


VOSEVI (sofosbuvir, velpatasvir, and voxilaprevir) tablet

Gilead Sciences, Inc.

INDICATION: Treatment of adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have:

  • genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV
  • regimen containing an NS5A inhibitor
  • genotype 1a or 3 infection and have previously been treated with an HCV regimen
    containing sofosbuvir without an NS5A inhibitor
  • Additional benefit of VOSEVI over sofosbuvir/velpatasvir (SOF/VEL)was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir
    without an NS5A inhibitor


  • Estimated 2.7 to 3.9 million people in US with chronic HCV; may lead to liver cancer and death
  • At least six genetically distinct HCV genotypes or strain; 75% (genotype 1); 20-25% (genotypes 2 or 3), small number (genotypes 4, 5, 6)
  • First treatment approved for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A


  • Fixed-dose, combination tablet with two previously approved drugs – sofosbuvir and velpatasvir – and a new drug, voxilaprevir
  • Required Pediatric Assessments:  PK, safety and treatment response  in pediatric subjects 12 -18 years with chronic HCV genotype 1- 6
  • Postmarketing Requirement:  Assess signals of serious risk due to treatment-emergent resistance substitutions

MECHANISM OF ACTION: Combination of 3 drugs that are direct-acting antiviral (DAA) agents against the hepatitis


  • two trials in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis
  • VOSEVI vs Placebo or VOSEVI vs. SOF/VEL
  • Serum HCV RNA values measured using COBAS AmpliPrep/ COBAS Taqman HCV test,  lower limit of quantification (LLOQ) of 15 IU/mL
  • Primary Endpoint: Sustained virologic response (SVR12) – HCV RNA < LLOQ at 12 weeks; Relapse- HCV RNA >LLOQ; Virologic Failure- breakthrough, rebound, or non-response
  • 90-100% vs 0%  achievement of SVR12 in VOSEVI vs. placebo
  • 96% vs 85% achievement of SVR12 in VOSEVI vs. SOF/VEL


  • Most common adverse reactions: Headache, fatigue, diarrhea and nausea
  • Contraindication: Rifampin
  • Hepatitis B virus (HBV) reactivation: Need for screening


D2 Dressing (QuikClot+)

Z-Medica, LLC

INDICATION FOR USE: For temporary control of internal organ space bleeding for patients displaying class III or class IV bleeding. It may also be used for control of severely bleeding wounds such as surgical wounds and traumatic injuries

REG PATHWAY: De Novo request

  • Regulatory Classification: Class II
  • Product Code: POD
  • Non-absorbable, hemostatic gauze for temporary internal use
  • Intended to be placed temporarily for control of severely bleeding wounds such as surgical wounds and traumatic injuries. The gauze is coated or impregnated with a hemostatic material which may enhance hemostasis by physical means. The device is intended to be removed once the patient is stabilized.


  • Biocompatibility, performance bench, performance animal testing, clinical data on a previous formulation of the device (D1 Dressing)


  • Infection: Shelf Life Testing, Sterilization Validation, Labeling
  • Bleeding (Hemostasis Failure, Bleeding Recurrence): Animal Performance Testing, Technological Specifications
  • Vascular Obstruction (Ischemiam, Emboli Formation): Animal Performance Testing, Labeling
  • Adhesion Formation: Animal Performance Testing, Labeling
  • Adverse Tissue Reaction: Animal Performance Testing. Biocompatibility Evaluation
  • Device Retained in Body Leading to ReOperation: Animal Performance Testing, Non-Clinical Performance Testing, Labeling

Image Credits: Janssen, Puma, Gilead, Z-Medica

FDA News and Views: Addressing Opioid Epidemic, NASEM Report on Opioid Abuse, Precision Medicine Approvals, Clinical Trials in India, Class II Device Exemptions

FDA BRIEF: Week of July 10, 2017

 Marshaling FDA Benefit-Risk Expertise to Address the Current Opioid Abuse Epidemic

By: Scott Gottlieb, MD, Commissioner & Janet Woodcock, MD, Director, CDER

Addressing the opioid crisis is a national priority and role of prescription opioids is critical FDA focus 

  • Need to consider both benefits of opioids for severe and chronic pain, as well as the multiple adverse effects
  • FDA assesses diverse risks and benefits to ensure that it is considering the full public health implications of any decisions
  • Sought market withdrawal of Opana ER over concerns about illicit use
  • Placed specific restrictions on certain prescription fentanyl formulations to prevent life-threatening respiratory depression
  • Placed limits on prescribing of sodium oxybate to prevent abuse
  • Continuing efforts to support development of abuse-deterrent opioids
  • Commissioned study from National Academies of Sciences, Engineering, and Medicine (NASEM) to identify additional actions FDA should consider to address opioid crisis


 National Academies of Sciences, Engineering, and Medicine (NASEM) report on pain management and prescription opioid abuse

By Scott Gottlieb, MD, Commissioner

NASEM Report on prescription opioid abuse, misuse and pain management
  • Opioid approval and removal decisions made within a benefit-risk framework evaluating outcomes when used as prescribed as well as public health effects of inappropriate use
  • Reducing rate of new addictions by ensuring only appropriately indicated patients are prescribed, for durations and doses matching clinical reason
  • Securing the critical data needed to better understand the impact of opioid medications

 Will require coordinated effort including federal, state, and local partners to properly address its continued destruction of individual lives and families


Two Recent Scientific Advances Underscore an Encouraging Future for Precision Medicine at FDA

By: Janet Woodcock, MD, Director, CDER

Two recent FDA drug approvals point to an encouraging future for “precision medicine”

  • Involve diseases resulting from particular genetic characteristics identified by laboratory testing
  • KALYDECO (ivacaftor) indicated for 33 Cystic Fibrosis  mutations
  • KEYTRUDA (pembrolizumab) to treat cancers having specific genetic feature (instead of location)

FDA has also approved “targeted therapies”

  • 25 new drugs that benefit patients with specific genetic characteristics
  • New uses for marketed drugs based on specific genetic characteristics e.g. rare genetic disorders


Leslie Ball, M.D., FDA Assistant Commissioner of International Programs and Elizabeth Wiley, M.D., J.D., M.P.H., AAAS Science and Technology Policy Fellow

FDA Collaborates to Promote Safety, Quality in Clinical Trials Done in India

 By: Leslie Ball, MD, Assistant Commissioner for International Programs, Letitia Robinson, PhD, RN, FDA India Office, Elizabeth Wiley, MD, JD, MPH, Office for International Programs

India holds vast potential for clinical research and has become a global leader in generic drugs

  • FDA’s Office of International Programs (OIP) and India Foreign Office adopted strategic engagement approach- inspections, targeted engagements, training, collection and use of data- to inform FDA decision-making

Joint training workshop for Indian regulators, academic representatives, and drug industry on scientific and ethical standards for clinical trials

  • Identifying general concepts in inspections of clinical investigators, clinical trial sites, ethics committees, and bioanalytical study sites
  • Identifying techniques for maintaining data integrity in clinical trials
  • Reviewing inspections to develop evidence and determining appropriate observations to include in inspection reports

Effort to promote data integrity, credible and accurate results, and protection of subjects in clinical trials


Class II Device Exemptions from Premarket Notification 

Federal Register announced 1,003 class II exempt device types sufficiently well understood and do not present risks

  • To decrease regulatory burden
  • To reduce private costs and expenditures
  • Follows streamlined procedures established by the 21st Century Cures Act
  • Some device types are partially exempt from premarket requirements
  • New product codes issued


Image credit: FDA





FDA BRIEF: Week of July 3, 2017

FDA approved

DIGNICAP Cooling System

 Dignitana Inc.

EXPANDED INDICATION FOR USE: To reduce the frequency and severity of hair loss during chemotherapy in solid tumor cancer patients in which alopecia-inducing chemotherapeutic agents and doses are used

ADDRESSING UNMET NEED: First cooling cap cleared for use in cancer patients with solid tumors

REG PATHWAY:  510(k)

  • First clearance via De Novo pathway (2015) – For use in patients with breast cancer
  • Classification Name: Scalp Cooling System
  • Regulation Number: 878.4360
  • Regulation Name: PMC


  • Computer-controlled system – cap is worn on the head and circulates liquid to a cap to cool the scalp during chemotherapy treatment
  • Cap is covered by a second cap made from neoprene to hold cooling cap in place and act as an insulation cover
  • Cooling intended to constrict scalp blood vessels to reduce amount of chemotherapy reaching hair follicles
  • Cold temperature also decreases hair follicles activities, slows cell division, making them less affected by chemotherapy
  • Combined actions thought to reduce the effect chemotherapy has on the cells, which may reduce hair loss


De Novo Indication for use in breast cancer:

  • Stage I and Stage II breast cancer undergoing chemotherapy associated with hair loss (n=122)
  • Primary endpoint: Self-assessment of hair loss using standardized photographs
  • 66% reported losing less than half their hair

510(k) for expanded indication for use in solid tumors

  • Evidence from published, peer-reviewed articles analyzing DigniCap use in cancer patients with solid tumors in other areas of the body besides the breast
  • These studies provided valid scientific evidence to support expanded indication


  • Contraindicated for pediatric patients, patients with certain cancers and patient undergoing specific chemotherapy treatments
  • Not appropriate for patients with cold sensitivity or susceptibility to cold-related injuries
  • Most common side effects: Cold-induced headaches, neck and shoulder discomfort, chills and pain associated with extended use
  • Long-term effects of scalp-cooling and risk of scalp metastasis have not been fully studied

Scalp Cooling System

Image result for sickle cell

ENDARI (L-glutamine) oral powder 

Emmaus Medical Inc

INDICATION: To reduce the acute complications of sickle cell disease (SCD) in adult and pediatric patients 5 years of age and older


  • SCD is an inherited blood disorder with red blood cells (RBC) abnormally sickle shaped
  • Restricts blood flow leading to severe pain and organ damage
  • 100,000 US patients; mostly in African-Americans, Latinos, other minority groups

REG PATHWAY: NDA, Standard Review, Orphan Drug Designation

  • Postmarketing commitment: Dose-finding trial in adult and pediatric SCD patients with body weight less than or equal to 65 kg

MECHANISM OF ACTION: L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione

  • Randomized, double-blind, placebo-controlled, multi-center clinical trial (n=230)
  • Efficacy: Reduction in number of sickle cell crises through Week 48 and prior to start of tapering among patients


  • Common side effects: Constipation, nausea, headache, abdominal pain, cough, pain in the extremities, back pain and chest pain


PRAXIS Extended RAS Panel


INTENDED USE: Qualitative in vitro diagnostic test using targeted high throughput parallel sequencing for the detection of 56 specific mutations in RAS genes [KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4)] in DNA extracted from formalin‐fixed, paraffin‐embedded (FFPE) colorectal cancer (CRC) tissue samples.

The Praxis™ Extended RAS Panel is indicated to aid in the identification of patients with colorectal cancer for treatment with Vectibix® (panitumumab) based on a no mutation detected test result. The test is intended to be used on the Illumina MiSeqDx® instrument

ADDRESSING UNMET NEED: First FDA-approved NGS test that can detect multiple RAS gene mutations for colorectal cancer in a single test


  • Product Code: PQP


  • Qualify DNA sample that can be used for the test
  • Manually prepare samples for sequencing – library preparation – Hybridization, Extension‐Ligation, PCR Amplification, and Library Normalization
  • Sequence prepared sample using SBS (sequencing by synthesis) chemistry on the MiSeqDx


  • Studied retrospectively using available specimens from mCRC patients enrolled in  multi-center clinical trial with Vectibix plus FOLFOX to FOLFOX alone
  • Progression-free survival and overall survival in wild-type RAS patients demonstrated that the efficacy of panitumumab in patients whose tumors do not have a KRAS or NRAS mutation is supported
  • Analytical validation demonstrated that the panel performs consistently and accurately in the detection of the select KRAS and NRAS mutations in mCRC patients.


Vectibix Label


FDA News: Biomarker for Acute Pancreatic Injury, Innovation Initiative and Cures Act, Nail Care Products

FDA BRIEF: Week of July 3, 2017

Spotlight on CDER Science

Lab Tests in Rodents Suggest Potential New Biomarker for Acute Pancreatic Injury

Biomarkers are measurable indicators that can signify presence/severity of disease 

  • FDA prioritizes identification of new, reliable and sensitive biomarkers

Acute pancreatic injury requires sensitive biomarkers

  • Numerous drugs, including those to treat type-2 diabetes, linked to pancreatic injury
  • Not evident in pre-approval, non-clinical safety and clinical trials with traditional pancreatic injury biomarkers, serum amylase and lipase
  • Thus more sensitive and specific biomarkers required to detect /monitor pancreatic injury potential of new drugs

Division of Applied Regulatory Science research suggest microRNAs (miRNAs) may be good biomarker candidates

  • Have a key role in the regulation of genes by repressing gene expression
  • Can increase rapidly after tissue injury
  • miR-216a, miR-217, miR-216b, miR-375, miR-148a able to detect pancreatic injury earlier and were more specific to pancreatic injury in rats and mice. These miRNAs also found in humans.
  • Additional data needed to determine utility in patients


Dr. Scott Gottlieb

Innovation Initiative: How FDA Plans to Help Consumers Capitalize on Advances in Science

FDA will soon unveil a comprehensive Innovation Initiative
  • Modern and efficient regulatory processes
  • Efficient and science-based regulatory principles
  • Remove regulatory barriers to beneficial new medical innovations
  • Help facilitate access to new innovations after FDA approval
  • Help maintain costs and hence, pricing, of new medical innovations

Detailed work plan to implement different aspects of Cures Act. Examples-

  • CDER: Modeling and simulation to predict clinical outcomes, inform clinical trial designs, support evidence of effectiveness, optimize dosing, predict product safety, and evaluate potential adverse event mechanisms
  • CDRH: In silico regulatory models for product design and evaluation, digital library of models, family of “virtual patients” for device testing
  • CBER: Implementing the Regenerative Medicine Advanced Therapy designation,


How to Safely Use Nail Care Products

Cosmetic Nail Care Products: Ingredients and Warnings

  • Do not need FDA approval for marketing
  • But required to be safe when used as intended
  • Must include instructions or warnings needed for safe use
  • Consumers must read label prior to use
  •  FDA’s nail care products webpage

Nail Drying and Curing Lamps—and UV Exposure

  • Viewed as low risk when used as directed by the label
  • FDA has not received any reports of burns or skin cancer

Report Problems with Nail Care Products

  • FDA Consumer Complaint Coordinator
  • Medwatch


Image credit: FDA 

FDA News: eMDR Enhancements, Enhance Generic Drug Development, Compounded Drug Safety, Antibiotic Misuse/Resistance

FDA BRIEF: Week of June 26, 2017

eMDR System Enhancements and HL7 Individual Case Safety Reporting

Electronic Medical Device Reporting (eMDR) program’s system update

  • Mandatory medical device reports from Manufacturers, Importers, Device User Facilities
  • Updates available for public access, download, and review
  • Specific changes being implemented outlined

 Health Level 7 (HL7) Individual Case Safety Reporting (ICSR)

  • Standard for capture of information needed to support submission of MDR reportable events
  • Files have also been updated for review

eMDR System Enhancements

Health Level 7 (HL7) Individual Case Safety Reporting (ICSR) Files

Generics have the same quality as brand name drugsGeneric Drug Development and Access Enhancements


Safety of Compounded Drugs by Drug Quality and Security Act (DQSA)

Need for robust oversight over human drug compounding, dispensing prescription and strong coordination with state regulatory partners to protect public health

  • Enactment of DQSA in 2013
  • Oversight of compounding and implementing compounding provisions of the law
  • > 400 inspections, including 109 inspections of outsourcing facilities
  • > 150 warning letters issued
  • > 50 letters referring inspectional findings to state regulatory agencies
  • > 125 recalls involving compounded drugs
  • 21 draft guidances, 10 final guidances, 3 proposed rules, a final rule, a draft memorandum of understandin
  • Taking risk-based approach to maximize public health purpose



Antibiotic Misuse and Resistance

Dr. Woodcock discusses the issues surrounding the use and misuse of antibiotic medicines, as well as the emergence of antibiotic-resistant bacteria and how the issues are related.


Image credit: FDA




FDA BRIEF: Week of June 26, 2017

FDA approved

Image result for bevyxxa logo

BEVYXXA (betrixaban) capsules

Portola Pharmaceuticals, Inc.

INDICATION:  For the prophylaxis of venous thromboembolism (VTE) in adult patients  hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for  VTE


  • Required Pediatric assessments

MECHANISM OF ACTION: Oral FXa inhibitor, selectively blocks active site of FXa, decreases thrombin generation


  • Single randomized, double-blind, multinational study, n=7,513, patients hospitalized for acute medical illness, moderate or severe immobility, additional VTE risk
    factors, extended duration BEVYXXA vs. short duration enoxaparin
  • Composite Efficacy Endpoint: Asymptomatic proximal Deep Vein Thrombosis (DVT), Symptomatic proximal or distal DVT, Non-fatal Pulmonary Embolism (PE), VTE-related death
  • Composite Outcome, n(%) : 165 (4.4) vs. 223 (6.0)


  • Most common adverse reactions (≥5%): Related to bleeding (betrixaban vs enoxaparin)
    • at least one adverse reaction: 54% vs. 52%
    • serious adverse reactions: 18% vs. 17%
    •  incidence rate for all bleeding episodes: 2.4% vs. 1.2%
    • major bleeding episodes: 0.67% vs. 0.57%


Related image


Beckman Coulter, Inc.

INTENDED USE: Authorized test for use with flow cytometry to aid in the detection of  several leukemias and lymphomas, including chronic leukemia, acute leukemia, non-Hodgkin lymphoma, myeloma, myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN)


  • First FDA authorized test for use with flow cytometry to aid in the detection of several leukemias and lymphomas
  • For laboratories and health care professionals to have an FDA-validated test that provides consistent results to aid in the diagnoses of these serious cancers
  • Regulation Number: 21 CFR 864.7010
  • Regulatory Classification: Class II
  • Product Code: PWD


  • Study designed to demonstrate the test’s performance, n=279 samples at 4 independent clinical sites
  • Study compared the test’s results to alternative detection methods
  • Results of test aligned with the study site’s final diagnosis 93.4% of time
  • Correctly detected cancer presence 84.2% of time
  • Device:  Flow Cytometric Test System For Hematopoietic Neoplasms
  • Definition:  Reagents intended for in vitro diagnostic use as a panel for qualitative identification of cell populations by multiparameter immunophenotyping on a flow cytometer.These reagents are used as an aid in the differential diagnosis of hematologically abnormal patients having, or suspected of having the following hematopoietic neoplasms: chronic leukemia, acute leukemia, non-hodgkin’s lymphoma, myeloma, myelodysplastic syndrome (mds), and/or myeloproliferative neoplasms (mpn)


BioSphere Medical, S.A. (Merit Medical)

INDICATION FOR USE: embolization of arteriovenous malformations, hypervascular tumors, including symptomatic uterine fibroids, and prostatic arteries for symptomatic benign prostatic hyperplasia (BPH)


  • Regulation Number: 21 CFR 876.5550
  • Regulation Name: Prostatic artery embolization device
  • Regulatory Classification: Class II
  • Product Code: NOY

GENERIC DEVICE TYPE: Intravascular implant intended to occlude the prostatic arteries to prevent blood flow to the targeted area of the prostate, resulting in a reduction of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). This does not include cyanoacrylates and other embolic agents which act by in situ polymerization or precipitation, or embolization devices used in neurovascular applications


  • Adverse tissue reaction: Biocompatibility evaluation
  • Infection: Sterilization validation, Shelf-life validation, Non-clinical performance testing, Labeling
  • Non-target ischemia: Clinical data, Non-clinical performance testing, Labeling
  • Urinary retention: Labeling
  • Post-prostatic artery embolization syndrome (nausea, vomiting, regional pain, non-infectious fever, minor hematuria or hematochezia): Labeling


Image credits: Portola, Beckman Coulter, Merit

FDA News: Sickle Cell Research, Office of Orphan Products Development (OOPD), Biomarker Qualification Case Study, Generic Drug Access, Bodybuilding Products

FDA BRIEF: Week of June 19, 2017

group picture of ethnically diverse patients

Celebrate World Sickle Cell Day by Learning About Clinical Trials

Sickle Cell Disease is most common inherited blood disorder in US

  • Chronic condition with no cure
  • Can cause severe pain, organ damage, stroke
  • One way to help advance scientific discovery is through clinical trials

Learn more about clinical trials in videos

  • Brings awareness to importance of having diverse participants in clinical trials
  • Help ensure medical products are safe and effective for everyone


Office of Orphan Products Development (OOPD)

To promote the development of products for the treatment, diagnosis, and prevention of rare diseases and conditions

  • Drugs, Devices, Biologics, Medical Foods

Designation Programs

  • Orphan Drug Designation
  • Rare Pediatric Disease Designation
  • Humanitarian Use Device Designation

Grant Programs

  • Orphan Products Grants
  • Orphan Products Natural History Grants
  • Pediatric Device Consortia Grants

Medical Device Humanitarian Use Device (HUD) and Humanitarian Device Exemption (HDE) programs


FDA Case Study 1

Case Study for Biomarker Qualification Program

CDER Biomarker Qualification Program works with external stakeholders to develop biomarkers for drug development process

  • Fictional case studies part of an educational series on qualifying biomarkers
  • Intended to help patients, patient advocacy groups, health professionals, small businesses, and pharmaceutical and clinical innovators learn more
  • Provide “real-world” examples

Case Study on fictional biomarker of drug-induced kidney injury in rats

  • Understand role of biomarker qualification in drug development
  • Understand validation studies necessary to support qualification
  • Understand collaborative efforts in qualification for a specific context of use


Think it's easy becoming a generic drug in America? Think againFDA Working to Lift Barriers to Generic Drug Competition

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

FDA doesn’t have direct role in drug pricing – but taking steps to help address access

  • Expediting approval of lower-cost, generic medicines.
  • Facilitating increased competition for prescription drugs

Drug Competition Action Plan Federal Register

  • Understand ‘gaming’ of FDA’s rules to create obstacles to generic access
  • Blocking availability of branded products for comparative testing
  • Misusing REMS by having single shared program to delay generic entry

Policy and programmatic changes to address issues

  • Using FDA authorities more forcefully
  • Collaborate with sister agencies
  • Coordinate with Federal Trade Commission in identifying and publicizing anti-competitive practices
  • Simultaneously strike a careful balance between pharmaceutical innovation and access to lower cost generic products



FDA issues warning about body-building products labeled to contain steroid and steroid-like substances

Illegally marketed products labeled to contain steroid and steroid-like substances and promoted to increase muscle mass and strength

Illegally marketed as dietary supplements 

  • Unapproved drugs without FDA review of safety and effectiveness
  • Safety assessment based on more than seven years of adverse event reports
  • Risk of serious liver injury and other adverse health consequences including kidney injury, increased risk of heart attack and stroke, shrinkage of testes, male infertility





FDA BRIEF: Week of June 19, 2017

FDA approved

Image result for baxdela logo

BAXDELA (delafloxacin) Tablets and Injection 

Melinta Therapeutics

INDICATION: Treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following:

Gram-positive organisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillinsusceptible [MSSA] isolates), Staphylococcus haemolyticus, taphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis.

Gram-negative organisms: Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

ADDRESSING UNMET NEED: Antibacterial product treating serious or life-threatening infections


  • Qualified infectious disease product (QIDP)  under Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act
  • Fast Track Designation, Priority Review
  • Postmarketing Requirements: Surveillance for resistance, tissue distribution

MECHANISM OF ACTION: Fluoroquinolone class of antibacterial drugs,  antibacterial activity due to inhibition of both bacterial topoisomerase IV and DNA gyrase
(topoisomerase II) enzymes for DNA replication, transcription, repair, recombination.


  • 2 multicenter, multinational, double-blind, double-dummy, non-inferiority trials. (n=1510), adults with ABSSSI, BAXDELA vs. comparator (intravenous combination of vancomycin and aztreonam)
  • Objective Clinical Response: 20% or greater decrease in lesion size determined by digital planimetry of the leading edge of erythema 48 to 72 hr post initiation.
  • Investigator Assessment of response was made at Follow-up (Day 14 ± 1)
  • Positive Clinical Response and Investigator Assessments in both trials


  • Boxed Warning:  Increased risk of disabling and potentially irreversible serious adverse reactions that have occurred together including tendinitis and tendon rupture, peripheral neuropathy, and central nervous system effects.
  • Contraindication: Hyersensitivity to fluoroquinolones
  • Adverse reactions: Nausea, diarrhea, headache, transaminase elevations (an enzyme that is an indicator of liver injury) and vomiting


Image result for haegarda logo

HAEGARDA (C1 Esterase Inhibitor Subcutaneous [Human])

CSL Behring 

INDICATION:  Plasma-derived concentrate of C1 Esterase Inhibitor (Human) (C1-INH)  indicated for routine prophylaxis to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients.


  • HAE patients have absence or low levels of endogenous or functional C1-INH
  • HAEGARDA replaces missing or malfunctioning C1-INH protein
  • First C1-INH for subcutaneous  administration for rare genetic disease


  • Orphan Drug Designation

DESCRIPTION: Human plasma-derived, purified, pasteurized, lyophilized (freeze-dried) concentrate prepared from large pools of human plasma from U.S. donors.


  • A multicenter, randomized, double-blind, placebo-controlled, crossover study (n=90), 16-week treatment period, HAEGARDA (2 doses) vs placebo
  • Efficacy Endpoint: Time-normalized number of HAE attacks (the rate of attacks) relative to placebo
  • Significant decreases with both doses (p<0.001); median reduction 89%, 95%
  • Responders (95% CI) with a ≥50% reduction vs placebo was 83% (73%, 90%)
  • Significant decrease in time-normalized number of uses of rescue medication


  • Most common side effects: Injection site reactions, hypersensitivity reactions, nasopharyngitis and dizziness


RITUXAN HYCELA (rituximab and hyaluronidase human) injection


INDICATION: For the treatment of Follicular Lymphoma (FL),  diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL)

Indicated for the following previously approved indications for Rituxan:

  • Relapsed or refractory FL as a single agent
  • Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
  • Non-progressing (including stable disease), FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
  • Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
  • Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC).


  • Subcutaneous route of administration that shortens administration time to 5 to 7 minutes vs. several hours for intravenous infusion
  • Provides for flat dosing.



  • Rituximab is monoclonal antibody targeting CD20 antigen and mediates B-cell lysis
  • Hyaluronidase increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan


  • Based on Pharmacokinetic (PK) results
  • Non-inferior rituximab trough concentrations (Ctrough) levels for Rituxan Hycela 1,400 mg/23,400 Units compared to a intravenous rituximab 375 mg/m2
  • NBon-inferior rituximab Ctrough levels for Rituxan Hycela 1,600 mg/26,800 Units compared to intravenous rituximab 500 mg/m2
  • Comparable Overall Response, Progression Free Survival, Overall Survival Rates of Rituxan vs, Rituxan Hycela


  • Boxed Warning: Severe mucocutaneous reactions, Hep B Virus reactivation, progressive multifocal leukoencephalopathy
  • Most common adverse events: FL- infections, neutropenia, nausea, constipation, cough, and fatigue, DLBCL-infections, neutropenia, alopecia, nausea, and anemia, CLL- infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema


Image Credits: Melinta, CSL Behring, Genentech

FDA News: FDA Science, Digital Health Devices, Abuse-Deterrent Opioids, Creative FDA Regulation

FDA BRIEF: Week of June 12, 2017

2017 FDA Science Forum

FDA Science: Working at the Speed of Emerging Technologies

By: Luciana Borio, M.D.,  Acting Chief Scientist

Innovation is happening extraordinarily fast in biomedical sciences and at FDA

  • FDA’s 11,000 scientists play essential role in advancing biomedical innovations
  • Scientific research presented at Science Forum at FDA
  • Research concentrates on developing knowledge to ensure medical products are safe and effective

2017 Science Forum topics

  1. Identification and Evaluation of New Biomarkers
  2. FDA Response to Urgent Public Health Needs
  3. Microbiome and Human Health
  4. Advanced Manufacturing and 3D Printing
  5. Omics Technologies at FDA
  6. Patient and Consumer Engagement and Communication
  7. Computational Modeling and Simulation at FDA
  8. Current Progress in Nanotechnology Research at FDA

Mobile communications also included

  • Healthy Citizen @FDA to collaborate and communicate with citizens on public health outcomes


Everyone at FDA is committed to focusing on all aspects of the opioid epidemic

New policy steps

  • Steering committee formation to examine regulatory and policy action
  • Evaluate efforts to reduce number of new addiction cases

Abuse-deterrent opioid formulations and public health effect assessment

  • Formulations intended to deter abuse
  • However, effect in a real-world, meaningful decrease of opioid misuse/abuse unknown
  • Public meeting on opioid medications with abuse-deterrent properties to discuss impact of these products in the real world
  • Publicly available issues paper outlining existing regulatory and public health challenges


Sapien 3

By: Jeffrey Shuren, M.D., J.D., and Bram Zuckerman, M.D.

FDA was first to approve Sapien 3 valve interatin to treat high-risk patients with transcatheter valve replacement (TAVR)

  • For high-risk patients with worn out aortic or mitral bioprosthetic valves; Sapien 3 slips into these valves – “valve-in-valve” option
  • FDA Heart Valve Review Team streamlined FDA’s nonclinical testing expectations
  • More consistent, predictable, and transparent about clinical study expectations
  • Industry collaboration on creative clinical trial designs and use of other sources of clinical evidence

Use of real-world evidence for approval

  • Based on Transcatheter Valve Therapy (TVT) Registry, partnership of American College of Cardiology and Society of Thoracic Surgeons
  • Collection of clinical data on TAVR performance both on-label and off-label uses
  • 100,000 TAVR patients since 2011 first approval; >600 patients for off-label, valve-in-valve uses
  • Reliance on real-world evidence to evaluate the benefits and risks of off-label use

FDA working to broaden and improve the opportunities to leverage real-world evidence

  • Establishment of National Evaluation System for health Technology (NEST)
  • Integrate data from clinical registries, electronic health records, and medical billing claims


Image credits: FDA

FDA Approvals: SYMJEPI

FDA BRIEF: Week of June 12, 2017

FDA approved

SYMJEPI (epinephrine injection)

Adamis Pharmaceuticals Corporation


Emergency treatment of allergic reactions (Type I) including anaphylaxis  to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitoes), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis.

For immediate administration in patients who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions.

Anaphylactic reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema.

For immediate administration as emergency supportive therapy only and is not a
substitute for immediate medical care.

ADDRESSING UNMET NEED: New drug alternative to EpiPen


  • 505(b)(2) pathway
  • Postmarketing Commitment: Fault Tree Analysis and quantification to support device reliability specification

MECHANISM OF ACTION: Acts on both alpha and beta-adrenergic receptors

EFFICACY & SAFETY: Established based on initial approval in 1939


Image credit: Adamis

FDA Guidances: Drug Development Tools, Clinical Consultative Review, Certifications, Reusable Medical Devices, QT/QTc Prolongation

fda guidances

Updated Process for Qualification of Drug Development Tools (DDT) Under New FD&C Act Section 507

DDT Qualification to follow updated, multi-stage process under 21stCentury Cures Act 

  • 3 submission milestones: Letter of Intent (LOI), Qualification Plan (QP), Full Qualification Package (FQP)2
  • Transparency provisions and public posting of information by FDA
  • To transition from legacy qualification program process to new section 507 DDT Qualification Process


Good Review Practice: Clinical Consultative Review of Drugs Regulated with OND

Describes  clinical consultative review process in the CDER Office of New Drugs (OND)  for INDs, NDAs, BLAs, and supplemental NDAs and BLAs

  • To gather expertise of second review division because of familiarity with drug for other uses, expertise in another aspect of disease or organ system


Form FDA 3674 – Certifications To Accompany Drug, Biological Product, and Device Applications/Submissions

Form 3674: All Drug, Biologic, Device Submissions require certification that all applicable requirements have been met (implemented in 2007)

  • Form FDA 3674 can be obtained at LINK
  • Requires submitter to confirm compliance with all applicable requirements of Title VIII, including applicable implementing regulations, e.g., the requirement to register applicable clinical trials
  • Guidance to provide clarifications and additional details


Validated Instructions for Use and Validation Data Requirements for Resuable Medical Devices


List of reusable medical devices for which the FDA will require for premarket submissions:

  • validated instructions for use
  • validation data regarding cleaning, disinfection, and sterilization
  • in accordance with the requirements of 21st Century Cures Act
  • facilitates 510(k) reviews


E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs — Questions and Answers (R3)

ICH E14 guidance Clinical Evaluation of QT/QTc Interval Prolongation finalized in 2005

  • This guidance for clarifying key issues
  • Sex Differences, Incorporating New Technologies, Concentration-Response Relationships, Combination Products, Large Targeted Proteins and Monoclonal Antibodies, and Special Cases, Use of Concentration Response Modeling


  • Electrocardiograms Methodology
  • Gender
  • Positive Control
  • Study Design
  • Concentration Response Modeling
  • Special Cases
  • Electrocardiograms monitoring in late stage clinical trial



FDA Approvals, Classifications: SAPIEN 3, SENTINEL System, GLEOLAN, TRUVADA generic

Week of June 5, 2017

FDA approved

EXPANDED INDICATION FOR USE: Indicated for patients with symptomatic heart disease due to failure (stenosed, insufficient, or combined) of a surgical bioprosthetic aortic or mitral valve who are judged by a heart team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., predicted risk of surgical mortality ≥ 8% at 30 days, based on the STS risk score and other clinical co-morbidities unmeasured by the STS risk calculator).

 REG PATHWAY: PMA supplement

  • Priority Review status because device availability is in the best interest of patients
  • Device Generic Name: Aortic or mitral valve, prosthesis, percutaneously
  • Device Procode: NPT, NPU
  • Original PMA approved in 2015
  • Current supplement to expand to include patients with failed bioprosthetic heart valve in the aortic or mitral position


  • Analysis of real-world off-label use data captured in Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) Registry (n=314)
  • Valve Performance:  Clinically significant improvements;  mean aortic valve pressure gradient decreased from 39.3 ± 15.8 mmHg to 21.5 ± 11.3 mmHg at 30 d
  • NYHA: 85.4% of the patients had an improved NYHA class at the 30-day visi
  • Quality of Life (QoL) – KCCQ clinical summary score: Improved from 39.4 at baseline to 75.3 at 30 d


  • Did not include specific information
  • Patients/physicians likely to prefer due to less invasive approach (FDA belief)
  • High off-label use supports this belief


  • All-cause death: 4.5% and 6.8% at 30 days in aortic and mitral valve-in-valve patients, respectively
  • Aortic valve-in-valve patients: Stroke and reintervention – 1.0%, 0.3 %
  • Mitral valve-in-valve patients: Stroke, heart failure-related readmission – 0.7%,  0.8%, 0.4%



SENTINEL Cerebral Protection System

Claret Medical

INDICATION FOR USE:  For use as an embolic protection device to capture and remove thrombus/debris while performing transcatheter aortic valve replacement procedures. The diameters of the arteries at the site of filter placement should be between 9 – 15 mm for the brachiocephalic and 6.5 – 10 mm in the left common carotid.

REG PATHWAY: De Novo request

  • Regulation Number: 21 CFR 870.1251
  • Regulation Name: Temporary catheter for embolic protection during transcatheter  intracardiac procedures
  • Regulatory Classification: Class II
  • Product Code: PUM

GENERIC DEVICE TYPE:  Temporary catheter for embolic protection during transcatheter intracardiac procedures

  • Single use percutaneous catheter system that has (a) blood filter(s) at the distal end. This device is indicated for use while performing transcatheter intracardiac procedures. The device is used to filter blood in a manner that may prevent embolic material (thrombus/debris) from the transcatheter intracardiac procedure from  traveling towards the cerebral circulation.


  • Device failure leading to debris embolization and stroke or death: Non-clinical Performance Testing, Animal Testing, Clinical Performance Testing
  • Impeded or disrupted blood flow leading to peripheral ischemia: Non-clinical Performance Testing, Animal Testing, Clinical Performance Testing, Labeling
  • Device incompatibility with transcatheter intracardiac procedure device leading to prolonged treatment time or device failure: Non-clinical Performance Testing, Animal Testing, Clinical Performance Testing, Labeling
  • Adverse tissue reaction:  Biocompatibility Evaluation
  • Vascular Injury due to device delivery, deployment, placement, or retrieval:  Non-clinical Performance Testing, Animal Testing, Clinical Performance Testing, Labeling



GLEOLAN (aminolevulinic acid hydrochloride, ALA HCl)

NX Development Corp.

INDICATION:  In patients with glioma [suspected World Health Organization (WHO) Grades III or IV on preoperative imaging] as an adjunct for the visualization of malignant tissue during surgery


  • Orphan designation, Priority Review

MECHANISM OF ACTION:  ALA occurs endogenously as a metabolite; accumulation of ALA metabolite PpIX in tumor cells. Gleolan used with an operating microscope adapted with a blue emitting light source allows tumor tissue to be visualized as red fluorescence. Tissue lacking sufficient PpIX concentrations appears blue


  • 3 clinical studies (n=527), patients with preoperative MRI compatible with high-grade glioma (WHO Grade III or IV) undergoing surgical resection
  • Presence of fluorescence (positive/negative) was compared to tumor status (true/false) using histopathology as reference standard
  • High predictive value for visualization of malignant tissue


  • Phototoxic reactions, hypersensitivity reactions, and interpretation errors (false negatives and false positives)
  • Increase in extent of resection might increase risk of serious neurologic deficits
  • Adverse reactions: Pyrexia, hypotension, nausea, and vomiting


Image result for truvada logoTRUVADA (Emtricitabine and tenofovir disoproxil fumarate) generic

Teva Pharmaceuticals

INDICATION: For the treatment of HIV-1, in combination with other antiretroviral agents, and for pre-exposure prophylaxis (PrEP) in combination with safer sex practices to prevent sexually-acquired HIV infection in adults at high risk

REG PATHWAY: ANDA, Therapeutic Equivalence Code- AB

SAFETY: Diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash



Image credits: FDA, Claret Medical, NX Corp, Gilead

FDA News: UDI for Class I Devices, HUD IRB Policy, Opana ER Removal, Dermal Fillers Information, Outsmart Poison Ivy

FDA BRIEF: Week of June 5, 2017

UDI Compliance Dates for Class I and Unclassified Devices

Unique Device Identification (UDI) system established in 2013  to adequately identify devices though distribution and use

Extending  compliance dates for lower-risk medical devices

  • For class I and unclassified devices
  • Not applicable to class I/unclassified implantable, life-supporting or life-sustaining devices – should already be compliant
  • Guidance to provide enforcement discretion policy for labeling, data submission, standard date formatting, and direct mark requirements


Humanitarian Use Devices; 21st Century Cures Act; Technical Amendment

The 21st Century Cures Act removed local Institutional Review Board (IRB) review

  • Rely on a central IRB
  • Investigational Device Exemption (IDE) studies
  • Humanitarian Device Exemption (HDE) devices
  • Same measures and policies to protect patients who are involved in clinical research or are treated with Human Device Exemption (HDE) for HUD


Wrinkle Filler

Dermal fillers are FDA approved medical device implants

  • to create smoother and/or fuller facial appearance including nasolabial folds, cheeks and lips
  • increasing volume of back of hand

NOT approved for breast, buttock augmentation, increase fullness of the feet, implant into bone, tendon, ligament, or muscle

Risks and Serious Adverse Events reported with use

Information for Healthcare Providers and Patients

Approved Dermal Fillers


Endo Pharmaceuticals

FDA Requests Removal of Opana ER for Abuse-Related Risks

FDA requested Endo Pharmaceuticals removal of reformulated injectable Opana ER

  • concern that benefits may no longer outweigh its risks
  • public health consequences of abuse.
  • first time to remove marketed opioid pain medication from sale

FDA decision based on

  • review of all available postmarketing data
  • significant shift in route of abuse (nasal to injection) after product reformulation
  • injection abuse associated with serious HIV and hepatitis outbreaks, cases of  serious blood disorder (thrombotic microangiopathy)
  • March 2017 FDA advisory committee voted that benefits no longer outweigh risks

FDA will continue to examine risk-benefit profile of all approved opioid analgesic products in response to public health crisis



Outsmarting Poison Ivy and Other Poisonous Plants






FDA Approvals: ZYKADIA Supplemental Indication, STRATTERA first time generics

Week of May 29, 2017

FDA approved

Brand logo alt

ZYKADIA (ceritinib)


SUPPLEMENTAL INDICATION:  treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.


  • Original  accelerated approval (2014) for patients with ALK-positive metastatic NSCLC whose disease has progressed or who are intolerant to crizotinib


  • Open-label, randomized, active-controlled, multicenter study, LK-positive NSCLC patients with no prior systemic therapy (n=376),   ZYKADIA vs chemotherapy plus maintenance chemotherapy
  • Major efficacy outcome: Progression-free survival (PFS) determined by blinded independent review committee (BIRC) according to RECIST v1.1
  • Additional efficacy outcomes: Overall survival (OS), overall response rate (ORR),  duration of response (DOR) determined by BIRC, overall intracranial response rate (OIRR), duration of intracranial response (DOIR), and patient reported outcomes (PRO)
  • PFS: 16.6 mo. vs. 8.1 mo., p-value <0.0001
  • Confirmed ORR: 73% vs. 27%, Median DOR: 23.9 mo. vs. 11.1 mo., OSS: immature
  • Overall OIRR: 57% vs,  22%, DOIR: 16.6 mo. vs. not estimable
  • PRO Exploratory analyses: Delay in time to development/worsening of

    shortness of breath with ZYKADIA


  • Most common adverse reactions: Diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, and cough
  • Serious adverse reactions in 38%, discontinuation occurred in 12%, dose interruption due to adverse reactions 77%, dose reductions in 66%.


First Time Generic

First generic versions of STRATTERA (atomoxetine) 

Apotex Inc., Teva Pharmaceuticals, Aurobindo Pharma,  Glenmark Pharmaceuticals


INDICATON: Treat attention-deficit/hyperactivity disorder (ADHD) in pediatric and adult patients



  • Most common side effects ( children and adolescents,): Upset stomach, decreased appetite, nausea or vomiting, dizziness, tiredness, and mood swings
  • Most common side effects (adults): Constipation, dry mouth, nausea, decreased appetite, dizziness, sexual side effects, and problems passing urine.
  • Boxed Warning : Increased risk of suicidal ideation


Image credits: Novartis, FDA

FDA News: Commissioner Remarks, Supply Chain Security Toolkit, Measuring Cancer Patient Benefit, Fighting Misleading Ads

FDA BRIEF: Week of May 29, 2017

Image result for fda science forum

FDA Commissioner Remarks to the 2017 FDA Science Forum

FDA’s work environment encourages creativity, efficiency, and superior science

  • Address challenges  in promoting and protecting the public health
  • Ability to use tools of science to meet public health challenges

Volume and complexity of regulated products increasing

  • More novel drugs and medical devices
  • New technologies such as gene therapy, gene editing, regenerative medicine

Broader societal challenges

  • Addiction to opioids and the abuse of opioid drugs, tobacco products
  • Address health care costs without sacrificing medical innovation

Science at FDA

  • CDRH developing novel methods to create models of virtual patient outcomes
  • Massive longitudinal study on Population Assessment of Tobacco and Health
  • Progress in nanotechnology, 3D printing, computational modeling and simulation
  • GenomeTrakr network
  • Human organ systems in miniature, micro-engineered chips to evaluate toxicity


drug supply chain

FDA Leads Effort to Create a Supply Chain Security Toolkit for Medical Products

Medical Product Security Toolkit covers entire supply chain and lifecycle- from raw materials to use by patients

  • Developed in collaboration with Asia Pacific Economic Cooperation (APEC)
  • Processes, procedures, and tools to enhance quality and supply chain security
  • Help support global sourcing and manufacturing of medical products

Addresses areas of vulnerability in the medical product supply chain

  • Prevent, detect substandard/falsified medical products prior to reaching consumer
  • Respond to incidents
  • Tools and training for 10 categories covering supply chain


Rick Pazdur

In cancer treatment, there’s more than one way to measure patient benefit

By: Richard Pazdur, M.D., Director, Oncology Center of Excellence

Randomized controlled study demonstrating improvement in overall survival (OS) is gold standard for new cancer therapies 

Not viable for:

  • Slow growing tumors
  • Targeting specific mutations
  • Comparison with standard therapy with modest benefit (loss of equipoise)

Alternative endpoints:

  • Progression-free survival (PFS)
  • Overall response rate (ORR)
  • Supported by patient and advisory committee feedback
  • Several approvals – renal cell carcinoma, Merkel cell carcinoma, medullary thyroid cancer, gastrointestinal stromal tumor, metastatic basal cell carcinoma, pancreatic neuroendocrine tumor, multiple myeloma, chronic myelogenous leukemia, chronic lymphocytic leukemia, certain types of lung cancer

Approval based on meaningful difference for patients and their loved ones:

  • Incorporate patient’s experience and quality of life in benefit-risk assessments
  • Evaluate post-approval real-world use; inform labeling


#IAmHHS: Fighting Misleading Prescription Drug Ad Claims

  • Develop policies for advertising and promotion of prescription drugs
  • Truthful and not misleading
  • Ensure pharmaceutical industry understand the rules of the road


Image credits: FDA



FDA News: Forceful steps for Opioid Crisis, Cybersecurity Workshop

FDA BRIEF: Week of May 22, 2017


FDA Commissioner Asks Staff for ‘More Forceful Steps’ to Stem the Opioid Crisis

By: Scott Gottlieb, M.D., Commissioner. @SGottliebFDA

Dr. Scott Gottlieb

Highest initial priority is reduce epidemic of opioid addiction; Establishing Opioid Steering Committee

  • Explore and develop additional FDA tools to answer following questions
  • ? Mandatory education for health care professionals: appropriate prescribing recommendations, identify abuse risk, treat addicted patients
  • ? Additional risk management to tailor prescription of opioid doses
  • ? Proper policy framework  for risk of abuse and misuse


Public Workshop – Cybersecurity of Medical Devices: A Regulatory Science Gap Analysis

Hosted by FDA, National Science Foundation (NSF) and Department of Homeland Security, Science and Technology (DHS, S&T)


  • Examine opportunities for FDA engagement with new and ongoing research
  • Catalyze collaboration among stakeholders to identify regulatory science challenges
  • Discuss innovative strategies to address those challenges
  • Encourage proactive development of analytical tools, processes, and best practices





FDA Supplemental Approvals: ACTEMRA, KEYTRUDA

FDA BRIEF: Week of May  22, 2017

FDA approved

ACTEMRA (tocilizumab) injection


SUPPLEMENTAL INDICATION:  Treatment of giant cell arteritis (GCA) in adult patients


  • Giant cell arteritis is a form of vasculitis causing inflammation of blood vessels
  • Standard treatment involves high doses of corticosteroids tapered over time
  • First FDA approved therapy specific to vasculitis


  • Breakthrough Therapy, Priority Review
  • Subcutaneous Actemra previously approved for treatment of moderate to severely active rheumatoid arthritis
  • Intravenous Actemra previously approved for treatment of moderate to severely active rheumatoid arthritis, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis


  • Single, randomized, double-blind, multicenter study, n=251 patients with active GCA, 2 SC doses of ACTEMRA vs. 2 different placebo control groups (pre-specified prednisone-taper regimen), 2-week blinded period, followed by a 104-week open-label extension
  • Primary efficacy endpoint: Proportion of patients achieving sustained remission from Week 12 through Week 52; defined as absence of GCA symptoms, normalization of inflammatory laboratory tests, tapering prednisone use
  • Sustained remission: 56.0% and 3.1% s. 14.0% and 17.6%


  • Generally consistent with known safety profile
  • Boxed Warning: Serious infections.


KEYTRUDA (pembrolizumab) injection


SUPPLEMENTAL INDICATION:  Treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

  • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
  • colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan


  • MSI-H and dMMR tumors contain abnormalities that affect proper DNA repair
  • Tumors with these biomarkers commonly found in colorectal, endometrial, gastrointestinal cancers, cancers in breast, prostate, bladder, thyroid gland etc
  • First FDA approval based on common biomarker rather than the location in the body where the tumor originated


  • Previous approvals: Metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, urothelial carcinoma
  • Accelerated approval:  Based on tumor response rate and durability of response. Continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials


  • 5 uncontrolled, open-label, multi-cohort, multi-center, single-arm trials; patients with MSI-H or dMMR solid tumors 2 doses of KEYTRUDA, 15 cancer types, n=149, 24 months
  • Major efficacy outcome measures: Objective Response Rate (ORR) assessed by blinded independent central radiologists’ (BICR), RECIST 1.1, Duration of Response (DOR)
  • Complete or Partial Response: 39.6%,  DOR of 6 mo. for 78% responders


  • Common side effects: Fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation and nausea
  • Serious conditions: Immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis


Image credits: FDA, Genentech, Merck


FDA Supplemental Indication Approvals: KALYDECO, KEYTRUDA

FDA News: Week of May 15, 2017

FDA approved

KALYDECO (ivacaftor) tablets, oral granules

Vertex Pharmaceuticals

SUPPLEMENTAL INDICATION: Treatment of cystic fibrosis (CF) in patients age 2 years and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.


  • CF affects cells that produce mucus, sweat and digestive juices; rare disease that affects about 30,000 people in US
  • Expanded indication triples the number of rare gene mutations that the drug can now treat
  • Many rare mutations have small patient populations precluding clinical trials
  • Alternative approach, based on precision medicine, to identify certain gene mutations that are likely to respond to Kalydeco


  • Approval based, in part, on the results of laboratory testing, used in conjunction with evidence from earlier human clinical trials
  • Pathway for adding additional rare mutations of the disease based on laboratory data
  • Serves as an example of how successful patient-focused drug development can provide greater understanding about disease
  • Cystic Fibrosis Foundation maintains 28,000-patient registry, including genetic data, for research


  • Evidence from laboratory-based in vitro assay data
  • Previous approval covered 10 different mutations; efficacy against 23 additional mutations based on stringent criteria
  • Good understanding of the disease, thorough knowledge of clinical aspects of disease, data on thousands of CF patients and their mutations
  • Existing large efficacy and safety database, well-established risk/benefit profile
  • Solid understanding of the drug’s mechanism of action
  • In vitro data also able to identify types of CFTR mutations  NOT responsive to drug


  • Common side effects: Headache; upper respiratory tract infection,  abdominal pain; diarrhea; rash; nausea; and dizziness.
  • Risks: Elevated transaminases, pediatric cataracts


Image result for keytruda IMAGE

KEYTRUDA (pembrolizumab) injection



  • Treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy
  • Treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

REG PATHWAY: sNDA, Priority Review, Breakthrough Designation

  • Regular approval for locally advanced or metastatic urothelial carcinoma with progression during or following platinum-containing chemotherapy
  • Accelerated approval for locally advanced or metastatic urothelial carcinoma not eligible for cisplatin-containing chemotherapy
  • Accelerated approval based on tumor response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials


Previously Treated Urothelial Carcinoma: Multicenter, randomized, active-controlled trial, n=270, patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy; KEYTRUDA vs. investigator’s chemotherapy choice

  • Major efficacy outcomes: Overall survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR) assessed by BICR per RECIST 1.1
  • Median OS: 10.3 vs. 7.4 months (p=0.004)
  •  ORR:  21% vs. 11%, (p=0.002)
  • No statistically significant difference in PFF

Cisplatin Ineligible Patients with Urothelial Carcinoma: Multicenter, open-label, single-arm trial, n=370, patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy

  • Major efficacy outcome measures: ORR according to RECIST 1.1, Duration of Response (DOR)
  • ORR: 28.6% (95% CI 24, 34), median DOR not reached (range 1.4+, 17.8+ months)


  • Most common adverse reactions: Fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash
  • Serious adverse reactions: Immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, and endocrinopathies


Image credits: Vertex, Google

FDA News: New Commissioner’s Remarks, Reducing Preventable Medication Harm, Conformity Assessment Accreditation, Sunscreens

FDA BRIEF: Week of May 15, 2017


Dr. Gottlieb’s First Remarks to FDA Staff

Remarks by Commissioner Scott Gottlieb, M.D. at FDA All Hands Meeting

  • People’s lives depend on what FDA does
  • Great promise with scientific advances to make regulatory process more modern and efficient
  • Immediate challenge – opioid abuse and FDA’s role in minimizing use
  • Also help address challenge of prohibitive drug pricing – even though FDA does not have a direct role
  • Overall, need for risk-based, patient-centric, science-based approach and maintaining  gold standard for regulatory science and independent, science-led decision-making


Safe Use blog image

Reducing Preventable Harm from Medications: Too Big for FDA to Do Alone

By: John J. Whyte, M.D., M.P.H. , Director of Professional Affairs and Stakeholder Engagement, CDER 

Harm from medications also may come from known risks that could have been prevented

  • 1.5 million preventable adverse drug events occur each year
  • Prescribers and other providers struggle with intricacies of health care system
  • Patients have difficulty following detailed directions
  • Manufacturers need careful packaging and labeling to avoid confusion

Reducing preventable harm from medications is a big part of FDA’s mission

  • Hosting a one-day public meeting  “Safe Use Symposium: A Focus on Reducing Preventable Harm From Drugs in the Outpatient Setting.”
  • Meeting with all stakeholders to discuss sources of preventable harm from drugs in outpatient setting


Accreditation Scheme for Conformity Assessment Pilot Program

Voluntary consensus standards establish safety & performance criteria for medical device design and manufacturing

  • Support claims of safety and quality in FDA premarket review
  • Sponsors include a `Declaration of Conformity” to attest to standards


  • Appropriate use of FDA recognized consensus standards not consistently applied
  • Require substantial specialized knowledge to interpret and apply correctly

Addressing Challenge

  • FDA and Industry to establish an FDA Accreditation Scheme for Conformity
    Assessment (ASCA) Program
  • Recognize accredited testing laboratories that evaluate medical devices according to FDA standards
  • Ease industry regulatory burden by allowing them to use recognized accredited test laboratories to ensure accurate conformance with the consensus standard
  • FDA requesting comments on proposal by June 30


Family walking on the beach. Mom says: Boys! You have sunscreen on now, but don't forget you need to reapply every 2 hours while we're at the beach. If you're in and out of the water, we'll need to reapply more often.  Boys say: Ok mom!

Sunscreen: FDA Regulated Product

Sunscreen is an FDA-regulated product, for protection from sunburn, skin cancer, early skin aging and other risks of sun overexposure 

Sun protection factor (SPF) in Label

  • Indicates level of sunburn protection: Amount on UVB and UVA radiation to cause sunburn with sunscreen vs without
  • Higher SPF values (up to 50) provide greater sunburn protection
  • “Broad Spectrum SPF [value]” in label indicate protection from both

Other Label Information  

  • List of acceptable active/inactive ingredients
  • Expiration dates based on stability testing
  • Ex-US products may not have same label standards as FDA


Image credits: FDA


FDA BRIEF: Week of May 8, 2017

FDA approved

Image result for radicava image

RADICAVA (edaravone) intrvenous infusion

Mitsubishi Tanabe Pharma America

INDICATION:  Treatment of amyotrophic lateral sclerosis (ALS)


  •  ALS is rare disease; attacks and kills nerve cells controlling voluntary muscles leading to paralysis
  • 12,000-15,000 Americans have ALS; most  die from respiratory failure within 3-5 years


  • Leveraged data from Japanese trials
  • Orphan drug designation



  • 6-month, randomized, double-blind study, n =137 Japanese patients with ALS, RADICAVA vs. placebo
  • Primary efficacy endpoint: Change in the ALS Functional Rating Scale – Revised (ALSFRS-R) total scores from baseline at week 24
  • Decline in ALSFRS-R scores from baseline significantly less in the RADICAVA-treated patients (p=0.0013)


  • Most common adverse reactions: Bruising (contusion), gait disturbance
  • Serious risk: Hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug


Image result for BAVENCIO IMAGE

BAVENCIO (avelumab)

EMD Serono

SUPPLEMENTAL INDICATION: Treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:

  • Have disease progression during or following platinum-containing chemotherapy
  • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy


  • Accelerated approval, Priority review
  • Approved based on tumor response and duration of response
  • Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials


  • Open-label, single-arm, multi-center study, n=242 patients with locally advanced or metastatic UC with disease progression
  • Efficacy outcome measure: Confirmed overall response rate (ORR) using RECIST criteria, duration of response (DOR); followed for minimum of both 13 weeks and 6 months
  • ORR: For at least 13 weeks : 13.3% (n=30), 6 weeks 16.1% (n=26)
  • Median time to response: 2.0 months


  • Most frequent serious adverse reactions: Urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestinal obstruction, and pyrexia
  • Most common adverse reactions: fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection


Image result for keytruda IMAGE

KEYTRUDA (pembrolizumab) injection



  • Most common AEs : Fatigue, nausea, constipation
  • Most common grade 3-4 adverse reactions: Fatigue, dyspnea, nausea, vomiting, diarrhea, and rash
  • Most common adverse reaction: Acute kidney injury
  • Immune-mediated adverse reactions: Pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis


Picture of the device, highlighting upper esophageal pouch, oral catheter, magnet, stomach, gastric catheter, and gastronomy site.

FLOURISH Pediatric Esophageal Atresia Device

Wilson-Cook Medical 

INDICATION FOR USE:  For use in pediatric patients, up to one year of age, with esophageal atresia without a tracheoesophageal fistula (TEF) or for whom a TEF has been closed as a result of a prior procedure. This device should be used only when the gap between the upper and lower portions of the esophagus is less than 4 centimeters apart.


  • 1 in every 2,500 babies born with esophageal atresia; birth defect causing gap in esophagus
  • Condition cannot feed normally, also have a tracheoesophageal fistula, breathing inteference
  • First non-surgical option to treat this birth defect

REG PATHWAY: Humanitarian Device Exemption


  • 2 catheters  with a magnet at its tip
  • One inserted through mouth and other through stomach
  • Magnetic ends attract one another and pull ends of esophagus together; surrounding tissue grows together


  • Implanted in 16 patients
  • All had successful joining of esophagus within 3-10
  • However, 13 of 16 patients developed anastomotic stricture requiring balloon dilation procedure, a stent or both to repair


  • Contraindicated in infants with existing tracheoesophageal fistula or who have esophageal segments that are more than 4 centimeters apart
  • Potential complications: Ulceration, tissue irritation, gum irritation
  • Potential long-term complication: Gastroesophageal reflux


Image credits: FDA, Google

FDA News: 23rd Commissioner, Clinical Trial Protocol Template, Depression Treatments, Continuous Manufacturing

FDA BRIEF: Week of May 8, 2017

Image result for scott gottlieb fda images

Meet Scott Gottlieb, M.D., Commissioner of Food and Drugs

Dr. Scott Gottlieb was sworn in as the 23rd FDA Commissioner on May 11

  • Physician, medical policy expert, public health advocate
  • Previously served at FDA and CMS
  • Senate appointment to serve on Federal Health Information Technology Policy Committee


FDA and NIH Release Final Template for Clinical Trial Protocols

NIH-FDA Joint Leadership Council issued protocol template for drugs and medical devices:
  • Describing trial objectives, trial design, methodology, statistical considerations, and trial organization
  • Standard protocol format to facilitate review by regulators and others (e.g., institutional review boards)
  • Following ICH E6 Good Clinical Practice guidelines
  • Contributing to important time and money-saving efficiencies


FDA Device Approvals, Classifications: POWERLOOK Software, ASTRON Pulsar Stent, OCULEVE Tear Stimulator

FDA BRIEF: Week of May 8, 2017

FDA approved

Image result for iCAD PowerLook® Tomo Detection Software

PowerLook® Tomo Detection Software

iCAD Inc. Nashua, NH, USA

INDICATION FOR USE: Software device intended to be used concurrently by radiologists while reading GE Senoclaire breast tomosynthesis exams. The system detects up to five soft tissue densities (masses, architectural distortions and asymmetries) in the 3D tomosynthesis images. The detections are blended with the standard 2D synthetic image and the computer assisted detection (CAD)-enhanced 2D synthetic image is viewed on a mammography review workstation.

The CAD-enhanced 2D synthetic image assists radiologists in identifying densities (masses, architectural distortions and asymmetries) that may be confirmed or dismissed by the radiologist in the digital breast tomosynthesis (DBT) images.


  • Class III, Product Code: MYN


  • Software in conjunction with the GE Senoclaire and mammography review workstation create a CAD-enhanced 2D synthetic image
  • Allow radiologists to review tomosynthesis images more quickly without a statistically significant decrease in performance
  • Detects soft tissue densities (masses, architectural distortions and asymmetries)
  • Blending algorithm processes CAD detections from  3D planes and merges into GE’s existing 2D volume preview
  • Software uses pattern recognition technology to identify potential regions of interest
  • Enhancement step to project 3D structure onto the V-Preview image


  • Pivotal Reader Study was a retrospective, multi-reader, multi-case study
  • Average radiologist performance with CAD noninferior to performance using GE DBT images without CAD enhanced 2D V-Preview images
  • Average AUC increased by 0.009 (95% CI: -0.012, 0.030; non-inferiority p < 0.01), from 0.841 without CAD to 0.850 with CAD
  •  Average radiologist reading time was improved with CAD


  • Aid in the interpretation of existing DBT images
  • Does not modify the existing DBT image acquisition process nor alter native DBT images
  • Use of the software does not directly involve the patient
  • Risk is increased false positives or false negatives


Pulsar-18 Image

ASTRON Pulsar Stent System

Biotronik, Inc, Oswego, OR, USA

INDICATION FOR USE: The Astron Pulsar and Pulsar-18 stent systems are indicated for use to improve luminal diameter in patients with symptomatic de novo, restenotic or occlusive lesions located in the superficial femoral or proximal popliteal arteries, with reference vessel diameters from 3.0 to 6.0 mm and total lesion lengths up to 190 mm.


  • Class III, Product Code : NIP


  • Self-expanding stent loaded on an over-the-wire (OTW) delivery system
  • Delivery system consists of inner shaft and outer shaft
  • Safety tab prevents accidental stent release
  • Black release marker that indicates completion of stent deployment, ends with a Luer port
  • Stent mounted between inner shaft and outer shaft between two radiopaque markers to facilitate fluoroscopic visualization and positioning across lesion
  • Guide wire to facilitate advancement of the delivery system toward and through lesion


  • Prospective, non-randomized, multi-center study with two treatment cohorts, iliac lesion treatment and superficial femoral artery (SFA) or proximal popliteal artery (PPA) lesion treatment
  • Primary effectiveness endpoint: Stent patency at 12 months as evidenced by peak systolic velocity ratio (PSVR)<2.4 from duplex ultrasound (DUS)
  •  Pre-specified endpoint not met : Primary patency rate numerically above performance goal; however the 95% lower confidence bound not met
  • Kaplan Meier analysis and imputed analysis for missing data supported primary patency rates similar to the observed rate; secondary endpoints met


  • Primary safety endpoint: Freedom from composite rate of procedure- or stent-related Major Adverse Events at 30 days post-index procedure : 99.7%, 95%
  • Higher than performance goal of 88% (p<0.001)




Image result for Oculeve Intranasal Tear Neurostimulator

OCULEVE Intranasal Tear Stimulator 

Oculeve Inc (Allergan), Dublin, IRELAND

INDICATION FOR USE: Provides temporary increase in tear production during neurostimulation in adult patients.

REG PATHWAY: De Novo request

  • Regulation Number: 21 CFR 886.5300
  • Regulation Name: Tear Electrostimulation Device
  • Regulatory Classification: Class II
  • Product Code: PQJ

GENERIC DEVICE TYPE: Tear electrostimulation device is a non-implantable, electrostimulation device intended to increase tear production


  • Tissue damage due to over-stimulation/understimulation or mechanical injury, device breakage:  Non-clinical performance testing, Software verification, validation and hazard analysis, Electrical, thermal, and mechanical safety testing, Labeling
  • Pain, headache, or discomfort: Non-clinical performance testing, Electrical, thermal, and mechanical safety testing, Labeling
  • Adverse tissue reaction: Biocompatibility, Labeling
  • Infection : Labeling
  • Electrical shock or burn: Electrical, thermal, and mechanical safety testing, Software verification, validation and hazard analysis, Labeling
  • Interference with other devices: Electromagnetic compatibility testing, Software verification, validation and hazard analysis, Labeling

Classification Order

Image sources: iCAD, Biotronik, Google



FDA BRIEF: Week of May 8, 2017

FDA approved

Image result for Device imfinzi

IMFINZI (durvalumab) injection

AstraZeneca. Wilmington, DE, USA

VENTANA PD-L1 (SP263) Assay

Ventana Medical Systems, Inc., Tucson, AZ, USA

INDICATION: Treatment of patients with locally advanced or metastatic urothelial carcinoma who:

  • have disease progression during or following platinum-containing chemotherapy
  • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum containing chemotherapy.

REG PATHWAY: Accelerated Approval

  • Based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials
  • Also approval for complementary diagnostic for the assessment of the PD-L1 protein in formalin-fixed, paraffin-embedded urothelial carcinoma tissue

MECHANISM OF ACTION:  Human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of PD-L1 with PD-1 and CD80;  releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity


  • Multicenter, multicohort, open-label clinical trial, n=182 patients with locally advanced or metastatic urothelial carcinoma; had progressed while on or after a platinum-based therapy
  • Major efficacy outcome measures: Confirmed Objective Response Rate (ORR) according to RECIST v1.1 by Blinded Independent Central Review (BICR), and duration of response (DoR)
  • Responding patients: 31; 45% had ongoing responses of 6 months or longer, 16% had ongoing responses of 12 months or longer
  • Confirmed ORR: 26.3%  in 95 patients with a high PD-L1 score, 4.1% in 73 patients with a low or negative PD-L1 score


  • Most common adverse reactions: Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection
  • Infection and immune-related adverse events: Pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, diabetes



Image result for alunbrig

ALUNBRIG (brigatinib) tablets

Ariad Pharmaceuticals, Inc. (Takeda), Cambridge, MA, USA

INDICATION:  Treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib

REG PATHWAY: BLA. Accelerated Approval, Breakthrough Therapy Designation, Orphan Drug Designation, Priority Review

  • Accelerated approval based on tumor response rate and duration of response
  • Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial

MECHANISM OF ACTION:  Tyrosine kinase inhibitor with in vitro activity against multiple kinases,  inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins, dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice


  • Two-arm, open-label, multicenter trial, n=222, patients with locally advanced or metastatic ALK-positive NSCLC who had progressed on crizotinib, had documented ALK rearrangement based on an FDA-approved test  or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis® ALK Break-Apart fluorescence in situ hybridization Probe Kit test. BRIGATINIB 90 mg or 180 mg
  • Major efficacy outcome measure: Confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) evaluated by an Independent Review Committee (IRC); Additional measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR
  • ORR: 48% (90 mg), 53% (180 mg) with DOR of 13.8 months in both arms
  •  Intracranial ORR: 42% (90 mg), 67% (180 mg), DOR of at least 4 mo.


  • Most common adverse reactions: Nausea, diarrhea, fatigue, cough, headache
  • Most common serious adverse reactions: Pneumonia and ILD/pneumonitis
  • Fatal adverse reactions: Pneumonia, sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis, urosepsis


Image Source: Google

FDA News: AAMI Technical Information Report, Fraudulent Cancer Products

FDA BRIEF: Week of April 24, 2017

Logo of AAMI: Advancing Safety in Healthcare Technology

AAMI Technical Information Report on “Risk Management of Radio-frequency Wireless Coexistence for Medical Devices and Systems.”

FDA + Association for the Advancement of Medical Instrumentation (AAMI) report

  • Applies to medical devices and medical electrical equipmen) that incorporate Radio Frequency (RF) wireless technology
  • Used to perform or control a medical function or to communicate medical data
  • Directly support the medical device’s intended use
  • In alignment with FDA Guidance on RF wireless technology

Provides consensus process for risk management of coexistence of wireless medical devices and systems with other wireless products

  • Includes implanted cardiac pacemakers and cardioverter defibrillators, numerous physiological monitoring devices, implantable neurostimulators, drug and insulin infusion devices, diagnostic imaging systems, and a wide range of other medical devices


image of fake cancer cures

FDA Takes Action Against Fraudulent Cancer Products

14 companies peddling bogus cancer cures have received warning letters from FDA

  • Untested and potentially dangerous products,  selling on the internet
  • Fraudulent products attempt to subvert compliance and enforcement efforts by changing the names of their products, their companies, and/or their websites

Fraudulent claims, Red Flags

  • Treats all forms of cancer
  • Miraculously kills cancer cells and tumors
  • Shrinks malignant tumors
  • Selectively kills cancer cells
  • More effective than chemotherapy
  • Attacks cancer cells, leaving healthy cells intact
  • Cures cancer

FDA response

  • Compliance and enforcement actions against unscrupulous companies
  • Consumer education to decrease demand



FDA BRIEF: week of April 24, 2017

FDA approved

Image result for Brineura use

BRINEURA (cerliponase alfa) injection, for intraventricular use

BioMarin Pharmaceutical Inc., Novato, CA

INDICATION:  To slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency


  • CLN2 disease is rare (2-4/100,000 live births) inherited disorder primarily affecting nervous system affecting essential motor skills
  • Individuals require wheelchair use by late childhood and typically do not survive past teenage
  • First drug for the treatment of this form of Batten disease


  • Priority Review, Breakthrough Therapy designation, Orphan Drug Designation,Rare Pediatric Disease Priority Review Voucher
  • Post-marketing Requirements: Observational post approval safety study to evaluate the long-term safety,  sensitive cellular uptake assay  to evaluate neutralizing capacity of anti-drug antibodies,  immunogenicity study

MECHANISM OF ACTION:  Enzyme replacement therapy. Active ingredient, cerliponase alfa, is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease.


  • Non-randomized single-arm dose escalation clinical study with extension in symptomatic pediatric patients with CLN2 disease, confirmed by TPP1 deficiency, 96 weeks, n=24, BRINEURA vs. natural history cohort
  • Primary endpoint: Motor domain of a CLN2 Clinical Rating Scale to assess disease progression; Scores from 3 (grossly normal) to 0 (profoundly impaired)
  • Descriptive Comparison: 21 (95%) did not decline vs 42 (50%) in natural history cohort
  • Cox Proportional Hazards Model adjusted for age, initial motor score, and genotype:  Lesser decrease in motor function in treated patients


  • Most common adverse reactions: Fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure
  • Not to be administered if signs of acute intraventricular access device-related complications
  • Routinely test patient CSF samples to detect device infections


sidebar imageROXYBOND (oxycodone hydrochloride) tablets

Inspirion Delivery Sciences, KS, USA

INDICATION: For the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate

  • Limitations of Use:  Because of the risks of addiction, abuse, and misuse with opioids, reserve for use in patients for whom alternative treatment options have not been tolerated, have not provided adequate analgesia


  • First immediate-release opioid analgesic approved with labeling describing its abuse-deterrent properties consistent with the FDA’s Guidance


  • Schedule II
  • Post-marketing Requirements: Toxicology studies, Abuse and related clinical outcomes,  Formal observational studies to assess whether use result in a meaningful decrease in misuse and abuse, consequences, addiction overdose, death

MECHANISM OF ACTION: Full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses

  • Has physicochemical properties expected to make abuse via injection difficult – forms viscous gel when in contact with liquid
  • Not expected to deter oral abuse


  • Evaluate ability of abuse-deterrent technology to reduce abuse potential
  • In vitro laboratory manipulation, extraction, and syringeability studies; In vivo intranasal clinical abuse potential study
  • Human Abuse Potential Study: Randomized, double-blind, double-dummy, placebo-controlled, single-dose four-way crossover study, n=29, non-dependent recreational opioid users with history of intranasal drug abuse
  • Endpoint: Abuse potential of crushed intranasal ROXYBOND tablets vs. crushed intranasal oxycodone immediate release tablets
  • Drug liking and willing to take drug again measured on visual analog scale (VAS)
  • Statistically significantly lower drug liking and take drug again (Emax) scores with ROXYBOND

SAFETY: Boxed Warning for Addiction, Abuse and misuse, life threatening respiratory depression, accidental ingestion, neonatal opioid withdrawal syndrome, Cytochrome P450 interactions, risks from concomitant use with benzodiazepines or other CNS depressants.


RYDAPT (midostaurin) capsules

Novartis Pharmaceuticals, East Hanover, NJ, USA

LEUKOSTRAT CDx FLT3 Mutation Assay

Invivoscribe Technologies Inc., San Diego, CA, USA


  • Acute Myeloid Leukemia: In combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by FDA approved test (LeukoStrat CDx FLT3 Mutation Assay)
  • Systemic Mastocytosis: Treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL)


  • 19,930 people diagnosed with AML in 2016; 10,430 were projected to die of disease
  • First targeted therapy to treat patients with AML, in combination with chemotherapy
  • Ability to detect gene mutation with diagnostic test helps identification of specific patients who may benefit from treatment


  • Priority Review, Fast Track (for the mastocytosis indication) and Breakthrough Therapy (for the AML indication) designations
  • Post-marketing Requirements: Worldwide Pregnancy Surveillance Program

MECHANISM OF ACTION: Inhibits multiple receptor tyrosine kinases, FLT3 receptor signaling and cell proliferation, induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Can inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.


  • Randomized, double-blind placebo-controlled trial, n=717 patients with newly-diagnosed FLT3-mutated AML; RYDAPT RYDAPT  in combination with daunorubicin /cytarabine
  • Primary Endpoint: Overall Survival (OS), date of randomization until death by any cause;  Hazard Ratio 0.77; 95% CI 0.63, 0.95; 2 sided p=0.016
  • Single-arm, open-label, multicenter trial, n=116 in patients with ASM, SM-AHN, and MCL, RYDAPT as single agent
  • Primary Endpoint: Confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles
  • Confirmed major or partial responses: 46 of 73 patients with KIT D816V mutation, 7 of 16 with wild-type or unknown status, 21 of 32 having prior therapy for SM


  • Common side effects:  Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia and upper respiratory tract infection
  • Patients with pulmonary toxicity should stop treatment
Image result for stivarga

STIVARGA (regorafinib) tablets 

Bayer, Whippany, NJ, USA

SUPPLEMENTAL INDICATION: Treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

  • HCC originates in the liver and is the most common form of liver cancer
  • 40,710 people will be diagnosed; 28,920 will die
  • First FDA-approved treatment for a liver cancer in almost a decade

REG PATHWAY: Supplemental NDA

  • Priority Review, Orphan Drug Designation

MECHANISM OF ACTION:  Inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity


  • International, multicenter, randomized (2:1), doubleblind, n=760 patients with previously-treated metastatic colorectal cancer, STUVARAG vs placebo
  • Major efficacy outcome: Overall survival (OS); additional efficacy outcome measures included progression-free survival (PFS) and overall tumor response rate
  • Number of Deaths:  275 (55%) vs. 157 (62%), p=0.0102
  • Number of Deaths or Progressions: 417 (83%) vs. 231 (91%), p<0.0001
  • Common side effects: Pain, hand-foot skin reaction, fatigue, diarrhea, decreased appetite, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash and nausea
  • Serious risks: Hepatotoxicity, infections, hemorrhage, gastrointestinal perforation or fistula, dermatologic toxicity, hypertension, cardiac ischemia and infarction, reversible posterior leukoencephalopathy syndrome, wound healing complications


Photo Sources: Google, Novartis, Inspirion, Bayer



FDA BRIEF: Week of April 17, 2017

FDA approved


RENFLEXIS (infliximab-abda) intravenous infusion

Samsung Bioepis Co., Incheon, Republic of Korea


  • Crohn’s Disease
  • Pediatric Crohn’s Disease
  • Ulcerative Colitis
  • Rheumatoid Arthritis
  • Ankylosing Spondylitis
  • Psoriatic Arthritis
  • Plaque Psoriasis

REG PATHWAY: Biosimilar to REMICADE (infliximab)

  • Biological product approved based on showing high similarity to  reference product (infliximab)
  • No clinically meaningful differences in safety and effectiveness from reference
  • Only minor differences in clinically inactive components






Philips Medical Systems, Nederland B.V.


Automated digital slide creation, viewing, and management system. The PIPS is intended for in vitro diagnostic use as an aid to the pathologist to review and interpret digital images of surgical pathology slides prepared from formalin-fixed paraffin embedded (FFPE) tissue.

The PIPS is not intended for use with frozen section, cytology, or non-FFPE hematopathology specimens.

The PIPS comprises the Image Management System (IMS), the Ultra Fast Scanner (UFS) and Display. The PIPS is for creation and viewing of digital images of scanned glass slides that would otherwise be appropriate for manual visualization by conventional light microscopy.

It is the responsibility of a qualified pathologist to employ appropriate procedures and safeguards to assure the validity of the interpretation of images obtained using PIPS.


  • First authorized whole slide imaging system
  • Enables pathologists to read tissue slides digitally in order to make diagnoses
  • Streamlined slide storage and retrieval system

REG PATHWAY: De Novo request

  • Regulation Number: 21 CFR 864.3700
  • Regulation Name: Whole Slide Imaging System
  • Regulatory Classification: Class II
  • Product Code: PSY

GENERIC DEVICE TYPE: Whole Slide Imaging System

Automated digital slide creation, viewing, and management system intended as an aid to the pathologist to review and interpret digital images of surgical pathology slides. The system generates digital images that would otherwise be appropriate for manual visualization by conventional light microscopy.


  • Inaccurate or missing results leading to, for example, incorrect diagnosis: General and Special Controls
  • Delayed results: General and Special Controls



GAMMACORE Non-invasive Vagus Nerve Stimulator

electroCore, LLC, Basking Ridge, NJ, USA

INDICATION FOR USE:  To provide noninvasive vagus nerve stimulation (nVNS) on the side of the neck. The gammaCore device is indicated for the acute treatment of pain associated with episodic cluster headache in adult patients.

REG. PATHWAY: De Novo Request

  • Regulation Number: 21 CFR 882.8592
  • Regulation Name: External vagal nerve stimulator for headache
  • Regulatory Classification: Class II
  • Product Code: PKR

GENERIC DEVICE TYPE: External vagal nerve stimulator for headache

Prescription device used to apply an electrical current to a patient’s vagus nerve through electrodes placed on the skin for the treatment of headache.


  • Adverse tissue reaction resulting from patient contacting components:  Biocompatibility evaluation, Labeling
  • Electrical shock injury from device failure: Electrical safety, thermal, and mechanical testing, Software verification, validation, and hazard analysis, Labeling
  • Stimulation side effects such as Seizure, Cardiac side effects, Worsening of headache: Labeling
  • Ineffective therapeutic response due to device failure: Non-clinical performance testing, Software verification, validation and hazard analysis, Labeling
  • User error: Labeling




FDA BRIEF: Week of April 10, 2017

FDA approved

INGREZZA (valbenazine) capsules

Neurocrine Biosciences, San Diego, CA

INDICATION:  Treatment of adults with tardive dyskinesia


  • Neurological disorder characterized by repetitive involuntary movements
  • Can be disabling and can further stigmatize patients with mental illness
  • Serious side effect seen in patients antipsychotic medications
  • First drug for the treatment


  • Fast Track, Priority Review and Breakthrough Therapy designations.
  • Postmarketing Requirements: In vitro studies, PK studies,  clinical dependence and withdrawal symptom assessment study

MECHANISM OF ACTION: Reversible inhibition of vesicular monoamine transporter 2 (VMAT2) that regulates monoamine uptake from cytoplasm to synaptic vesicle for storage and release


  • Randomized, double-blind, placebo-controlled trial, n=234,  patients with moderate to severe tardive dyskinesia, INGREZZA vs. placebo, 6 weeks, then on INGREZZA for 48 weeks
  • Primary efficacy measure: Abnormal Involuntary Movement Scale (AIMS) change from baseline
  • AIMS change  statistically significantly different from placebo; consistent across multiple subgroups


  • Serious side effects: Sleepiness, QT prolongation.