News and Views: Budget and Real World Evidence, Inclusion/Exclusion in Clinical Trials, Gene Therapies, Balancing Opioid Access, Information and Usage Labeling, Mobile Medical Apps Regulation, Drug Shortages Task Force

CaptureFDA Budget Matters: A Cross-Cutting Data Enterprise for Real World Evidence 

FDA committed to new tools to collect data from routine medical care and develop valid scientific evidence  appropriate for regulatory decision making

  • Leverage “real world data” relating to patient health status and/or the delivery of health care obtained at the point of care
  • Enable more efficient medical product development by integrating safety and benefit information from clinical care
  • Can overcome limitations of traditional randomized clinical trials with defined inclusion and exclusion criteria

FDA’s Sentinel System and the National Evaluation System for health Technology (NEST) analyzes real world data for ‘real world evidence’

  • Need to govern responsible use of data and provide timely access through creation of national resource
  • Maintain strict data security and privacy of personal information
  • $100M medical data enterprise proposal budget for modern system for electronic health records from about 10 million lives

Current initiatives

  • Post-Market Data Sources: Claims Data vs. EHRs and access to clinical medical information in de-identified electronic health records and real-time information
  • Establishing a System that can Leverage All Data Sources by full interoperability
  • Improving Clinical Trials by using real world data for efficient recruitment, integration across clinical care settings, innovative statistical approaches to reduce  size and duration
  • Investing in Tools to More Wisely Use Data to Improve Health for data standards and data quality



Evaluating Inclusion and Exclusion Criteria in Clinical Trials

Eligibility criteria define patient population under investigation

  • Inclusion criteria identify population in which it is expected that the effect of the drug can be shown
  • Exclusion criteria specify characteristics that disqualify patients from participation
  • Both exclude patient subgroups who may eventually receive drug once approved

Strategies to Support Better Development of Eligibility Criteria and Increase Enrollment

  • Improving transparency and increasing patient involvement in clinical trial design
  • Re-examining exclusion and inclusion Practices
  • Increasing the use of innovative and alternative trial designs and methods to support inclusion



FDA’s Efforts to Advance Development of Gene Therapies

For novel technologies like gene therapy, FDA tailoring regulatory path for assuring safety and efficacy

  • Six scientific guidance documents for modern, comprehensive framework
  • Clear recommendations to support innovation

Disease Specific Gene Therapy Guidances

Human Gene Therapy for Rare Diseases

Guidances on Manufacturing Gene Therapies



Balancing access to appropriate treatment for patients with chronic and end-of-life pain with need to take steps to stem misuse and abuse of opioids

New policy to strike right balance between

  • reducing new addiction rate by decreasing exposure to opioids prescribing  – and –
  • make sure that patients with pain have access to appropriate, evidence-based care
  • Mostly, opioid treatment for acute pain and prescribed for short durations
  • Patient-Focused Drug Development meeting  for additional patient viewpoints

New steps to aggressively confront the addiction epidemic

  • Revised Blueprint for opioid drug manufacturers required to make available to prescribers
  • Required training on non-opioid alternatives
  • Develop evidence-based guidelines on appropriate prescribing
  • lnnovation challenge to spur development of medical devices ‒ including digital health and diagnostics – to provide novel solutions to treating pain
  • New series of guidance documents on development of new drugs targeted to the treatment of various types of pain
  • Collaboration with NIH public-private partnership to advance pharmacological treatments for pain and addiction




Steps to encourage more informative labeling on prescription drug and biological products’ indications and usage

General Principle: To enable health care practitioners to readily identify appropriate therapies for patients by clearly communicating drug’s approved indication(s)

  • Scope of an Indication Relative to Population Studied
  • Age Groups in Indication
  • Distribution of Information Among Labeling Sections

Content and Format

  • Indication: Disease, Condition, or Manifestation Being Treated, Prevented, Mitigated, Cured, or Diagnosed
  • Other Information Necessary To Describe the Approved Indication
  • Limitations of Use : Appropriate and Inappropriate situations

Other considerations

  • Identification of Outcomes, Endpoints, and Benefit(s)
  • Accelerated Approval
  • Required or Recommended Language
  • Preferred Wording and Wording Generally To avoid



FDA Regulation of Mobile Medical Apps

Efficient regulation of mobile medical apps – Software as Medical Device (SaMD) – tailored to potential benefits and risks

  • Traditional FDA regulatory framework can stifle the development/access
  • New framework being developed to  recognize distinctive aspects of digital health technology, clinical benefit, unique user interface, and compressed commercial cycles

FDA initiatives

  • Working with International Medical Device Regulators Forum (IMDRF) on internationally harmonized regulatory framework
  • Digital Health Innovation Action Plan to implement the software provisions of the Cures Act
  • Precertification program to qualify for a more streamlined premarket review process
  • New guidance on Mobile Medical Apps

Firm-based approach based on culture of excellence and leveraging

  • Postmarket data collection
  • Clinical data from device registries, EHRs
  • Other electronic health information sources through the National Evaluation System for health Technology (NEST)



Formation of a new drug shortages task force and FDA’s efforts to advance long-term solutions to prevent shortages

New Drug Shortages Task Force – including CMS and VA

  • Understand root causes – e.g. low margins with low incentives, reimbursement issues, limited manufacturing capacity
  • Consider regulations coupled with financial incentives to market critical access drugs
  • Conduct a risk assessment and mitigation plans  to proactively address shortage
  • Emerging technology program  to prevent shortages and new quality metrics initiatives


Image credits: FDA, HHS


Market Authorizations: EPIDIOLEX, ZEPHYR Endobronchial Valve, ELLIPSYS System, EVERLINQ System, DreaMed decision-support software, EVERSENSE CGM system


EPIDIOLEX  (cannabidiol) oral solution

GW Pharmaceuticals

INDICATION:  Treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients 2 years of age and older


  • Treatment of rare genetic conditions in pediatric population
  • First botanical marijuana product to be FDA approved

MECHANISM OF ACTION: Precise mechanisms of anticonvulsant effect unknown; does not appear to exert its anticonvulsant effects through interaction with cannabinoid receptors


  • Three randomized, double-blind, placebo-controlled clinical trials, n=516 patients with either Lennox-Gastaut syndrome or Dravet syndrome, Epidiolex + other medications vs. placebo, 14-week treatment period
  • Primary efficacy measure: %change from baseline in the frequency (per 28
    days) of drop seizures (atonic, tonic, or tonic-clonic seizures)
  • Significant decrease in seizures vs placebo; p≤0.01


  • Most serious risks: Thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks
  • Also caused liver injury, generally mild, but raising the possibility of rare, but more severe injury
  • Most common side effects:  Sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections
  • Must be dispensed with a patient Medication Guide



  • Orphan designation, Fast Track, Priority Review, Priority Review Voucher
  • Postmarketing requirements: Embryofetal development study, juvenile toxicology, carcinogenicity,  potential for chronic liver injury, pregnancy outcomes study, risk of drug-drug interactions or QT interval prolongation.


  • Currently controlled in Schedule I under the Controlled Substances Act
  • FDA scheduling recommendation has been transmitted to DEA
  • Final DEA scheduling decision pending



ZEPHYR Endobronchial Valve (Zephyr Valve)


INTENDED USE: Treat breathing difficulty associated with severe emphysema

ADDRESSING UNMET NEED:  Less invasive treatment that expands the options available to emphysema patients


  • Flexible bronchoscope to place Zephyr Valves, similar in size to pencil erasers, into diseased areas of lung airways
  • Device design intended to prevent air from entering damaged parts of lung and allow trapped air and fluids to escape
  • During inhalation, valves close, preventing air from entering damaged part of lung
  • During exhalation, valves open, letting out trapped air, which is intended to relieve pressure


  • Study, n=190 emphysema patients, Zephyr Valves + medical management (medications and pulmonary rehabilitation) vs. Control group received medical management only, one year treatment
  • Primary endpoint: % with at least a 15% improvement in pulmonary function scores (the volume of air that can forcibly be blown out in one second after full inhalation)
  • 47.7 % with Zephyr Valves  vs. 16.8% in control group


  • Adverse events: Death, air leak (pneumothorax), pneumonia, worsening of emphysema, coughing up blood, shortness of breath and chest pain
  • Contraindication: Active lung infections; those who are allergic to nitinol, nickel, titanium or silicone; active smokers and those who are not able to tolerate the bronchoscopic procedure


  • Breakthrough designation


Ellipsys Vascular Access System 

Avenu Medical

INDICATION FOR USE:  Creation of a proximal radial artery to perforating vein  anastomosis via a retrograde venous access approach in patients with a minimum vessel diameter of 2.0mm and less than 1.5mm of separation between the artery and vein at the fistula creation site who have chronic kidney disease requiring dialysis


EVERLINQ endoAVF System 

TVA Medical

INDICATION OF USE: Creation of an arteriovenous fistula (AVF) using the ulnar artery and ulnar vein in patients with minimum artery and vein diameters of 2.0 mm and less than 2.0 mm separation between the artery and vein at the fistula creation site who have chronic kidney disease and need hemodialysis


ADDRESSING UNMET NEED: Additional, less-invasive vascular access options for patients who will require hemodialysis

DEVICE TYPE: Percutaneous catheter for creation of an arteriovenous fistula for hemodialysis access

  • Single use percutaneous catheter system that creates an arteriovenous fistula (AVF) in the arm of patients with chronic kidney disease who need hemodialysis


  • Safely deliver, deploy, and remove the device
  • Create an arteriovenous fistula
  • Attain blood flow rate and diameter suitable for hemodialysis
  • Use fistula for vascular access for hemodialysis
  • Patency of the fistula


  • Unintended vascular or tissue injury
  • Adverse hemodynamic effects
  • Failure to create a durable fistula that is usable for hemodialysis
  • Use of the device adversely impacts future vascular access sites
  • Adverse tissue reaction
  • Infection
  • Electrical malfunction or interference leading to electrical shock, device failure, or inappropriate activation
  • Software malfunction leading to device failure or inappropriate activation


  • Regulation Number: 21 CFR 870.1252
  • Regulation Name: Percutaneous catheter for creation of an arteriovenous fistula for hemodialysis access
  • Regulatory Class: Class II
  • Product Code: PQK




DreaMed Advisor Pro decision-support software

DreaMed Diabetes, Ltd

INDICATION FOR USE:  Decision-support software intended for assisting healthcare professionals in the management of patients with Type 1 diabetes who:

  • use insulin pumps as their insulin delivery therapy
  • monitor their glucose levels using either of the following: CGM, or o CGM and self-management blood glucose meter
  • Are above the age of 6 and under 65 years old
  • Use rapid acting U-100 insulin analogs in their pump

Use by healthcare professionals when analyzing continuous glucose monitoring (CGM), self-monitoring blood glucose (SMBG) and pump data to generate recommendations for optimizing a patient’s insulin pump settings for basal rate, carbohydrate ratio (CR), and correction factor (CF); without considering the full clinical status of a particular patient.

DreaMed Advisor Pro does not replace clinical judgment

DEVICE TYPE: Insulin Therapy Adjustment Device

  • Incorporate biological inputs, including glucose measurement data from a CGM to recommend insulin therapy adjustments as an aid in optimizing insulin therapy regimens for patients with diabetes mellitus


  • Required data inputs, including timeframe over which data inputs must be collected and number of data points required
  • Types of device outputs and insulin therapy adjustment recommendations, including how the recommendations are generated
  • Clinical validity of the device outputs and insulin therapy recommendations
  • Input data specifications, including accuracy requirements for CGM  and other devices generating data inputs
  • Clinical justification for each specification
  • Ensure secure and reliable means of data transmission to and from device, data integrity checks, accuracy checks, reliability checks, security measures
  • Users can understand and appropriately interpret recommendations
  • Mitigation strategy to minimize dosing recommendation errors


  • Erroneous or extreme changes in insulin dosing recommendations may cause hypoglycemia or hyperglycemia
  • Incorrect interpretation of results may lead to inappropriate clinical decision making
  • Incorrect understanding of appropriate device use may lead to inappropriate treatment decisions
  • Patient harm due to insecure transmission of data
  • Data corruption may lead to inappropriate treatment recommendations


  • 21 CFR 862.1358
  • Regulation Name: Insulin Therapy Adjustment Device
  • Regulatory Class: Class II
  • Product Code: QCC



EVERSENSE Continuous Glucose Monitoring (CGM) system


INDICATION FOR USE: For continually measuring glucose levels in adults (18 years and older) with diabetes for up to 90 days.The system is intended to:

  1. Provide real-time glucose readings
  2. Provide glucose trend information
  3. Provide alerts for the detection and prediction of episodes of low blood glucose (hypoglycemia) and high blood glucose (hyperglycemia)

The system is a prescription device. Historical data from the system can be interpreted to aid in providing therapy adjustments. These adjustments should be based on patterns seen over time.The system is indicated for use as an adjunctive device to complement, not replace, information obtained from standard home blood glucose monitoring devices.


  • More seamless digital system giving patients ability to effectively manage diabetes
  • Modern regulatory approach for products that’s carefully adapted to the unique characteristics of these opportunities

DESCRIPTION: Continuous Glucose Monitor, Implanted, Adjunctive Use


  • Clinical study, n=1254 diabetes patients, comparing readings by Eversense CGM vs.  laboratory-based glucose analyzer
  • Safety based on procedure used to implant; <1% experiences serious adverse event
  • Potential adverse effects: Related to insertion, removal and wear of the sensor include allergic reaction to adhesives, bleeding, bruising, infection, pain or discomfort, scarring or skin discoloration, sensor fracture during removal, skin inflammation, thinning, discoloration or redness
  • Other risks: Hypoglycemia or hyperglycemia in cases where information provided by the device is inaccurate or where alerts are missed


  • Advisory Committee meeting:  8 to 0 vote, committee recommended that benefits outweigh the risks for patients with diabetes

PMA Listing

Image credit: GW, Pulmonx, Avenu, TVA, DreaMed, Senseonics

FDA News: Marijuana Research, Inhaled Antibiotics, Quality Metrics for Drugs, Compounded Drugs Enforcement


Importance of conducting proper research to prove safe and effective medical uses for the active chemicals in marijuana and its components

Marijuana is a Schedule I compound with known risks

  • Safety and effectiveness in treatment of medical disorders held to the same standard as other drug compounds
  • FDA approved purified form of drug cannabidiol (CBD) to treat seizures with rare, severe forms of epilepsy
  • Approval based on well-controlled clinical trials, reliable  dosage form, through  reproducible route of delivery to ensure anticipated benefits

Path for other marijuana-derived products 

  • Robust clinical development program, purity and  manufacturing controls
  • FDA Botanicals Team with expertise on botanical issues
  • Involvement of other federal agencies- National Institute on Drug Abuse, Drug Enforcement Administration
  • Continued vigilance of illegal marketing of unapproved CBD-containing products with unproven medical claims



Development of Inhaled Antibacterial Drugs for Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis


Public workshop held on “Development of Inhaled Antibacterial Drugs for Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis.”


Discuss the clinical trial design challenges and future considerations for inhaled antibacterial products to treat cystic fibrosis (CF) and non-CF bronchiectasis.



Quality Metrics for Drug Manufacturing

Quality metrics

  • Used throughout drugs and biologics industry to monitor quality control
  • Foundation for continual improvement of product and process quality
  • Element of companies’ commitment to quality culture

Two new programs on use of quality metrics to modernize pharmaceutical quality systems and advance innovation

  1. Quality Metrics Feedback Program: New drugs, generics, pharmaceutical ingredients (API) establishments, contract manufacturing organizations (CMOs), OTC products
  2. Quality Metrics Site Visit Program:  Experiential and firsthand learning opportunities to FDA staff i

Provide an opportunity for FDA to continue learning about the advantages and challenges companies have experienced in implementing Quality Systems



Continued efforts relating to compounded drugs for patients who cannot use an FDA-approved drug

Compounded drugs are not FDA-approved

  • Quality of products important
  • Developing policies and conducting oversight to minimize risks to patients
  • Taking actions to protect patients and enforce existing laws

Fraud enforcement actions 

  • Billing reimbursors for medically unnecessary compounded drugs
  • Examples: topical pain creams comprised of multiple ingredients to increase billing amount, include non-topical products such as antidepressants, anticonvulsants, antivirals, narcotics
  • Clinicians and patients not aware of potential safety risks, lack of effectiveness

FDA Actions:

  • Draft guidance on evaluation of  clinical need
  • Inspection of compounding facilities
  • Prescription requirement


Image credit: FDA

Authorizations: SYNOJOYNT, TRUETEAR Tear Neurostimulator, CURVE Positive Airway Pressure System




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


  • Sterile, non‐pyrogenic, clear, viscoelastic solution of hyaluronan contained in a single‐use prefilled syringe
  • Viscous solution of sodium hyaluronate in buffered physiological sodium chloride
  • Sodium hyaluronate is a high molecular weight fraction (approximately 2.5×106 daltons) of a natural complex sugar polymer consisting of repeating disaccharide units of Na‐glucuronate‐N acetylglucosamine


  • Double-blind, prospective, multi-site, randomized, threearm, parallel group, n=599,  injected into the target knee of  subjects with OA, vs. placebo, 26 weeks
  •  Adaptive investigation, two interim analyses (after approximately 50% and 75% of the planned sample size), sample size reassessment as needed
  • WOMAC pain scores : -167.73 (9.32) vs.  -131.64 (9.35) in placebo group, p=0.0033
  • Statistically significant differences in the WOMAC Pain score, WOMAC Stiffness score, WOMAC Physical Function score
  • Incidence of TEAEs  similar to that of saline placebo treatment


  • Classification: III
  • Product Code: MOZ



TRUETEAR Intranasal Tear Neurostimulator


INDICATION FOR USE:  Provides a temporary increase in tear production during neurostimulation to improve dry eye symptoms in adult patients with severe dry eye symptoms

GENERIC DEVICE TYPE:  Intranasal electrostimulation device for dry eye symptoms

  • Prescription non-implantable, electrostimulation device intended to increase tear production for improvement in dry eye symptoms


  • Tissue damage due to overstimulation/understimulation or mechanical injury (ex: tips too long), device breakage: Non-clinical performance testing, Software verification, validation, and hazard analysis, Electrical, thermal, and mechanical safety testing, Labeling
  • Adverse tissue reaction:Biocompatibility evaluation, 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 (EMC) testing
    Software verification, validation, and hazard analysis, Labeling
  • Pain, headache, or discomfort: Clinical performance testing, Non-clinical performance testing, Electrical, thermal, and mechanical safety testing, 
  • Failure to mitigate dry eye symptoms: Clinical performance testing, Training


  • Regulation Number: 21 CFR 886.5310
  • Regulation Name: Intranasal electrostimulation device for dry eye symptoms
  • Regulatory Class: Class II
  • Product Code: QBR

CLassification Order


CURVE Positive Airway Pressure System

Fresca Medical

INDICATION FOR USE:  To treat Obstructive Sleep Apnea by delivering a therapeutic breathing pressure to a patient. It provides positive airway pressure during expiration and also during an incipient apnea. The system includes a dedicated flow generator and a patient interface, and is intended for use in the home environment. This system is to be used by adult patients weighing more than 66 lbs (30 kg)

GENERIC DEVICE TYPE: Positive airway pressure delivery system

  • Prescription noninvasive ventilatory device that delivers expiratory positive airway pressure for patients suffering from obstructive sleep apnea. The system also provides positive airway pressure during incipient apnea. The system may include a dedicated flow generator and a patient interface


  • Adverse tissue reaction: Biocompatibility evaluation, Labeling
  • Electromagnetic interference: Electromagnetic compatibility testing
  • Infection:Reprocessing validation, Labeling
  • Device software failure: Software verification, validation, hazard analysis
  • Device hardware failure/malfunction leading to high airway pressure, carbon
    dioxide rebreathing or ineffective treatment: Non-clinical performance testing
  • Electrical shock injury or thermal injury: Electrical safety, thermal safety, and
    mechanical testing, Software verification, validation, and hazard analysis, Labeling
  • Use error leading to ineffective therapy or patient injury: Labeling


  • Regulation Number: 21 CFR 868.5273
  • Regulation Name: Positive airway pressure delivery system
  • Regulatory Class: Class II
  • Product Code: QBY

Classification Order

Image credit: Teva, Allergan, Fresca Medical




News: Software Precertification Working Model, Opioid Announcement


Software Precertification Model: A Working Model

Software Precertification Program

  • Voluntary pathway to provide more streamlined and efficient regulatory oversight of software as medical devices (SaMD)
  • From manufacturers who have demonstrated a robust culture of quality
    and organizational excellence (CQOE)
  • Committed to monitoring real-world performance


  • Tailored, pragmatic, least burdensome regulatory oversight
  • Assess – to establish trust of CQOE for high quality SaMD
  • Transparency –  across entire lifecycle of SaMD
  • Verify – continued safety, effectiveness, and performance of SaMD in real world


  • Excellence Appraisal and Precertification (Component 1)
  • Review Pathway Determination (Component 2)
  • Streamlined Premarket Review Process (Component 3)
  • Real-World Performance (Component 4)



FDA Announcement related to opioids

FDA supports U.S. Department of Health and Human Services’ 5-Point Strategy To Combat the Opioid Crisis

  • decreasing exposure to opioids and preventing new addiction
  • supporting treatment of those with opioid use disorder
  • fostering development of novel pain treatment therapies
  • fostering development of opioids more resistant to abuse and misuse
  • taking action against illegal importation and sale of opioids
  • evaluate how marketed opioids are used in both medical and illicit settings and take regulatory action where needed

Action against 53 websites marketing unapproved opioids More information

Patient Focused Drug Development for chronic pain More information

Approval of first generic versions of Suboxone sublingual film More information

Image credit: FDA, DHHS

Briefs: Communications for value-based care, New reimbursement model to fight antibiotic resistance, Patient Voice in regulatory decision-making, CDER organizational improvements


New efforts to advance medical product communications to support drug competition and value-based health care

HHS blueprint proposes measures for access to underinsured or uninsured

  • Prices to reflect the value in how medicines are prescribed and the outcomes they deliver
  • Control rising spending and reduce the burden of drug costs for consumers
  • Models to tie price of drugs closely to usefulness of  clinical setting in which they are prescribed. We want to encourage competitive contracting based on measures of value that matter most to purchasers and patients, not get in the way of these competitive negotiations

FDA will provide clear guidance to pharmaceutical companies about open, responsible communication with payors, formulary committees and others

First  guidance document

  • Inform market participants developing value-based contracts
  • Communication of outcomes important to purchasers like a health plan or hospital
  • Endpoint may not be expressly described in drug’s approved labeling

Second guidance document

  • Manufacturers’ communication of information that is not contained in the FDA-required labeling for their products, but that is consistent with that labeling
  • Such as data from post-market studies and surveillance
  • Additional information from the pre-market studies that were used to support approval of the product



FDA’s efforts to foster discovery and development of new tools to fight antimicrobial-resistant infections

Increase in serious antimicrobial drug resistant infections is critical public health concern

  • At least 2 million people become infected with bacteria that are resistant to antibiotics and 23,000 people die each year as direct result
  • Need for good antibiotic stewardship and use in appropriate clinical scenarios

In discussions with CMS, idea to change reimbursement model

  • For certain new, anti-microbial drugs that meet critical, public health needs
  • Move to licensing model – instead of paying for drugs that meet a narrow set of criteria on a per use basis
  • Acute care institutions would pay a fixed licensing fee to use a certain number of annual doses



New agency efforts to advance the PATIENT VOICE in medical product development and FDA regulatory decision-making

Need for systematic, methodologically-sound approaches to collect patient input to  inform regulatory decision-making

New guidance on Patient-Focused Drug Development: Collecting Comprehensive and Representative Input

  • Sampling methods for collecting patient experience – throughout the medical product lifecycle
  • How to operationalize and standardize the collection, analysis and dissemination of patient experience data



Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making

FDA Patient-Focused Drug Development Guidance Series 

  • To address, in a stepwise manner, how stakeholders can collect and submit patient experience data
  • Intended to facilitate the advancement and use of systematic approaches to collect and use robust and meaningful patient and caregiver input



Proposed modernization of FDA’s drug review office

CDER undertaking steps to modernize the organization and functions of  Office of New Drugs

  • Elevate role of scientists and medical officers to take on even more thought leadership
  • More time, better tools and greater support to advance the clinical and regulatory principles
  • Develop hundreds of new clinical guidance documents and make sure they stay up-to-date to reflect latest science

Allow review staff to have more time for reviewing and providing feedback to sponsors

  • Engage sponsors earlier in the development process
  • Ensure trial designs are efficient and  effectively structured for benefit/risk assessment
  • Ability to engage external stakeholders, such as disease specialists, academic researchers and regulatory partners at other agencies
  • Ongoing relationships and interactions with patient groups
  • Creating many new therapeutic-specific divisions to engage in discrete areas of medicine

Improve FDA review process

  • Integration around a common review process, common review template
  • Integrated across  discrete areas of science and regulatory expertise
  • Better organization of review process and development of key review memos

New alignment and processes will improve efficiency by 20% at a minimum overall


Image credit: FDA


Authorizations: DOPTELET, OSTEODETECT AI for Fractures, CUSTOMFLEX Artificial Iris


DOPTELET (avatrombopag) 

 AkaRx Inc.

INDICATION:  Treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure


  • Patients with chronic liver disease who have low platelet counts and require a procedure are at increased risk of bleeding
  • Doptelet safely increases platelet count; may decrease or eliminate platelet transfusions

MECHANISM OF ACTION:  Thrombopoietin (TPO) receptor agonist stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets


  • Two multicenter, randomized, double-blind, placebo-controlled trials, n= 435, patients with chronic liver disease and severe thrombocytopenia
  • Major efficacy outcome: Proportion of patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure.
  • Higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy with Doptelet


  • Most common side effects: Fever, stomach (abdominal) pain, nausea, headache, fatigue and swelling in the hands or feet (edema);  increased risk of developing blood clots when taking Doptelet


  • Priority review
  • Postmarketing required pediatric assessmenrs





INDICATION FOR USE: OsteoDetect analyzes wrist radiographs using machine learning techniques to identify and highlight distal radius fractures during the review of posterior-anterior (PA) and lateral (LAT) radiographs of adult wrists


  • AI algorithms have tremendous potential to help health care providers diagnose and treat medical conditions
  • Software can help providers detect wrist fractures more quickly and aid in the diagnosis of fractures

GENERIC DEVICE TYPE: Radiological Computer Assisted Detection and Diagnosis Software

  • Image processing device intended to aid in the detection, localization, and characterization of fracture, lesions, or other disease specific findings on acquired medical images (e.g. radiography, MR, CT)
  • Detects, identifies and characterizes findings based on features or information extracted from images, and provides information about the presence, location, and characteristics of the findings to the user
  • Analysis is intended to inform the primary diagnostic and patient management decisions that are made by the clinical user
  • Not intended as a replacement for a complete clinician’s review or their clinical judgment that takes into account other relevant information from the image or patient history


  • Retrospective study of 1,000 radiograph images that assessed the independent performance of the image analysis algorithm for detecting wrist fractures and the accuracy of the fracture localization of OsteoDetect against the performance of three board certified orthopedic hand surgeons
  • Retrospective study of 24 providers who reviewed 200 patient cases
  • Readers’ performance in detecting wrist fractures was improved using the software, including increased sensitivity, specificity, positive and negative predictive values vs. standard clinical practice


  • Regulation Number: 21 CFR 892.2090
  • Regulation Name: Radiological Computer Assisted Detection and Diagnosis Software
  • Regulatory Class: Class II
  • Product Code: QBS


CUSTOMFLEX  Artificial Iris

HumanOptics AG

INDICATION FOR USE:  Iris prosthesis for the treatment of iris defects. The CustomFlex™ Artificial Iris is indicated for use in children and adults for the treatment of full or partial aniridia resulting from congenital aniridia, acquired defects, or other conditions associated with full or partial aniridia


  • Congenital aniridia is a rare genetic disorder in which the iris is completely or partially absent
  • Affects approximately 1 in 50,000 to 100,000 people in the U.S.
  • CustomFlex Artificial Iris is indicated to treat iris defects due aniridia, other reasons or conditions, such as albinism, traumatic injury or surgical removal due to melanoma


  • Foldable iris prosthesis custom-made for each individual patient
  • Manufactured from a commercially available ophthalmic silicone
  • Colorized silicone paste is applied by hand in a pattern to match the color of the natural iris using a photograph of the existing iris or, in the case of aniridia, the color of the photograph selected by the patient
  • Surgeon makes a small incision, inserts the device under the incision, unfolds it and smooths out the edges using surgical instruments
  • Prosthetic iris is held in place by the anatomical structures of the eye or, if needed, by sutures


  • Non-randomized clinical trial, n=389 adult and pediatric patients with aniridia or other iris defects
  • Primary Endpoint: Self-reported decrease in severe sensitivity to light and glare post-procedure, health-related quality of life, and satisfaction with the cosmetic improvement or appearance of the prosthesis
  • >70 % reported significant decreases in light sensitivity and glare as well as an improvement in health-related quality of life following the procedure
  • 94% satisfied with the artificial iris’ appearance
  • Low rates of adverse events: Device movement or dislocation, strands of device fiber in the eye, increased intraocular pressure, inflammation of the iris (iritis), adhesion of the iris to the cornea or lens (synechiae) and the need for secondary surgery to reposition, remove or replace the device


  • Breakthrough device designation


Image credits:  AkaRx Inc., Imagen, HumanOptics AG



FDA news: Right to Try Act, Shared System REMS, Innovation Challenge for Devices targeting Abuse, Software Functions excluded as Devices, Liver Toxicity Understanding, Sunscreen Effectiveness


Statement from FDA Commissioner Scott Gottlieb, M.D., on the signing of the Right to Try Act

May 30th: President signed into law the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017 (Right to Try Act)

  • FDA to implement legislation to promote access and protect patients
  • Patients facing terminal conditions have an additional avenue to access promising investigational medicines
  • Will build on FDA’s exisiting Expanded Access program that enhances access to promising investigational medicines for those unable to access products through clinical trials
  • Will recognize the important balance between making sure patients have the assurances Congress intends, while enabling timely access to promising treatments in these devastating circumstances



New policies to reduce the ability of brand drug makers to use REMS programs as a way to block timely generic drug entry

Risk Evaluation and Mitigation Strategy (REMS) requirements have been exploited to block timely generic entry

  • At the front end of the drug development process- Restrict availability of branded drugs needed to run bioequivalence studies for generic drugs
  • At the back end of the process for drug approval and marketing – Delayed agreements for generics to enter branded drug Shared System REMS

New policy to help generic drug makers maintain safety controls sought by REMS



As part of efforts to combat opioid crisis, FDA launches innovation challenge to spur development of medical devices ‒ including digital health and diagnostics ‒ that target pain, addiction and diversion

FDA working to address opioid crisis and support goals of  U.S. Department of Health and Human Services’ Five-Point Strategy to Combat the Opioid Crisis

  • Significant focus on decreasing exposure to opioids and preventing new addiction
  • Supporting treatment of those with opioid use disorder
  • Fostering development of novel pain treatment therapies and opioids more resistant to abuse and misuse
  • Taking action against those who contribute to the illegal importation and sale of opioid products

Innovation challenge to encourage medical product developers to submit proposals

  • Diagnostics to identify patients at increased risk for addiction
  • Treatments for pain that eliminate the need for opioid analgesics
  • Treatments for opioid use disorder or symptoms of opioid withdrawal
  • Devices or technologies that can prevent diversion of prescription opioids
  • Devices with improved benefit-risk profile vs.  opioids in pain management

Benefits for accepted proposals

  • Enhanced interactions with FDA review divisions during development and evaluation
  • Breakthrough Device designation granted

Deadline: June 1 – Sept. 30, 2018


Capture.JPGFDA seeking comments on risks and benefits to health associated with software functions excluded from the device definition by the Cures Act

Per the Cures Act, certain medical software functions are not medical devices

  • for administrative support of a health care facility
  • for maintaining or encouraging a healthy lifestyle
  • to serve as electronic patient records
  • for transferring, storing, converting formats, or displaying data
  • to provide limited clinical decision support

FDA requesting input on risks and benefits  with these non-device software functions

  • From all interested parties, including patients, consumers, healthcare providers, startup companies, health plans or other third-party payers, venture capital investors, information technology vendors, health information technology vendors, small business purchasers, employers, and other stakeholders
  • FDA will incorporate input to develop report on risks and benefits of these software functions

submit your comments

Capture.JPGNCTR… Improving Understanding of Liver Toxicity

  • Role of Cytochromes in Dronedarone-Induced Liver Toxicity
  • Therapeutic Bile Acids and the Risks for Liver Toxicity
  • Monograph Published on Drug-Induced Liver Toxicity
  • Early and Sensitive Biomarkers of Liver Toxicity Discovered



New FDA actions to keep consumers safe from the harmful effects of sun exposure, and ensure the long-term safety and benefits of sunscreens

Most cases of melanoma can be attributed to cumulative UV exposure

  • Policy efforts to promote innovation in sunscreen (Sunscreen Innovation Act)
  • Help promote product innovation when it comes to better sunscreens

New efforts to advance framework for sun protection products

  • Making sure that products deliver advertised benefits
  • Warning letters to companies illegally marketing pills and capsules labeled as dietary supplements with unproven claims about protection from sun exposure harm
  • Encouraging industry to conduct research on additional sunscreen active ingredients to enhance safety
  • New FDA process to review the safety and effectiveness of sunscreen active ingredients
  • New draft guidance regarding Maximal Usage Trials (MUsT) for topically-applied active ingredients



Image credits: Congress, FDA

Device Market Authorizations: ULTRA Contact Lens, THINPREP Integrated Imager, ILLUMINOSS Bone Stabilization System


ULTRA (samfilcon A) Contact Lenses

Bausch + Lomb


Single Vision Spherical (SVS) Vision Correction : For extended wear for up to 7 days;  correction of refractive ametropia (myopia and hyperopia) in aphakic and/or not-aphakic persons with non-diseased eyes, exhibiting astigmatism of 2.00 diopters or less, that does not interfere with visual acuity.
Presbyopia Vision Correction: For extended wear for up to 7 days;  correction of refractive ametropia (myopia, hyperopia and astigmatism) and presbyopia in aphakic and/or not-aphakic persons with non-diseased eyes, exhibiting astigmatism of 2.00 diopters or less, that does not interfere with visual acuity.
Astigmatism Vision Correction: For extended wear for up to 7 days;  correction of refractive ametropia (myopia, hyperopia and astigmatism) in aphakic and/or not-aphakic persons with non-diseased eyes, exhibiting astigmatism up to 5.00 diopters.


  • Contact Lenses are 46% water and 54% samfilcon A material
  • Samfilcon A material is a hydrophilic copolymer of siloxane methacrylate, a siloxane cross-linker, and N-vinyl pyrrolidone
  • Tinted blue for visibility with Reactive Blue Dye 246, a color additive that conforms to 21 CFR Part 73.3106
  • Utilizes MoistureSeal® technology
  • In its hydrated state, when placed on the cornea acts as a refracting medium to focus light rays on the retina


  • Prospective, multi-center, two-arm cohort study, randomized, double-blinded, 12-month clinical study, n= 816, B+L ULTRA vs. B+L PureVision control group
  • Primary effectiveness endpoint: High contrast, distance visual acuity with dispensed lenses at the 12-Month Follow-up Visit.  97% of subject eyes achieved at least 20/25 with ULTRA
  • Secondary effectiveness endpoint: Lens wear time reported as average extended lens wear time (days/week) since last visit. Average wearing time was 6.7 (±0.031) days for both groups
  • Line change in visual acuity from baseline:  3.0% eyes in Ultra group vs. 3.8% eyes in PureVision group experienced worsening of ≥ 2 lines (≥ 10 letters)
  • Unfavorable lens performance: Higher proportion for PureVision group


  • The primary safety endpoint: Rate of serious or significant non-serious adverse
    events during the 12-month follow-up: No serious AEs for either lens group
  • 3.0% of Ultra eyes experienced significant non-serious AEs vs. 2.4% of PureVision eyes – Noninferiority was met using a predetermined threshold of 5.0%.


  • Device Procode: LPM



ThinPrep Integrated Imager 

Hologic, Inc.

INDICATION FOR USE: Uses computer imaging technology to assist in primary cervical cancer screening of ThinPrep® Pap Test slides for the presence of atypical cells, cervical neoplasia, including its precursor lesions (Low Grade Squamous Intraepithelial Lesions, High Grade Squamous Intraepithelial Lesions), and carcinoma as well as all other  cytologic criteria as defined by the Bethesda System: Terminology for Reporting Results of Cervical Cytology


Three major subsystems

  1. Microscope: Imaging camera, slide ID reader, automated stage, hand controls and adjustable touch screen user interface
  2. Controller: Controls the electromechnical components of the Microscope
  3. Computer: Hosts system application software and system database

Two major functions

  1. Imaging: Takes high magnification frames at more than 500 x-y locations covering entire cell spot. z-locations (focal plane)  calculated based on x-y locations. Software
    analyzes images of cell spot, identifies objects of interest based on optical density
  2. Review: Retrieves locations of the objects of interest and sequentially positions  for evaluation and interpretation by the cytotechnologist (CT)

Two work modalities

  1.  Sequential: Slide is imaged and then reviewed immediately by the CT.
  2. Batched:  Slides can be imaged in succession, with the coordinates stored in the
    computer database, for review by the CT or pathologist at a later time.


  • Multi-center, two-armed clinical study, n= 1,260 patient cases that covered all cytologic diagnosis categories, similarity of ThinPrep Integrated Imager (TI) to ThinPrep Imaging System (TIS)
  • Significantly higher sensitivity  and slight decrease in specificity, with TI
  • Workload assessment:  The number of slides that a CT can scan and review in one day is less on I2 than TIS although not significant


  • Incorrect diagnosis leading either to unnecessary care or delayed follow up care
  • Worst case scenario of false negative test result mitigated by multiple factors (aspects of the standard of care in the context of cervical precancer screening e.g. repeat testing,)


  • Device Procode: MKQ, MNM


Capture.JPGIlluminOss Photodynamic Bone Stabilization System

IlluminOss Medical, Inc.

INDICATION FOR USE: Skeletally mature patients in the treatment of impending and actual pathological fractures of the humerus, radius, and ulna, from metastatic bone disease


  • Used in fixation and stabilization of actual and impending pathological fractures of the humerus, radius, and ulna through a minimally invasive procedure
  • Catheter to deploy an inflatable, noncompliant, thin wall PET balloon into the medullary canal of the bone across the fracture site
  • Balloon is infused using a standard 20cc syringe with a photodynamic (light cured) monomer
  • Activation of light system allows for visible spectrum light to be delivered through a radially emitting light pipe
  • Curing (and hardening) occurs only when the photo initiator within the monomer is exposed to a specific frequency of light causing rapid polymerization of the monomer
  • Timer Key determines time the light source is activated during the curing process to ensure the appropriate cure time is used for each balloon size


  • Prospective, multi-center, historically controlled, open label, noninferiority study, n=81 implanted with the PBSS for the treatment of impending and actual pathological fractures in the humerus from metastatic bone disease
  • Primary efficacy parameters (Day 90 follow-up): Pain measured by the Visual Analog Scale (VAS) pain score, Function assessed by Musculoskeletal Tumor
    Society Rating Scale for Upper Extremity (MSTS)
  • Primary safety parameters: Major device-related adverse events, additional surgical interventions, radiographic evaluations for device fracture, migrations, mal-alignment, or loss of reduction or fixation
  • Average VAS pain reduction: 53 points from baseline to Day 90; large reduction of pain using other characteristics
  • Substantial increase in function: 40-point baseline to Day 90; other functional outcomes showed similar result
  • Low Device and Procedure Related Adverse Events,  second surgeries.  No bone infections with only one wound site infection


  • Product Code: QAD
  • Device Type: In vivo cured intramedullary fixation rod
  • Class: II
  • Regulation: 21 CFR 888.3023

Image credits:  Bausch+Lomb, Hologic, IllumiNoss





 PALYNZIQ (pegvaliase-pqpz) 


INDICATION:  Reduce blood phenylalanine concentrations in adult patients with  phenylketonuria (PKU) who have uncontrolled blood phenylalanine (Phe) concentrations greater than 600 micromol/L on existing management


  • PKU affects about 1 in 10,000 to 15,000 people in US
  • Can cause chronic intellectual, neurodevelopmental, psychiatric disabilitie
  • Novel enzyme substitution therapy for PKU patients unable to control blood Phe levels with current treatment options

MECHANISM OF ACTION: PEGylated phenylalanine ammonia lyase (PAL) enzyme that substitutes for deficient PAH enzyme activity in PKU patients


  • Two clinical trials, n>100 PKU patients, unrestricted diet prior to and during the trial
  • First trial- Randomized, open-label, increasing doses of subcutaneous Palynziq
  • Second trial – 8-week, placebo-controlled, randomized withdrawal trial in patients previously treated with Palynziq
  • Statistically significant reductions in blood phenylalanine concentrations from their pre-treatment baseline blood Phe concentrations


  • Most common adverse events:  Injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal pain, throat pain, fatigue, vomiting, cough and diarrhea\
  • Most serious adverse reaction: Anaphylaxis
  • Boxed Warning and restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Palynziq REMS Program


  • Orphan Drug Designation
  • Postmarketing Studies: Prospective, longitudinal, observational study to assess long-term risks of severe immune-mediated adverse reactions, Pre-/Postnatal development study in rats, Assay developments


Capture.JPGAIMOVIG (erenumab-aooe)


INDICATION: Preventive treatment of migraine in adults


  • Migraine is 3X more common in women than in men; affects > 10% worldwide
  • Novel option for reducing the number of days with migraine

MECHANISM OF ACTION:  Binds to calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function


  • Three clinical trials
  • First study, n= 955 participants with history of episodic migraine, Aimovig vs. placebo, 6 mo.- average one to two fewer monthly migraine days vs. placebo
  • Second study, n=577 patients with history of episodic migraine, Aimovig vs. placebo, 3 mo.,- average one fewer migraine day per month vs. placebo
  • Third study, n=667 patients with history of chronic migraine, Aimovig vs. placebo, 3 mo. – average, 2 ½ fewer monthly migraine days vs. placebo


  • Most common side effects: Injection site reactions and constipation


  • Deferred pediatric studies



LUCEMYRA (lofexidine hydrochloride) 

US WorldMeds LLC

INDICATION:  Mitigation of opioid withdrawal symptoms to facilitate abrupt
opioid discontinuation in adults


  • First FDA-approved non-opioid treatment for management of opioid withdrawal symptoms
  • New option for providers to work with patients to select the treatment best suited to an individual’s needs

MECHANISM OF ACTION:  Central alpha-2 adrenergic agonist binds to receptors on adrenergic neurons; reduces release of norepinephrine and decreases sympathetic tone


  • Two randomized, double-blind, placebo-controlled clinical trials, n=866 adults meeting DSM -IV criteria for opioid dependence, physically dependent on opioids, undergoing abrupt opioid discontinuation
  • Primary endpoint: Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) – Paient-reported outcome instrument for opioid withdrawal symptoms including feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes, insomnia
  • Patients rated symptom severity: Nnone, mild, moderate and severe; higher score indicates greater withdrawal symptom severity.
  • SOWS-Gossop scores lower with Lucemyra vs. placebo
  • More patients completed treatment period with Lucemyra vs. placebo


  • Most common side effects: Hypotension, bradycardia, somnolence, sedation and dizziness
  • Also associated: Syncope,  increase risk of abnormal heart rhythms


  • Fast Track Designation, Priority Review
  • 15 postmarketing studies, including both animal and human safety studies and to support longer term use, use in pediatrics


Capture.JPGRETACRIT(epoetin alfa-epbx) 



  • Anemia Due to Chronic Kidney Disease
  • Anemia Due to Zidovudine in Patients with HIV-infection\
  • Anemia Due to Chemotherapy in Patients with Cancer
  • Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery


  • First epoetin alfa biosimilar for the treatment of anemia
  • Biosimilars can provide greater access to treatment options, increasing competition and potentially lowering costs


  • Biosimilar approved based on data showing that it is highly similar to a marketed biological product
  • Has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product
  • Approval based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Retacrit is biosimilar to Epogen/Procrit


  • Most common side effects:  High blood pressure, joint pain, muscle spasm, fever, dizziness, medical device malfunction, blood vessel blockage, respiratory infection, cough, rash, injection site irritation, nausea, vomiting, muscle pain, inflammation of the mouth and lips, weight decrease, reduction in white blood cells, bone pain, high blood sugar, insomnia, headache, depression, difficulty swallowing, low blood potassium, blood clots, itching, headache, injection site pain and chills
  • Must be dispensed with patient Medication Guide that provides information about the drug’s uses and risks


Image credits: Biomarin, Amgen, US WorldMeds, Pfizer

FDA Alerts: Efficacy Issue with KEYTRUDA, TECENTRIQ, Potential Risk with Dolutegravir, Quality Problems with IQVIA


Capture.JPGEFFICACY ISSUE identified in clinical trials for some patients taking KEYTRUDA (pembrolizumab, Merck) or TECENTRIQ (atezolizumab, Genentech)

As monotherapy to treat urothelial cancer with low expression of PD-L1

Decreased survival associated with the use of Keytruda  or Tecentriq 

  • Results from 2 two ongoing clinical trials KEYNOTE-361 and IMVIGOR-130
  • Decreased survival vs. patients receiving cisplatin- or carboplatin-based chemotherapy
  • Trial enrollment stopped

Populations differ from those labeled for accelerated approvals of both drugs

  • FDA recommends patient selection per Section 14 of each label


Capture.JPGPOTENTIAL RISK  of neural tube birth defects with HIV medicine dolutegravir (JULUCA, TIVICAY, TRIUMEQ)

Serious cases of neural tube birth defects involving the brain, spine, and spinal cord d in babies born to women treated with dolutegravir

  • Used to treat human immunodeficiency virus (HIV)
  • Results from an ongoing observational study in Botswana
  • Seen in women taking  dolutegravir in first trimester
  • Neural tube defects occur because spinal cord, brain, related structures do not form properly
  • No reports in women taking drug later in pregnancy
  • Ongoing monitoring will continue

Dolutegravir marketed for 5 years as single ingredient product and fixed dose combination

  • Works by blocking integrase prevent virus from multiplying and reduce amount in body
  • Stopping dolutegravir can cause the HIV infection to become worse

Advice to patients and Health care professionals


Capture.JPGQUALITY PROBLEMS for data provided by IQVIA used to inform estimates for some controlled substances

Inaccuracy in data provided to FDA by IQVIA National Sales Perspectives database, including data on certain opioid drug products

  • FDA found discrepancy in data that showed a >20% drop in 5-yr fentanyl sales (expressed in kilograms,)  vs. previously reported
  • Past data overestimated because of error in IQVIA’s methods due to wrong weight-based conversion factors
  • Error could impact other federal agencies (eg DEA) using this data; can impact ongoing work to fight opioid epidemic
  • Additional data quality issues related to several other controlled substances  including oxymorphone and hydrocodone
  • Errors raise serious concerns about systemic issues with IQVIA’s data and quality control procedures

Data integrity and validity are critical to FDA and such deficiencies taken very seriously

  • FDA Commissioner has called upon IQVIA to immediately retain qualified independent, third party auditor
  • Conduct complete review of data quality and quality control procedures
  • Hire third party to conduct independent audit of data quality and quality control of all IQVIA products

FDA will brief members of Congress on IQVIA’s data quality issues and their potential public health implications


Image credit: Merck, Genentech, ViiV, IQVIA


Reference Listed Drugs (RLD)


Reference Listed Drugs (RLD) Access Inquiries

Prospective generic applicants are unable to obtain samples of the reference listed drug (RLD) necessary to support their ANDA 

  • RLD sponsor imposed limitations on distributions
  • Subject to Risk Evaluation and Mitigation Strategies (REMS) impacting distribution

FDA providing transparency regarding these inquiries

  • Published a list of all drug products with FDA inquiries on RLD access
  • Details on RLD sponsor
  • Update this list on a semi-annual basis.

Part of Drug Competition Action Plan, to expand access to safe, high quality, effective generic medicines and lower drug cost


RLD Website


FDA News: Drug Prices, Stem Cell clinic Injunctions, Opioid Crisis and Patient Needs, Drug Compounding, Medical Devices Servicing

Capture.JPGStatement from FDA Commissioner Scott Gottlieb, M.D., on the Trump Administration’s plan to lower drug prices 

Drug Competition Action Plan (DCAP) to address the rising cost of drugs

  • Strengthen and enhance the overall generic drug review process
  • Calling out abuses of the system that impede competition and fixing them
  • Adopting strong policies and taking action against anticompetitive strategies to delay development and approval of important generic drug

Biosimilar Action Plan to facilitate development and approval of biosimilars

  • Help address patient access to costly biological products
  • Address Risk Evaluation and Mitigation Strategies (REMS) “gaming” abuses that can delay the entry of generic drugs



CapturePermanent injunctions against two stem cell clinics

Permanent injunctions to stop two stem cell clinics from marketing stem cell products without FDA approval and for significant deviations from cGMP requirements

  • Unapproved treatments that put patients’ health at risk
  • US Stem Cell Clinic LLC of Sunrise, Florida
  • California Stem Cell Treatment Center Inc., with locations in Rancho Mirage and Beverly Hills, California


Capture.JPGAddressing Needs of Patients While Stemming the Tide of the Opioid Crisis

FDA goals to develop new policy solutions to

  • Reduce overall exposure to opioids
  • Prevent new addictions
  • Support development and use of medications to treat e with opioid use disorder

Need to address concerns of Americans living with chronic pain

  • Continued access to necessary pain medication
  • Fear of being stigmatized as an addict
  • Challenges in finding health care professionals willing to prescribe opioids
  • Increased thoughts of or actual suicide because crushing pain

Strike right balance between reducing new addiction while providing appropriate access

  • Upcoming public meeting focused on needs of those suffering from chronic pain
  • Allow appropriate prescribing for those in need
  • Encourage medical professional societies to develop evidence-based prescribing  guidelines
  • New guidances on efficient, modern pathway for development of pain drugs


Capture.JPGHuman Drug Compounding and Policies

Preserve access to appropriately compounded drugs for patients who have a medical need while protecting patients from poor quality compounded drugs causing harm

  • Risk-Based Approach to Manufacturing Standards for Outsourcing Facilities
  • Restricting Compounding of Drugs that are Essentially Copies of FDA-Approved Drugs
  • Regulating Compounding from Bulk Drug Substances
  • Solidifying FDA’s Partnership with State Regulatory Authorities
  • Finalization of Biological Products Guidance and Clarifying Other Policies on Activities that Compounders Undertake
  • Compliance


CaptureFDA Report on the Quality, Safety, and Effectiveness of Servicing of Medical Devices

FDA’s conclusions based on information related to quality, safety, and effectiveness of medical device servicing 

  • Evidence not sufficient to conclude whether or not there is a widespread public health concern
  • Indicates that many original equipment manufacturers (OEMs) and third party entities provide high quality, safe, and effective servicing of medical devices
  • Majority of comments, complaints, and adverse event reports alleging inadequate
    “servicing” actually pertain to “remanufacturing” and not “servicing”
  • Continued availability of third party entities to service and repair medical devices is critical

Formal regulatory action is not warranted; will pursue the following actions

  • Promote the Adoption of Quality Management Principles
  • Clarify the Difference Between Servicing and Remanufacturing
  • Strengthen Cybersecurity Practices
  • Foster Evidence Development to Assess the Quality, Safety and Effectiveness


Image credit: FDA

FDA Qualification, Market Authorization: MLHFQ Tool, ANDEXXA, KYMRIAH, AQUABEAM System



University of Minnesota

QUALIFIED CONTEXT OF USE: The paper self-administered version of the MLHFQ can be used to determine whether a device treatment is effective for improving patients’ quality of life by reducing the adverse impact of heart failure.

The instrument can be used as a secondary endpoint in feasibility and pivotal studies of outpatients with symptomatic (NYHA class II and III) heart failure. The 21-item instrument is completed by patients after they have been properly instructed by study staff. Study staff should be properly trained to instruct the patient and if needed, administer the questionnaire, according to pre-set administration instructions.

The MLHFQ instrument may be used by medical device companies and sponsor-investigators in controlled clinical trials designed to test superiority or non-inferiority of medical devices in support of regulatory submissions.


  • 21-item paper self-administered questionnaire as a measure of heart failure
  • Quantifies overall score as measure of impact of heart failure on patient’s life
    • Physical symptoms and signs of heart failure
    • Common physical/social functions
    • Psychosocial and cognitive function
    • Adverse impact on quality of life


  • Long history of use in medical device and pharmaceutical clinical studies
  • Additional publications evaluating the psychometric and statistical properties of the score
  • Publications support reliability and validity of the MLHFQ total score

REGULATORY PATHWAY: Medical Device Development Tool Qualification

  • Clinical Outcome Assessment

Decision Summary


ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) 

Lyophilized Powder for Solution For Intravenous Injection


INDICATION: For patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding

MECHANISM OF ACTION: Exerts procoagulant effect by binding and sequestering the FXa inhibitors, rivaroxaban and apixaban. Also binds and inhibits activity of Tissue Factor Pathway Inhibitor (TFPI)


Two prospective, randomized, placebo-controlled studies, healthy volunteers; examine percent change in anti-FXa activity, from baseline to nadir

  • Apixaban reversal: At 3 hours after the last apixaban dose (~ Cmax), ANDEXXA or placebo was administered, n=8
  • Rivaroxaban reversal: At 4 hours after the last rivaroxaban dose (~ Cmax), ANDEXXA or placebo was administered, n=13
  • Reduction in Anti-FXa Activity : Percent change from baseline in anti-FXa activity at its nadir was statistically significant (p < 0.0001) in favor of ANDEXXA

Ongoing multinational, prospective, single-arm, open-label study

  • ANDEXXA administered to patients taking FXa inhibitors who presented with acute major bleeding, n=185
  • Interim results : Median decrease from baseline to nadir was -93% for  apixaban and -90% for rivaroxaban


  • Boxed Warning: Arterial and venous thromboembolic events, ischemic events, including myocardial infarction and ischemic stroke, cardiac arrest, sudden deaths
  • Most common adverse reactions: Urinary tract infections, pneumonia, infusion-related reactions


  • Accelerated Approval based on change from baseline in anti-FXa activity in healthy volunteers; improvement in hemostasis has not been established
  • Continued approval may be contingent upon results of studies to demonstrate an improvement in hemostasis in patients



KYMRIAH (tisagenlecleucel)


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


  • Single-arm, open-label, multi-center, phase 2 trial, adults with relapsed or refractory DLBCL and DLBCL after transformation from follicular lymphoma
  • Treated with at least two prior lines of therapy, including an anthracycline and rituximab, or relapsed following autologous hematopoietic stem cell transplant
  • Single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy, n=68
  • Overall response rate (ORR):  50% (95% CI: 37.6, 62.4)
  • Complete response (CR) rate: 32% (95% CI: 21.5, 44.8)
  • Estimated median response duration among patients in PR: 3.4 months


  •  Most common adverse reactions: Cytokine release syndrome (CRS), infections-pathogen unspecified, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache. Because of the serious risks of CRS and neurologic toxicities
  • Has a Risk Evaluation and Mitigation Strategy (REMS)


  •  Priority review, Breakthrough Therapy designation, Orphan Product designation




Procept BioRobotics Corporation

INDICATION FOR USE: For the resection and removal of prostate tissue in males suffering from lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia


Personalized image-guided prostate tissue removal system that uses a high-velocity water jet to resect and remove a predetermined volume of tissue. Comprised of nine main components along with accessories

  • Conformal Planning Unit, Console, Motorpack, Roll Stand, Foot Pedal, Handpiece Articulating Arms, Articulating Arm, Handpiece, Scope

GENERIC DEVICE TYPE: Fluid jet system for prostate tissue removal.

Prescription device intended for the resection and removal of prostatic tissue for the treatment of benign prostatic hyperplasia (BPH). The device cuts tissue by using a pressurized jet of fluid delivered to the prostatic urethra. The device is able to image treatment area, or pairs with an imaging modality, to monitor treatment progress.


  • Prospective, multicenter, international double-blinded randomized clinical trial,   AQUABEAM vs. standard transurethral resection ofthe prostate (TURP)
  • Primary efficacy endpoint: Change in International Prostate Symptom Score (IPSS) at 6 months
  • Primary safety endpoint: Occunence of Clavien-Dindo persistent grade 1 or grade 2 or higher perioperative complications at 3 months
  • Mean IPSS scores: Decreased from 22.9 at baseline to 5.9 at 6 months with AQUABEAM vs. from 22.2 at baseline to 6.8 in TURP group
  • Clavien-Dindo grade 1 persistent or grade 2 or higher event: 25.0% in AQUABEAM vs, 40.0% in TURP


  • Injury from device operation: Clinical performance testing, Animal testing, Labeling, Training
  • Adverse tissue reaction: Biocompatibility evaluation
  • Infection: Sterilization validation, Reprocessing validation, Shelf life testing
  • Failure to remove target tissue or removal of nontarget tissue: Clinical performance testing, Animal testing, Software verification, validation, and hazard analysis, Non-clinical performance testing, Labeling
  • Electrical shock or electromagnetic interference: Electrical safety testing, Electromagnetic compatibility testing, Labeling


  • 21 CFR 876.4350
  • Regulation Name: Fluid jet system for prostate tissue removal
  • Regulatory Class: Class II
  • Product Code: PZP


Image credits: Unv. of Minnesota, Portola, Novartis, Procept


FDA News: Digital Health Approach, Advancing Health Equity, INFORMED,Treatments for Neurological Disorders, Science of Nanotechnology, Brain Injury Monitoring


Transforming FDA’s Approach to Digital Health

Remarks by Scott Gottlieb, M.D., Commissioner 
Academy Health’s 2018 Health Datapalooza
Washington, DC, April 26, 2018

Digital health tools have vast potential to

  • Improve ability to accurately diagnose and treat disease
  • Enhance delivery of health care for the individual
  • Make medical care truly patient centric — empowering the individual

Digital Health Innovation Action Plan

  •  New policy  to streamline path for digital health products with several functions
  • Draft of Working Model for precertification pilot program

Launch of Program to Apply Digital Health to Drugs

  • Expand opportunities to use digital health tools as part of drug development
  • Improve safety and effectiveness of drug delivery
  • Mobile devices and software linked to specific drugs for medication compliance
  • Advance policy framework and new guidance

Artificial Intelligence

  • New regulatory framework to support use of AI-based technologies
  • Understand connection between decision-making in traditional health care settings vs. use of advanced technologies
  • Appropriate guardrails for to deliver benefits  and meet safety /effectiveness stds
  • Make drug/device development more predictable, efficient, more reflective of patients’ real-world experience

Launch of a New Premarket Digital Safety Program

  • Launch of Premarket Digital Safety Program with unified data standard for electronic reporting requirements
  • New digital framework can significantly improve efficiency and accuracy of premarket safety submission and review process

Launch of FDA’s New Digital Health Incubator

  • Creation of an internal data science incubator – Information Exchange and Data Transformation (INFORMED)
  • Conduct of regulatory science research in health technology and cancer analytics
  • Collaboration with nonprofit open-access Project Data Sphere, to develop algorithms for classification of tumor dynamics
  •  Joint fellowship program with NCI to design and develop digital biomarkers as drug development tools


CaptureMission Possible: Moving the Needle Forward to Advance Health Equity

FDA’s Office of Minority Health (OMH) protects, promotes, advances public health of vulnerable and underrepresented populations

  • Conduct and fund research on diseases that disproportionately affect minorities
  • Diversify the public health workforce
  • Help minorities make better informed health decisions
  • Engage with minority-serving institutions of higher learning
  • Serve as a voice for those in need; rural health challenges, need for telemedicine

Partnering with private- and public-sector organizations (including VA, Yale University) to further equity on all fronts

  • Getting culturally sensitive messages out to minority communities
  • Ensuring minority representation in clinical trials

New Journal Article: Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs


CaptureInformation Exchange and Data Transformation (INFORMED)

Incubator for collaborative oncology regulatory science research

  • In collaboration with the U.S. Department of Health and Human Services’ Innovation, Design, Entrepreneurship and Action (IDEA) Lab
  • Focused on supporting innovations with expertise of a diverse group of oncologists, data scientists, statisticians, and entrepreneurs-in-residence
  • Big data analytics and modern approaches in evidence generation for regulatory decisions
  • Special emphasis on systems thinking in oncology regulatory science research t

Research portfolio

  • Use of real world data for clinical evidence generation. prospective pragmatic clinical trials
  • Utility of biosensors, IoT to quantify intrinsic and extrinsic factors influencing patient’s experience
  • Opportunities for machine learning and artificial intelligence to improve existing practices
  • Utility of open-access platforms and emerging technologies such as blockchain


CaptureAdvancing Development of Treatments for Neurological Disorders

Published five guidances for industry related to neurological conditions

Noteworthy aspects

  • Recent explosion of new scientific knowledge about nervous system.
  • Drug developers looking for clear paths to treatment solutions
  • Worked with patient advocacy organizations and scientists to ensure voices were heard
  • Streamlined internal review process  to encourage development of short, concise documents free of unnecessary background information

Stakeholder community engagement

  • Alzheimer’s disease (AD), Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), migraine, and epilepsy communities
  • Frequent conversations with multiple drug developers about their needs



Advancing Science of Nanotechnology in Drug Development

Steady increase in approved drug products containing nanomaterials

  • Including investigational new drugs, new drug applications, and abbreviated new drug applications (commonly known as generics)

Uniqueness of drug products containing nanomaterials

  • May take on different chemical, physical, or biological properties
  • May impact quality, safety, or efficacy
  • May follow a different pathway in the body compared to small molecule drug; reach areas typically difficult to reach for a small molecule

Research to Address Challenges Related to Nanotechnology

  • FDA’s Office of Testing and Research (OTR) conducting research on manufacturing and quality issues
  • Identifying critical processes and material properties that can impact quality within context of efficacy and safety
  • Evaluating drug’s performance and release from the nano carriers
  • Encourage use of advanced manufacturing techniques to reduce variations in product quality
  • Characterizing excipients in complex formulations

Draft guidance on Drug Products, including Biological Products, that Contain Nanomaterials



Biomarkers for Brain Injury Monitoring

FDA Center for Devices and Radiological Health (CDRH), Office of Science and Engineering Laboratories, Division of Physics

“We envision a day when soldiers or civilians who have experienced a blast or a head impact will be able to stick a small sensor to their forehead and know if they have sustained a brain injury. Although we may not be the ones who develop such a device, we want to contribute research that can help advance the field.” 

Recent  Scientific Advances

  • Fexible microelectronics that are wearable and conformable for portable electroencephalogram (EEG) technology
  • Use to detect brain injury in victims of traumatic events e.g. accidents, explosions
  • Need scientific knowledge base related to validated brain injury biomarkers and models

Research project on field-deployable devices to rapidly collect and evaluate EEG signals 

  • Detect Traumatic Brain Injury (TBI) rapidly and non-invasively
  • Create “smart sensors”  to for emergency responders to detect EEG signals rapidly
  • But lack of validated biomarkers and models of brain injury
  • This research focuses on developing useful brain injury models, identifying and validating brain injury biomarkers, and studying new EEG technologies


 Image credit: FDA



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

  • Complementary diagnostic test, FoundationFocusTM CDx BRCA LOH, for tumor samples to determine  homologous recombination deficiency (HRD) status.


  • Randomized, double-blind, n=561, with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, RUCAPARIB  vs. placebo
  • Tumor tissue samples examined with next-generation sequencing assay for deleterious somatic or germline BRCA mutation (tBRCA); also percentage of genomic loss of heterozygosity (LOH); positive (HRD) status was tBRCA-positive and/or LOH high
  • Median progression-free survival (PFS):  10.8 vs. 5.4 months, p<0.0001, 13.6 vs. 5.4 months (HRD, p<0,0001), 16.6 vs 5.4 months (tBRCA, p<0.0001)


  • Most common adverse reactions: Nausea, fatigue (including asthenia), abdominal pain/distension, rash, dysgeusia, anemia, ALT/AST elevation, constipation, vomiting, diarrhea, thrombocytopenia, nasopharyngitis/URI, stomatitis, decreased appetite, and neutropenia
  • Myelodysplastic syndrome and/or acute myeloid leukemia


  • Priority Review, completes initial accelerated approval commitments
  • Initial approval for  deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer



TAFINLAR (dabrafenib) and MEKINIST (trametinib)


INDICATION: TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with  BRAF V600E mutation and with no satisfactory locoregional treatment options


  • Anaplastic thyroid cancer (ATC) is rare, aggressive; accounts for about 1 to 2 percent of all thyroid cancers
  • First FDA-approved treatment for patients with specific gene mutation
  • Targeting same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients


  • Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway; used in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive tumor xenografts compared with either drug alone.


  • Open-label clinical trial, n=23, patients with rare cancers with the BRAF V600E mutation including ATC
  • Partial reduction in tumore size: 57%
  • Complete response: 4%
  • No significant tumor growths for six months or longer: 64%


  • Side effects consistent with those seen in other cancers when the two drugs are used together
  • Common side effect: Pyrexia, rash, chills, headache, arthralgia, cough, fatigue, nausea, vomiting, diarrhea, myalgia, dry skin, decreased appetite, edema, hemorrhage, hypertension, dyspnea
  • Severe side effects of Tafinlar: Development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia.
  • Severe side effects of Mekinist: Development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes.


  • Priority review, breakthrough therapy designation and orphan drug designation
  • Both Tafinlar and Mekinist previously approved for use in BRAF V600 mutation-positive metastatic melanoma, BRAF V600E mutation-positive, metastatic non-small cell lung cancer

Tafinlar LABEL

Mekinist LABEL 



PartoSure test

Parsagen Diagnostics, Inc., Harvard Innovation Launch Lab

INDICATION FOR USE:  Rapid, qualitative test for detecting the presence of placental alpha microglobulin 1 (PAMG-1) in cervicovaginal secretions.

Indicated as an aid to rapidly assess the risk of spontaneous preterm delivery in ≤ 7 days from the time of cervicovaginal sample collection in pregnant women with signs and symptoms of early preterm labor, intact amniotic membranes and minimal cervical dilatation (<3 cm), sampled between 24 weeks, 0 days and 34 weeks, 6 days gestation in women with a singleton gestation


  • Spontaneous preterm delivery difficult to reliably predict
  • This test aids assessment of spontaneous preterm delivery; improves upon
    prediction of not undergoing preterm delivery


  • Sterile, Vaginal Swab: Taking vaginal secretion
  • Vial with Extraction Solvent: Saline solution with solubilizer and dispersant (Triton X100) and preservative (sodium azide); extracts vaginal secretions from swab
  • Lateral Flow Test Strip: Lateral flow, immunochromatographic assay to identify    presence PAMG-1; goat anti-mouse monoclonal antibodies at test region to detect PAMG-1 and goat anti-mouse anti-immunoglobulin antibodies at control region to detect IgG


  • For spontaneous preterm delivery in ≤ 7 days from the time of cervicovaginal sample collection in singleton pregnant women with signs and symptoms of early preterm labor, intact amniotic membranes and minimal cervical dilation (<3 cm)
  • US Study: 6 preterm deliveries within 7 days from sample collection – 3 predicted and 3 missed, Sensitivity of 50%, Specificity of  98.4% (CI: 97.1% – 99.2%)
  • Retrospective Spain study: 18 spontaneous preterm deliveries- 9 predicted, 9 were missed, Sensitivity of 50%, Specificity of 95.9%


  • False negative: Mother could progress unanticipated spontaneous preterm delivery without corticosteroids
  • Increased risk or increased severity of respiratory distress syndrome, intracranial hemorrhage, necrotizing enterocolitis, and death compared with neonates whose mothers do receive antenatal corticosteroids.


  • Product Code: QBB
  • Test results should always be considered in conjunction with other clinical evaluation and diagnostic procedures
  • Post-approval studies required for additional data to verify safety and effectiveness



Cala ONE

Cala Health Inc.

INDICATION FOR USE:  To aid in the transient relief of hand tremors in the treated hand following stimulation in adults with essential tremor


  • Delivers individualized therapy that is calibrated by a physician using on-board sensors to measure the individual’s tremor
  • Therapeutic device can be worn all day to provide on-demand
    relief at home, in social settings, at work, or whenever patients desire relief.

GENERIC TYPE OF DEVICE: External upper limb tremor stimulator

  • Prescription device which is placed externally on the upper limb and designed to aid in tremor symptom relief of the upper limb


  • Randomized, controlled, multi-center study
  • Improvements in the treatment group in both physician and patient-rated measures of tremor severity compared to the sham group


  • Tissue damage due to overstimulation: Non-clinical performance testing
    Software verification, validation, and hazard analysis, Electrical safety testing
    Shelf life testing, Labeling
  • Adverse tissue reaction: Biocompatibility evaluation, Labeling
  • Electrical shock or burn:  Electrical, thermal, and mechanical safety testing
    Software verification, validation, and hazard analysis , Labeling
  • Interference with other devices: Electromagnetic compatibility (EMC) testing
    Software verification, validation, and hazard analysis, Labeling


  • Regulation Number: 21 CFR 882.5897
  • Regulation Name: External upper limb tremor stimulator
  • Regulatory Class: Class II
  • Product Code: QBC


Image Credits: Clovis, Novartis, Parsagen, Cala


FDA Guidances: Multiple Function Device Products, Pregnant Women in Clinical Trials, Atopic Dermatitis Pediatric Studies, PRO Tool for COPD, BIMO Inspection Information


Multiple Function Device Products: Policy and Considerations

Products with at least one device function are referred to as “multiple function device products.”

  •  Function : Distinct purpose of the product, which could be intended use or subset
  • Examples: One function: analysis or three functions: storage, transfer, analysis
  • Product may contain multiple functions
    • – may / may not meet definition of ‘device’
    • -meet definition of device, but not subject to premarket review
    • -meet definition of device, but no enforcement of  compliance with applicable regulatory controls  (enforcement discretion policy)
  • Applies to device constituent of combination product


  • No regulation if does not meet ‘device’ definition
  • However, when assessing safety and effectiveness, FDA may assess the
    impact of the other function.
    235 compliance with applicable requirements. In accordance with existing policies, FDA intends not
    236 to review a device function subject to an enforcement discretion policy merely because it is part


  • Separation in design and implementation of device function
  • Impact of other function(s)
  • Assessing impact of other functions on device function-under-review
    • Impact on safety or effectiveness
    • Result in increased risk or adverse effect on performance
    • Impacts to safety and effectiveness

Content of premarket submission for Device Function-Under-Review

  • Indications for Use, Description of Functions, Architecture and Design, Risk Analysis, Requirements and Specifications, Submission Summary



Pregnant Women: Scientific and Ethical considerations for Inclusion in Clinical Trials

Inclusion of pregnant women in drug development clinical trials 

  • For safe and effective treatment during pregnancy
  • Establish dose/dosing regimen, safety, and efficacy of treatments during pregnancy
  • Enrollment of pregnant women may offer direct benefit to woman and/or fetus
  • For accessible treatment options for pregnant population

Ethical Considerations

  • FDA Regulations That Govern Research in Pregnant Women
  • Research-Related Risks
  • General Guidelines for Including Pregnant Women in Clinical Trials

Other Considerations

  • Disease Type and Availability of Therapeutic Options in Pregnant Population
  • Timing of Enrollment
  • Pharmacokinetic Data
  • Safety Data Collection and Monitoring
  • Stopping a Clinical Trial That Enrolls Pregnant Women



Atopic Dermatitis: Timing of Pediatric Studies During Development of Systemic Drugs

Relevant age groups to study and how early in a pediatric Atopic Dermatitis (AD) drug development

  • AD is chronic pruritic inflammatory skin disease primarily affecting pediatric patients
  • Based on input received Dermatologic and Ophthalmic Drug Advisory Committee


  • Base on labeling information on relevant pediatric populations and safe and effective use
  • Initiate early in development, typically after obtaining initial evidence of efficacy and safety from early phase adult studies
  • Discuss specifics as early as is feasible with FDA to submit pediatric study plans
  • Consider juvenile animal toxicity study with appropriate endpoints
  • Not generally necessary to have extensive adult safety database
  • Study all relevant age groups, including children < 2 yo



Chronic Obstructive Pulmonary Disease: Use of the St. George’s Respiratory Questionnaire (SGRQ) as a PRO Assessment Tool

Use of St. George’s Respiratory Questionnaire (SGRQ), a patient reported outcome measure (PRO) assessment tool for interventional clinical trials in COPD
  • COPD is chronic progressive disease caused by chronic inflammation and destruction of airways and lung parenchyma
  • Usually associated with tobacco smoking or prolonged exposure to other noxious particles and gases
  • SGRQ measures health status in patients with obstructive airway diseases
PRO assessment of efficacy
  • Use for stratification or enrichment purposes in protocol development phase.
  • Use as coprimary endpoint or as secondary endpoint
  • Clinically important and sponsor should report clinical trial data irrespective of  direction of results
Considerations for SGRQ
  • Use current version from St. George’s University of London Health Status Research website at
  • Administration
  • Scoring
  • Method of Analysis
  • Use of the SGRQ
Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions
To plan BIMO inspections for timely identification of inspection sites and provide information to FDA -ORA investigators 
  •  Clinical Study-Level Information
  • Comprehensive table listing all participating clinical sites
  • Table listing all entities with contracted clinical study-related activities
  • Protocol, protocol amendments, annotated Case Report Form(s)
  • Subject-level data line listings by clinical site
  • Summary-level clinical site dataset








Aug 13-14: Public Meeting – Pediatric Medical Device Development. Identify strategies that enhance medical device ecosystem toward development and innovation of devices that serve the complex needs of children. INFORMATION


Jul 9:  Public Meeting for Patient Focused Drug Development for Chronic Pain. Hearing patients’ perspectives on chronic pain, treatment approaches, challenges or barriers to accessing treatments and managed with opioids, acetaminophen, NSAIDs, antidepressants, non-pharmacologic interventions or therapies.INFORMATION


Jun 19-20: FDA/IMSN Summit with international drug regulators to discuss medication safety issues. Discussion among international drug regulators on medication safety issues with regulated pharmaceutical products and how to minimize medication errors with labeling and packaging. INFORMATION

Jun 22: Clinical Outcome Assessments (COAs) in Cancer Clinical Trials. Discussion between academia, industry, international regulatory, HTA bodies, and patient groups to advance measurement of the patient experience in cancer clinical trials; characteristics of PRO measurement tools, standardize PRO data analysis, FDA approaches to PRO data review. INFORMATION

Jun 25-26: 2018 Center for Biologics Evaluation and Research Science Symposium. Discuss scientific topics related to the regulation of biologics and highlight science conducted at CBER by showcasing how scientific research informs regulatory decision making and to provide a forum for developing collaborations within FDA and with external organizations.


May 2: Antimicrobial Drugs Advisory Committee Meeting. Discuss NDA for plazomicin, sponsored by Achaogen for proposed indications for treatment of complicated urinary tract infections & blood stream infections in adults  INFORMATION

May 3: Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Pediatric Advisory Committee Meeting. Discuss NDA for stannsoporfin injection, submitted by InfaCare, proposed for treatment of neonates with indicators of hemolysis who are at risk of developing severe hyperbilirubinemia INFORMATION

May 4: Annual Public Meeting; Reagan-Udall Foundation for the FDA. FDA Commissioner Scott Gottlieb as keynote speaker; discuss activities and how it supports FDA; panel discussion on “Evolution of FDA Science and Engagement.” INFORMATION

 ⊕ May 8: FDA Drug Topics: Protecting Patients – Pharmacists Requirements under the Drug Supply Chain Security Act. FDA’s Division of Drug Information in the Center for Drug Evaluation and Research (CDER) is presenting a series of continuing education webinars targeting the needs of all health care professionals. INFORMATION

May 8: CBER Update: Office of Vaccine Research and Review Data Submission. Update on best practices INFORMATION

May 9: Tissue Agnostic Therapies: Regulatory Considerations for Orphan Drug Designation; Public Workshop. Discuss factors when evaluating drugs for orphan designation that treat tissue agnostic disease or condition in oncology, additional factors related to orphan exclusivity when approving such a product INFORMATION

⊕ May 10: User Session – Digital Health Software Precertification (Pre-Cert) Pilot Program. Interactive session to discuss progress on Software Precertification Pilot Program, working model, key program areas, questions for public input.  INFORMATION

May 10: FDA Grand Rounds spotlights stakeholder opportunities in FDA predictive toxicology roadmap. Framework for integrating novel predictive toxicology methods into safety and risk assessments of its products. INFORMATION

May 10: Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Discuss NDA for volanesoren solution for subcutaneous injection, Akcea Therapeutics, Inc, for use as an adjunct to diet for the treatment of patients with familial chylomicronemia syndrome. INFORMATION

May 11: Medical Gas Workshop III. Provide opportunity for medical gas manufacturers and public to provide input on potential areas of Federal drug regulation that should be revised with respect to medical gases.  INFORMATION

May 15-16: FDA Regulatory Education for Industry (REdI). FDA-led forum that brings together the regulatory educators from FDA’s CDER and CDRH. Meeting Information

May 17:  Webinar: Pioneering Modeling Methodologies in Generic Drug Development. Discuss novel ways FDA is approaching the use of quantitative methods and modeling for development and demonstration of generic samenessINFORMATION 

May 18: MDIC workshop on Patient-Centered Clinical Trial Design. Method for incorporating patient preference information to set significance levels in clinical trial design. Focus on Parkinson’s disease; may be generalizable to other diseases.  In collaboratorion with FDA (CDRH), MIT, RTI Health Solutions and Michael J. Fox Foundation. INFORMATION

May 22: Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee.  Discuss NDA for buprenorphine sublingual spray, by INSYS, for the treatment of moderate-to-severe acute pain where the use of an opioid analgesic is appropriate INFORMATION

May 22-23: Accreditation Scheme for Conformity Assessment (ASCA) of Medical Devices to Food and Drug Administration-Recognized Standards; Public Workshop.  Discuss draft design of pilot program, including goals and scope, framework, requirements, and streamline standards. INFORMATION

May 24: FY 2018 Generic Drug Research Public Workshop.  Provide overview of regulatory science initiatives for generic drugs and public input on research priorities INFORMATION


Apr 3: Public workshop: CDER and You: Keys to Effective Engagement. Share information with stakeholders including patients, patient advocates, academic and medical researchers, health care professionals, drug developers. Share unique perspectives on drug development and safety. INFORMATION

Apr 6: US FDA and Health Canada: Joint Regional Consultation on the ICH. To provide information and receive comments on the current ICH activities as well as the upcoming meetings in Kobe, Japan INFORMATION

Apr 10: FDA Drug Topics: An Introduction to Drug Safety Surveillance and the FDA Adverse Event Reporting System. Introduce the many phases of drug safety surveillance from the earliest stages of drug development through post approval, and will focus on how FDA conducts pharmacovigilance, develops safety signals, and communicates our findings.INFORMATION

Apr 11-12: CDER Small Business and Industry Assistance Regulatory Education for Industry (REdI): Generic Drugs ForumInteract with FDA subject matter experts  on Generic Drug Review Program, program progress, current initiatives. INFORMATION

Apr 16: Evaluating Inclusion and Exclusion Criteria in Clinical Trials; Public Meeting. Discuss topics related to eligibility criteria in clinical trials and their potential impact on patient access to investigational drugs, and how to facilitate the enrollment of a diverse patient population. INFORMATION

Apr 16: Public Workshop: Study Design Considerations for Devices including Digital Health Technologies for Sleep Disordered Breathing (SDB). Appropriate design of clinical studies to evaluate devices including digital health technologies intended for the diagnosis, monitoring, or treatment of SDB INFORMATION

Apr 16-18: 2018 AAPS Workshop on Drug Transporters in ADME: From Bench to Bedside. Present next generation of transporters and transport mechanisms that may contribute to ADME properties of drugs in disease states considered in drug discovery and development. INFORMATION 

Apr 17: Public Meeting on Patient-Focused Drug Development for Opioid Use Disorder (OUD). To learn patients’ perspectives on OUD, effects on health and well-being, experience using prescription medical treatments and other treatments, challenges or barriers to accessing medical treatments for OUD. INFORMATION

Apr 19: Peripheral and Central Nervous System Drugs Advisory Committee Meeting Discuss NDA for cannabidiol oral solution, GW Pharmaceuticals, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older. INFORMATION

Apr 20: FDA/OCE Public Meeting on Relevant Molecular Targets in Pediatric Cancers: Applicability to Therapeutic Investigation FDARA 2017. Discuss provisional list of molecular targets for adult cancer indications but also relevant to cancer in children thereby providing a rationale for early pediatric evaluation. INFORMATION

Apr 21: Public Meeting on Electronic Submissions and Data Standards. Discuss current status of electronic submissions and data standards initiatives to improve predictability and consistency of electronic submissions process in support of human drug review program. INFORMATION

Apr 23: Arthritis Advisory Committee Meeting. Discuss NDA for baricitinib tablets, submitted by Eli Lilly and Company, for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. INFORMATION

Apr 23-25: 12th Annual FDA/DIA Biostatistics Industry and Regulator Forum. Discuss relevant statistical issues associated with the development and review of therapeutic drugs and biologics. INFORMATION

Apr 30Public Workshop – Orthopaedic Sensing, Measuring, and Advanced Reporting Technology (SMART) Devices. Enhance engagement with stakeholders to facilitate device development and to discuss scientific and regulatory challenges associated with Orthopaedic SMART Devices.   INFORMATION


Mar 1: Vaccines and Related Biological Products Advisory Committee Meeting. Hear  research program in the Laboratory of Mucosal Pathogens and Cellular Immunology (LMPCI), Division of Bacterial, Parasitic and Allergenic Products (DBPAP), Office of Vaccines Research and Review (OVRR), and discuss selection of strains to for vaccines for the 2018-2019 influenza season INFORMATION

Mar 1: 21st US-Japan Cellular and Gene Therapy Conference. Exchange ideas on cutting edge and diverse areas of biomedical research, and enhance opportunities for collaborations among scientists from the US and Japan.  INFORMATION

Mar 1: Neurological Devices Panel  Advisory Committee Meeting. Discuss safety and effectiveness of intracranial aneurysm treatment devices and factors affecting clinical outcomes such as aneurysm morphology, size, and location in the neurovasculature. INFORMATION

Mar 1-2: IASLC-FDA Lung Cancer Neoadjuvant Meeting.Discuss standardization and validation of endpoints in neoadjuvant lung cancer trials. INFORMATION

Mar 4-6: FDA-PhUSE Computational Science Symposium. Review progress on topics such as data standards, best-practices-driven analytical tool development, business processes for information systems, evaluation of current tools. INFORMATION

Mar 5: Risk Communication Advisory Committee Meeting. Committee will discuss  impact of pregnancy and lactation labeling information in prescription drug and biological products as modified under the Pregnancy and Lactation Labeling Rule.  INFORMATION

Mar 8: FDA Grand Rounds:  Stem cell-based cellular therapies. Use of stem cell-based products is new and characterizing the product still faces hurdles.  FDA conducting research into identifying cell therapy product characteristics that will predict the reliably of the performance of cell-based therapies in humans. INFORMATION

 Mar 8: Gastrointestinal Drugs Advisory Committee Meeting. Discuss sNDA for XELJANZ (tofacitinib) proposed for the treatment of adult patients with moderately to severely active ulcerative colitis. INFORMATION

Mar 8: Public Workshop: Safety Assessment for Investigational New Drug Safety Reporting. Engage external stakeholders in discussions related to finalizing the draft guidance entitled “Safety Assessment for IND Safety Reporting.” INFORMATION

Mar 15: Oncology Center of Excellence Listening Session; Solicit comments regarding what stakeholders desire of the OCE in terms of structure, function, regulatory purview, and activity. INFORMATION

Mar 20: Promoting the Use of Complex Innovative Designs (CID) in Clinical Trials. March 20, 2018. Discuss use of CID in drug development and regulatory decision making, CID pilot program. INFORMATION

Mar 21-22: Joint Meeting of the Blood Products Advisory Committee and the Microbiology Devices Panel. Discuss reclassification from Class III to Class II of nucleic acid and serology-based point-of-care and laboratory-based in vitro diagnostic devices indicated for use as aids in the diagnosis of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection.⊕ INFORMATION

Mar 22: Webinar – Duodenoscope Sampling and Culturing. FDA, CDC, ASM and other endoscope culturing experts will review the voluntary duodenoscope surveillance sampling and culturing protocols to monitor quality of reprocessing procedures.  INFORMATION

Mar 22:  Patient Engagement in the National Evaluation System for health Technology (NEST): Lessons Learned and Best Practices Workshop.  Gather lessons learned and best practices for patient engagement in evidence generation (planning, collection of data and information, analysis, and dissemination). INFORMATION

Mar 22: Pediatric Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee Meeting. To discuss major objectives of Phase 3 drug development program for treatment of children with achondroplasia (ACH) submitted by BioMarin Pharmaceutical Inc. INFORMATION

Mar 23: Advisory Committee Meeting: Pediatric. Discuss the following products for CDER – BANZEL, INTUNIV, LEXAPRO and CDRH – FLOURISH, ACTIVA, LIPOSORBER, IMPELLA RP SYSTEM. INFORMATION

Mar 26-28: Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics for Alcoholic Hepatitis and Alcohol Associated Liver Disease and Pediatric Irritable Bowel Syndrome and Pediatric Functional Constipation Workshop, Facilitate dialogue among industry, academia, and other stakeholders on common data elements needed to be included in clinical trials, clinical trial designs, potential surrogate and clinical benefit endpoints, and practical issues with managing clinical trials.  INFORMATION

Mar 27: Meeting of the Psychopharmacologic Drugs Advisory Committee. Discuss  NDA for  lofexidine hydrochloride, US WorldMeds, LLC, for mitigation of symptoms associated with opioid withdrawal and facilitation of completion of opioid discontinuation treatment. INFORMATION

Mar 28: Promoting the Use of Complex Innovative Designs in Clinical Trials
Inform development of guidance document and CID pilot program. INFORMATION


Feb 1: FDA-ISoP Public Workshop: Model Informed Drug Development (MIDD) for Oncology Products. Discuss integrating human pharmacokinetic, pharmacodynamic, efficacy, safety data into models, use of  novel imaging techniques, diagnostic, predictive biomarkers, shift from traditional endpoints,  regulatory implications.  INFORMATION

Feb 7-8: 10th Annual Sentinel Initiative Public Workshop.  Bring stakeholder community together to discuss a variety of topics on active medical product surveillance. INFORMATION

Feb 14-15:  Joint Drugs Advisory Committee Meeting: Anesthetic and Analgesic Products and Drug Safety and Risk Management. Discuss NDA for HYDEXOR, for the short-term management of acute pain severe enough to require an opioid analgesic while preventing and reducing opioid-induced nausea and vomiting. Also discuss sNDA  for EXPAREL (bupivacaine liposomal injectable suspension) to produce local analgesia and as a nerve block to produce regional analgesia. INFORMATION

Feb 22-23: FDA-AACR-ASTRO Regulatory Science and Policy Workshop – Clinical Development of Drug-radiotherapy Combinations. Address the lack of drug development for products intended specifically for use with radiation therapy.   INFORMATION

Feb 27:  Webinar – Custom Device Annual Reporting. Custom Device Exemption allows manufacturers to market medical devices designed to treat a unique pathology or physiological condition without premarket approval. Webinar to discuss custom device annual report requirement. INFORMATION

Feb 28: Public Meeting: Enhanced Drug Distribution Security under the Drug Supply Chain Security Act.Provide members of the drug distribution supply chain and other interested stakeholders an opportunity to discuss strategies and issues related to the enhanced drug distribution security provisions of the Act. INFORMATION


Jan 8: CLIA Waiver Applications Draft Guidance Documents. Discuss draft guidances on CLIA waiver applications and Dual 510(k) and CLIA waivers INFORMATION

Jan 9:  Webinar – Pediatric Information for X-ray Imaging Device Premarket Notifications:  Discuss final guidance on radiation safety of pediatric populations in the design of X-ray imaging devices. INFORMATION

Jan 10:  Webinar – Technical Considerations for Additive Manufactured Medical Devices. Technical aspects associated with AM processes, recommendations for device design, manufacturing, testing considerations. INFORMATION

Jan 11: Public Workshop – Self-Collection Devices for Pap Test. Obtain feedback on feasibility, benefits, risks for self-collection cervical sampling devices for cervical cancer screening by Pap testing INFORMATION

Jan 11:  Safety Assessment for IND Safety Reporting.Convened by the Duke-Robert J. Margolis Center for Health Policy at Duke University and FDA; to bring stakeholder community together to discuss IND safety topics INFORMATION

Jan 11: FDA Grand Rounds. Marker of brain injury increased in African Americans with Alzheimer’sBetter understanding of ethnicity and gender differences involved in the cause and progression of Alzheimer’s Disease could contribute to better drugs–and other types of interventions–to slow Alzheimer’s progression INFORMATION

Jan 16:  Webinar – FDA Categorization of Investigational Device Exemption (IDE) Devices to Assist the Centers for Medicare and Medicaid Services (CMS) with Coverage Decisions. Discuss final guidance on FDA categorization of IDE devices that is used by CMS to determine whether an IDE device, and certain related services, may be covered by CMS. INFORMATION

Jan 26: Evaluating Nicotine Replacement Therapies. Public comments on FDA’s approach to evaluating the safety and efficacy of nicotine replacement therapy (NRT) products, including how they should be used and labeled. INFORMATION

Jan 29: Weighing the Evidence: Variant Classification and Interpretation in Precision Oncology. To discuss how genetic sequencing data is best implemented in patient management to advance innovative regulatory strategies to support development of safe and effective precision-based drugs and devices. INFORMATION

Jan 30: Opioid Policy Steering CommitteePrescribing Information  Receive stakeholder input on how FDA REMS authority, might improve the safe use of opioid analgesics by curbing over-prescribing to decrease the occurrence of new addictions and limit misuse and abuse INFORMATION

Jan 30-31: Fostering Digital Health Innovation. Developing the Software Precertification Program. Discuss progress of pilot precertification program and seek input on ongoing development of the Software Precertification Program. INFORMATION

Image credit: FDA

FDA Market Authorization: CRYSVITA, TAVALISSE, MALDI Biotyper, CARDIOFORM Septal Occluder, GUARDIAN Connect System 


CRYSVITA (burosumab-twza) injection

Ultragenyx Pharmaceutical, Inc.

INDICATION:  Treatment of X-linked hypophosphatemia (XLH) in adult and pediatric
patients 1 year of age and older.


  • XLH, a rare, inherited form of rickets, affects ~ 3,000 children and 12,000 adults in US
  • XLH differs from other forms of rickets in that vitamin D therapy is not effective
  • First drug approved to treat adults and children ages 1 year and older with XLH 

MECHANISM OF ACTION: Binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.


  • 65 pediatric patients and 134 adults with XLH in 4 studies, CRYSVITA vs, placebo,
  • Achievement of normal phosphorus levels: Adults: 94% adults vs. 8%, Children: 94-100%
  • Improved radiographic evaluation of rickets vs.  natural history cohort: In both children and adults,


  • Most common adverse reactions: Back pain, headache, restless leg syndrome, decreased vitamin D, dizziness and constipation
  • Most common adverse reactions in children: Headache, injection site reaction, vomiting, decreased vitamin D and pyrexia


  • Orphan designation, Breakthrough therapy designation
  • Pediatric Priority Review Voucher granted
  • Exempt from required pediatric assessments
  • Postmarketing requirements: Post-approval surveillance program with safety objectives, lactation sub-study in lactating women ,  reanalyze banked immunogenicity serum samples

REIMBURSEMENT PATHWAY: For rare disease indication

  • Covered with limited issue in Medicaid and Medicare
  • However, increased scrutiny of rare disease therapies and evolution of
    precision medicine; need to articulate long-term benefit of early
    diagnosis and treatment to patient and the health care system



TAVALISSE (fostamatinib disodium hexahydrate) tablets

Rigel Pharmaceuticals, Inc.

INDICATION: Treatment of thrombocytopenia in adult patients with chronic immune
thrombocytopenia (ITP) who have had an insufficient response to a previous treatment


  • Two identical, double-blind, placebo-controlled trials, n=150,  patients with persistent or chronic ITP who had an insufficient response to previous treatment, TAVALISSE vs. placebo
  • Endpoint: Stable platelet response (at least 50 x109/L on at least 4 of the 6 visits between Weeks 14 to 24)
  • Study 1: 18% (n=9) vs, 0% (p=0.03)
  • Study 2: 16% (n=8) vs. 4% (n=1), (p=0.26)
  • Study 3: Stable response in 23% (n=10)
  • Durable platelet responses seen


  • Most common adverse reactions: Diarrhea, hypertension, nausea, dizziness, alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased, respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia
  • Serious adverse drug reactions: Febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis


  • Orphan desugnation
  • Postmarketing commitmenets: Quality assessments



MALDI Biotyper CA System

Bruker Daltonik GmbH

INDICATION FOR USE: Mass spectrometer system using matrix-assisted laser
desorption/ionization – time of flight (MALDI-TOF) for the identification and differentiation of microorganisms cultured from human specimens.

The MALDI Biotyper CA System is a qualitative in vitro diagnostic device indicated for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of bacterial and fungal infections – particularly  Candida auris (C. auris)


  • Emerging pathogen Candida auris (C. auris) can cause serious infections in hospitalized patients
  • Can cause serious infections in hospitalized patients (e.g., bloodstream infections) and is frequently resistant to multiple antifungal drugs used to treat Candida infections.

GENERIC DEVICE TYPE:  Clinical mass spectrometry microorganism identification and differentiation system

  • Qualitative in vitro diagnostic device intended for the identification and differentiation of microorganisms from processed human specimens. The system acquires, processes, and analyzes spectra to generate data specific to microorganism(s). The device is indicated for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of bacterial and fungal infection.


  • Evaluated use of a standard protocol for adding C. auris to system database in conjunction with the performance data of 28 C. auris isolates (samples)
  •  C.auris isolates obtained from various culture collections, including the U.S. Centers for Disease Control and Prevention’s and FDA’s Antibiotic Resistance Isolate Bank.
  • System can reliably identify C. auris 100% of the time


  • Incorrect identification or lack of identification of a pathogenic microorganism: Special Controls
  • Failure to correctly interpret test results: Special Controls
  • Failure to correctly operate the instrument: Special Controls


  • Add to cleared uses for identification of 333 species or species groups, covering 424 clinically relevant bacteria and yeast species
  • Regulation Number: 21 CFR 866.3378
  • Regulation Name: Clinical Mass Spectrometry Microorganism Identification and Differentiation System
  • Regulatory Class: Class II
  • Product Code: QBN



GORE® CARDIOFORM Septal Occluder

W. L. Gore and Associates, Inc.

SUPPLEMENTAL INDICATION FOR USE: Permanently implanted device indicated for the percutaneous, transcatheter closure of the following defects of the atrial septum:

  • ostium secundum atrial septal defects (ASDs)
  • patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke.


  • Implant (occluder) and delivery catheter (a small tube)
  • Occluder made of self-expanding, nickel-titanium (Nitinol) wires, covered in woven fabric
  • Occluder shaped as two discs connected in the cente
  • Occluder compressed to a small size to allow it to pass through the delivery catheter for implantation


  • Prospective, randomized (2:1), open-label, multi-center study, n=664, antiplatelet medical management and PFO closure with the GORE® CARDIOFORM Septal Occluder vs. antiplatelet medical management alone
  • Co-primary endpoints: Freedom from recurrent stroke and incidence of new brain infarction. PFO closure was associated with a statistically significant
    77% relative risk reduction in recurrent stroke
  • PFO closure was also associated with  a statistically significant 49% relative risk reduction in incidence of new brain infarction


  • No significant difference in overall rate of SAEs between the control (medical management) and device groups
  • Low rate of device- or procedure-related SAEs (3.6%)
  • Subjects had a higher incidence of atrial fibrillation or flutter (6.6%), but were non-serious
  • No device- or procedure related deaths.


  • For expanding the indications to include closure of the patent foramen
    ovale (PFO) to reduce the risk of recurrent ischemic stroke
  • Product Code: MLV
  • Postapproval studies: Safety through 5 years post-procedure, acute, subacute, and longterm safety and effectiveness


  • Approved CMS IDE study
  • Partnership with CODING STRATEGIES (an independent industry-leading resource in coding, coverage, and reimbursement education)



GUARDIAN Connect System 

Medtronic MiniMed, Inc.

INDICATION FOR USE: For continuous or periodic monitoring of glucose levels in the interstitial fluid under the skin, in patients (14 to 75 years of age) with diabetes mellitus.

Provides real-time glucose values and trends through a Guardian Connect app installed on a compatible consumer electronic mobile device. It allows users to detect trends and track patterns in glucose concentrations. The Guardian Connect app alerts if a Guardian Sensor (3) glucose level reaches, falls below, rises above, or is predicted to surpass set values.

The Guardian Sensor (3) glucose values are not intended to be used directly for making
therapy adjustments, but rather to provide an indication of when a finger stick may be
required. All therapy adjustments should be based on measurements obtained using a
home glucose monitor and not on values provided by the Guardian Sensor (3).


  • Provides real-time glucose values and trends through a Guardian Connect app installed on a compatible mobile device platform (e.g., iPhone or iPad)
  • Guardian Connect app is a mobile medical application that allows users to track patterns in glucose concentrations and to possibly identify episodes of low and high glucose
  • System is designed to provide continuous glucose monitoring for up to seven days
  • System consists primarily of a sensor, transmitter, and mobile medical app


  • Evaluate the performance of the Guardian Sensor (3) to support 7 days of use
  • Missed alerts and false negative hypoglycemia and hyperglycemic readings related to patients not being alerted to the need to perform a fingerstick to detect hypoglycemia or hyperglycemia


  • Device Procode: MDS
  • The Guardian Sensor (3) used with the Guardian Connect system is the same as the
    Guardian Sensor (3) used with the MiniMed 670G System (P160017) and the iniMed
    630G System (P150001/S008), which were previously approved


  • Continuous Glucose Monitors are reimbursed by CMS




FDA News: Predictive Toxicology Roadmap, 2019 FDA Budget, Medical Device Safety Action Plan, Opioid Use Disorder Treatments, Drug Safety Priorities


Predictive Toxicology Roadmap

Significant steps by FDA to upgrade toxicology toolboxes

  • Expand toxicology predictive capabilities
  • Potentially reduce the use of animal testing

Goals of roadmap for integrating predictive toxicology methods into safety and risk assessments

  • Develop and evaluate emerging toxicological methods and new technologies
  • Incorporate these methods and technologies into regulatory review



Remarks from FDA Commissioner Scott Gottlieb, M.D. on Fiscal Year 2019 budget request for FDA

President’s 2019 Budget request for $5.8 billion in total resources for FDA

  • Includes $190 million in user fees
  • Requests new FDA resources to advance science, domestic technology, public health
  • Advance new paradigm in regulation of digital health technology
  • Advanced manufacturing to bring more production back to US
  • Improve ability to respond to public health emergencies like flu
  • Modernize generic drug review
  • New approaches for treatments for rare pediatric diseases

Build knowledge management platform for drug and medical device review programs

  • Store and manage collected experience of review staff
  • Essential to modernizing medical product review and establish scientific precedents
  • Issue guidances documents focused on specific diseases using efficient approaches


CaptureMedical Device Safety Action Plan: Protecting Patients, Promoting Public Health

Outlines how Agency will encourage innovation to improve safety, detect safety risks earlier, and keep doctors and patients better informed

  • Robust medical device patient safety net
  • Regulatory options to streamline and modernize timely implementation of postmarket mitigations
  • Innovation towards safer medical devices
  • Advance medical device cybersecurity
  • Integrate premarket and postmarket offices and use of a Total Product Life Cycle (TPLC) approach to device safety


CaptureNew steps to encourage more widespread innovation and development of new treatments for opioid use disorder

Encouraging more widespread innovation and development of medication for use in medication-assisted treatments (MAT)

  • Three FDA-approved MAT drugs – methadone, buprenorphine and naltrexone
  • Facilitate development of new MAT products, and new formulations of existing drugs

FDA issued draft guidance: Opioid Dependence: Developing Buprenorphine Depot Products for Treatment

  • Drug development and trial design issues
  • Possible ways for innovations in buprenorphine products
  • Use of 505(b)(2) regulatory pathway for product development programs
  • Develop validated measurement of “craving” or “urge to use” illicit opioids



2017 Drug Safety Priorities

CDER’s efforts to enhance drug safety for the American public

  • Safety surveillance and oversight of marketed drug products 7,446 safety reviews
  • Importance of real-world evidence to help advance drug safety science: New scientific computing and data storage technologies to gain valuable information from “real world evidence.”
  • New tools and new approaches for fighting our Nation’s opioid crisis: To 1) decreasing exposure and preventing new addiction, 2) safely treating those with opioid addiction, 3) developing safe and effective novel alternative therapies to opioids, 4) improving enforcement of safety measures and assessing benefit-risk ratios.
  • Safety oversight for generic drugs: Flag early safety concerns
  • Efforts to reduce preventable harm from medications: Safe Use Initiative
  • Compounded drugs – continuing regulatory and oversight efforts: Conducted 140 inspections, sent 55 warning letters, and issued 40 recalls related to compounding.
  • Diverse strategies, tools, and services for communicating drug safety: Responded to 57,094 inquiries from the public


Image credit: FDA

Market Authorizations: ACUVUE OASYS Light Adaptive Contact Lens, IDx-DR retinal diagnostic software, OCS Lung System

Capture.JPGAcuvue Oasys Contact Lenses with Transitions Light Intelligent Technology 

Johnson & Johnson Vision care

USE: Soft Contact lenses that automatically darkens the lens when exposed to bright light. Indicated for daily use to correct the vision of people with non-diseased eyes who are nearsighted (myopia) or farsighted (hyperopia).

ADDRESSING UNMET NEED:  First contact lens to incorporate the same technology that is used in eyeglasses that automatically darken in the sun


  • Contains photochromic additive that adapts the amount of visible light filtered to the eye based on the amount of UV light to which they are exposed
  • Results in slightly darkened lenses in bright sunlight that automatically return to a regular tint when exposed to normal or dark lighting conditions. 


  • Clinical study of 24 patients that evaluated daytime and nighttime driving performance while wearing the contact lenses
  • No evidence of concerns with either driving performance or vision while wearing the lenses
  • May cause inflammation or infection in or around the eye or eyelids 


  • Classification: II
  • Regulation No. : 886.5925
  • Classification Product Code: LPL
  • Subsequent Product Code: MVN


  • Medicare provides limited coverage for contact lenses under Medicare Vision Services
  • Acuvue Brand covered by private payors


IDx-DR Retinal diagnostic software device


INDICATION FOR USE: For use by health care providers to automatically detect more than mild diabetic retinopathy (mtmDR) in adults diagnosed with diabetes who have not been previously diagnosed with diabetic retinopathy. IDx-DR is indicated for use with the Topcon NW400.


  • Diabetic retinopathy is the most common cause of vision loss among the more than 30 million Americans living with diabetes
  • Leading cause of vision impairment and blindness among working-age adults
  • First medical device to use Artificial Intelligence (AI) to detect greater than a mild level of the eye disease diabetic retinopathy in adults who have diabetes


  • Software program using AI to analyze eye images taken with retinal camera, Topcon NW400
  • Doctor uploads digital images of retinas to cloud server with IDx-DR software
  • Software provides doctor with one of two results
    1. “more than mild diabetic retinopathy detected: refer to an eye care professional”
    2. “negative for more than mild diabetic retinopathy; rescreen in 12 months.”
  • If positive result – further diagnostic evaluation and possible treatment as soon as possible

GENERIC DEVICE TYPE: Retinal diagnostic software device.

Prescription software device that incorporates an adaptive algorithm to evaluate ophthalmic images for diagnostic screening to identify retinal diseases or conditions.


  • Clinical study of retinal images, n=900 patients with diabetes, 10 primary care sites
  • Correctly identify presence of more than mild diabetic retinopathy: 87.4%
  • Correctly identify patients who did not have more than mild diabetic retinopathy: 89.5%


  • False positive results leading to additional unnecessary medical procedures (Diagnostic algorithm failure, Software failure): Clinical performance testing;
    Software verification, validation, and hazard analysis; Protocol for technical specification changes
  • False negative results leading to delay of further evaluation or treatment
    (Diagnostic algorithm failure, Software failure): Clinical performance testing
    Software verification, validation, and hazard analysis; Protocol for technical specification changes; Labeling
  • Operator failure to provide images that meet input quality specifications: Labeling,
    Training, Human factors validation testing


  • Regulation No.: 21 CFR 886.1100
  • Regulation Name: Retinal diagnostic software device
  • Regulatory Class: Class II
  • Product Code: PIB


  • AI diagnostic approach could support CMS’ value-based reimbursement



Organ Care System (OCS) Lung System

TransMedics, Inc.

INDICATION FOR USE:  Portable organ perfusion, ventilation, and monitoring medical device indicated for the preservation of standard criteria donor lungs in a near physiologic, ventilated, and perfused state for double lung transplantation.


  • Lung Console: Non-sterile, reusable, portable enclosure housing electronic display and non-sterile mechanical/electrical elements to warm, pump, ventilate, and manage gas content of perfusate
  • Lung Perfusion Set (LPS): Sterile, single-use perfusion module, organ chamber and circulatory system to perfuse and ventilate lung,  facilitate management of fluids
  • OCS™ Lung Solution: High oncotic solution used for ex-vivo flush and perfusion of donor lungs when combined with packed red blood cells (pRBCs)


  • Randomized, controlled, multi-center, international, prospective
    clinical trial, OCS™ Lung System vs. current cold storage standard of care (SOC), n=407
  • Primary Graft Dysfunction (PGD) grading,  including reduced survival and
    increased incidence of Bronchiolitis Obliterans Syndrome (BOS)
  • Patient survival at day 30 post-transplantation and ISHLT PGD3 within 72 hours post-transplantation
  • No-inferiority vs. SOC, longer-term (2-year) survival and BOS rates comparable
  • Similar lung graft-related serious adverse events (LGRSAEs) through 30 days post-transplantation


  • Class III, Product Code: QBA
  • Priority Review
  • Gastroenterology-Urology Devices Panel Meeting: Voted 11-2 that there is reasonable assurance the device is safe, 8-5 that there is reasonable assurance that the device is effective, and 9-4 that the benefits of the device do outweigh the risks
  • Post-approval studies : Long-term patient outcomes, OCS Lung Thoracic Organ Perfusion (TOP) PAS Registry


Image credit: J&J, IDX, TransMedic

Model Informed Drug Development

Capture.JPGModel-Informed Drug Development Pilot Program

Pilot Program to facilitate the development and application of exposure-based, biological, and statistical models derived from preclinical and clinical data sources

  • Quantitative methods to balance risks/benefits of drugs in development
  • Can improve clinical trial efficiency, increase probability of regulatory success, optimize drug dosing/therapeutic individualization without dedicated trials

Goals of the MIDD Pilot Program

  • Discuss application of MIDD approaches to development and regulatory evaluation of medical products
  • Provide advice about how particular MIDD approaches can be used in a specific drug development program


FDA News: Medical device needs for rare diseases, Accelerating next generation sequencing-based tests, Essure sale retsriction


Unmet medical device Needs for patients with rare diseases

FDA, National Center for Advancing Translational Sciences (NCATS)/Office of Rare Diseases Research (ORDR) at NIH sought to better understand medical device needs of patients with rare disease

  • Generate meaningful data to inform patients, practitioners, policymakers, and device developers
  • Needs, barriers, and incentives

Online survey of four clinician groups

  • satisfaction with current devices
  • unmet needs for specific rare diseases
  • impediments to medical device development

Survey Respondents: 1,342 clinicians


  • Patients with rare diseases face numerous unmet needs
  • Device needs of pediatric patients – grow with child, be modified to smaller size, less invasive
  • Creating entirely new devices needed vs. modifying/repurposing existing devices
  • Limitations included lack of sensitivity/specificity, cumbersome and invasive
  • Costs of research, lack of profitability, challenges of conducting trials are challenges



FDA finalizes guidances to accelerate the development of reliable, beneficial next generation sequencing-based tests

Finalized two guidances for  efficient development of novel technology that scans DNA to diagnose genetic diseases-next generation sequencing (NGS)

  •  Recommendations for designing, developing, and validating tests; for continued advancement of individualized, genetic-based medicine
  • Modern and flexible framework

Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics

  • Reliance on clinical evidence from FDA-recognized public databases to support clinical claims e.g. ClinGen

Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS)–Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases

  • Recommendations for designing, developing, validating tests to diagnose individuals with suspected genetic diseases

Based on extensive feedback from the public and stakeholders; continuation of creating regulatory efficiencies in the development and review of NGS tests


CaptureFDA Restricts the Sale and Distribution of Essure

Order to restrict the sale and distribution of the Essure device

  • Ensure  all women provided with adequate risk information so that they can make informed decisions
  • Taking this step because some women were not being adequately informed of Essure’s risks before getting the device implanted
  •  Boxed Warning including perforation of the uterus and/or fallopian tubes, identification of inserts in the abdominal or pelvic cavity, persistent pain, and suspected allergic or hypersensitivity reactions
  • FDA closely evaluating new information on the use of Essure; requires additional, meaningful safeguards to ensure women are able to make informed decisions

New Essure labeling

  • Restricts sale and distribution to only health care providers and facilities that provide information to patients about the risks and benefits of this device
  • Review “Patient-Doctor Discussion Checklist – Acceptance of Risk and Informed Decision Acknowledgement”
  • Patient and physician required to sign
  • FDA will review and monitor Bayer’s plan to ensure compliance of restriction


Image credit: FDA

Market Authorizations: DEXCOM iCGM, BLINCYTO, Lifeline/ReviveR Defibrillator


Dexcom G6 Integrated Continuous Glucose Monitoring System (iCGM)

Dexcom, Inc.

INDICATION FOR USE: Real time, continuous glucose monitoring device indicated for the management of diabetes in persons age 2 years and older.

The Dexcom G6 System is intended to replace fingerstick blood glucose testing for diabetes treatment decisions. Interpretation of the Dexcom G6 System results should be based on the glucose trends and several sequential readings over time. The Dexcom G6 System also aids in the detection of episodes of hyperglycemia and hypoglycemia, facilitating both acute and long-term therapy adjustments.

The Dexcom G6 System is also intended to autonomously communicate with digitally connected devices, including automated insulin dosing (AID) systems. The Dexcom G6 System can be used alone or in conjunction with these digitally connected medical devices for the purpose of managing diabetes


  • First type of CGM to be used as part of an integrated system with other compatible medical devices and electronic interfaces, which may include automated insulin dosing systems, insulin pumps, blood glucose meters or other electronic devices used for diabetes management
  • Enables developers of future iCGM systems to bring their products to market in the least burdensome manner possible.


  • Patch device applied to the skin of the abdomen and contains a small sensor that continuously measures the amount of glucose in body fluid
  • Device transmits real-time glucose readings every five minutes to a compatible display device such as a mobile medical app on a cell phone
  • Will trigger an alarm when a patient’s blood sugar enters a danger zone soaring too high or dropping too low
  • If integrated with an automated insulin dosing system, a rise in blood sugar would trigger the release of insulin from the pump
  • Patch device should be replaced every 10 days

GENERIC DEVICE TYPE: Integrated continuous glucose monitoring system.
Intended to automatically measure glucose in bodily fluids continuously or frequently for a specified period of time. iCGM systems are designed to reliably and securely transmit glucose measurement data to digitally connected devices, including automated insulin dosing systems, and are intended to be used alone or in conjunction with these digitally connected medical devices for the purpose of managing a disease or condition related to glycemic control.


  • Two clinical studies, n=324 adults and children aged 2 years and older with diabetes, multiple clinical visits within a 10-day period where system readings were compared to a laboratory test method that measures blood glucose values. No serious adverse events were reported during the studies.
  • Risks may include hypoglycemia (low blood sugar) or hyperglycemia (high blood sugar),  skin irritation or redness around the device’s adhesive patch


  • Clinical action based on falsely high or falsely low inaccurate glucose values or inaccurate alerts may lead to inappropriate treatment decisions: General and Special Controls
  • Clinical action in pediatric patients based on falsely high or falsely low inaccurate values or inaccurate alerts due to poorer or different performance in pediatric populations. General and Special Controls
  • The inability to make appropriate treatment decisions when glucose values are unavailable due to sensor signal drop-out or loss of communication with digitally connected devices. General and Special Controls
  • Patient harm due to insecure transmission of data. General and Special Controls
  • Use of an iCGM as part of another digitally connected medical device system, such as an AID system, when the iCGM has inadequate analytical or clinical performance to support the intended use of the digitally connected device. General and Special Controls


  • An earlier generation Dexcom G5 system, received FDA approval in 2016 but was not designed as an integrated system to be used with compatible devices
  • Regulation Number: 21 CFR 862.1355
  • Classification: III
  • Product Code: QBJ


  • Earlier generation Dexcom G5 system, covered by Medicare


Capture.JPGBLINCYTO (blinatumomab) for injection, for intravenous use

Amgen Inc.

SUPPLEMENTAL INDICATION: Treatment of B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children.


  • First FDA-approved treatment for patients with MRD-positive ALL
  • Approximately 5,960 people in US will be diagnosed with ALL this year and approximately 1,470 will die from the disease


  • Single-arm clinical trial, n=86, in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells
  • Efficacy: Achievement of undetectable MRD in assay that could detect at least one cancer cell in 10,000 cells after one cycle of Blincyto treatment, length of time that the patients remained alive and in remission (hematological relapse-free survival)
  • MRD was achieved by 70 patients, >50% patients remained alive and in remission for at least 22.3 months


  • Adverse Effects: Consistent with other uses. Infections, pyrexia, headache, infusion related reactions, neutropenia, anemia, febrile neutropenia,  thrombocytopenia
  • Boxed warning:  Cytokine release syndrome, Encephalopathy
  • Serious risks: Effects on the ability to drive and use machines,pancreatitis, and preparation and administration errors 


  • First approval in 2014  for treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory positive B-cell precursor ALL
  • This application granted  Priority Review, Orphan Drug Designation and Accelerated Approval
    • Based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • Accelerated Approval requirements:  Randomized trial to verify clinical benefit in adult and pediatric patients,
  • Modified REMS


  •  Eligible for inclusion in the Durable Medical Equipment (DME) External Infusion Pump Local Coverage Determination (LCD).



Lifeline/ReviveR ECG and DDU Automated Defibrillators

Defibtech, LLC

INDICATION FOR USE:  For use on victims of sudden cardiac arrest (SCA) who are:1) Unconscious and unresponsive; and 2) Not breathing or not breathing normally.


  • 2 multifunction defibrillation electrodes, placed on the patient’s chest, to acquire a patient’s electrocardiogram (ECG)
  • If abnormal heartbeat detected, it may advise the user that a high-energy shock is necessary
  • User interface will provide text/icon prompts and voice instructions to guide the user through the rescue process including cardiopulmonary resuscitation (CPR)
  • Will provide an audible rhythmic beeping sound to help the user deliver the correct rate of compressions while giving CPR
  • If defibrillation shock is required, the device will prompt user to deliver an electrical shock, through the electrodes.


  • Product Code: MKJ
  • Classification: III
  • Regulation No. : 870.5310
  • Description: Non-wearable prescription use only AED

PMA Order

Image credits: Dexcom, Amgen, Defibtech

FDA News: Blood Supply Model, Nanotechnology Programs, Patient Perspectives in Drug Development

Blood Supply and Demand Simulation Model Could Help Nation Prepare for Emergencies

FDA developed blood supply model to estimate amount of blood available in system during national emergencies

  • Estimates how much blood is available during pandemic influenza outbreak and  mass casualty event caused by nuclear device detonation
  • Could threaten blood supply by reducing number of people to donate or by increasing the amount of blood needed
  • Allows calculation of supply—and potential for shortages—based on how long RBCs (short half life) have been in storage

Based on real-world sources of data

  • National blood supply produced by America’s Blood Centers
  • Center for Medicare and Medicaid Center for Medicare and Medicaid Services database
  • National Blood Collection and Utilization Survey
  • Centers for Disease Control and Prevention

Ran simulation on how pandemic could affect inter-regional blood supplies

  • Estimated 541,000 RBC units were lost overall; South had highest percentage of blood lost (15.5%), while the East had the lowest lost (13.8%)

Based on current levels of blood collection, use, and other factors, the U.S. blood supply and demand system is flexible and reliable enough to respond to emergencies



Nanotechnology Programs at FDA

Build regulatory science knowledge, facilitate collaborations and partnerships to establish a flexible, product-focused, science-based approach to regulation

  • Nanotechnology Task Force
  • Nanotechnology Task Force Report
  • Nanotechnology Guidance Documents
  • Nanotechnology Partnerships at FDA

National and International Activities 

  • Member agency in the National Nanotechnology Initiative
  • World-class R&D program, transfer of new technologies,  educational resources,  infrastructure and tools to advance and responsible development of nanotechnology
  • International Organization for Standardization (ISO)
  • Organisation for Economic Co-operation and Development (OECD)



FDA’s efforts to enhance the patient perspective and experience in drug development and review

Patients are becoming driving force of medical research enterprise

  • Capturing patient experience may be quantitative or qualitative
  • Transforming nearly every aspect of medical product development
  • Informing about benefits that matter most and risks they are most concerned

Benefit-Risk Assessment in Drug Regulatory Decision-Making

  • Enhance benefit-risk assessment in human drug review and FDA’s decision-making process
  • Outline how patient experience data and related information can be used to inform benefit-risk assessment

Incorporating Patient Voice into Benefit-Risk Assessments

  • Inform clinical context and provide insights to frame assessment of benefits and risk
  • Provide a direct source of evidence regarding the benefits and risks based on  methodologically-sound data collection tools
  • Hosting patient-focused drug development public meetings
  • Encouraging patient stakeholders to conduct externally-led, patient-focused drug development meetings
  • Providing patients, caregivers, advocates  more channels to provide meaningful input
  • Launching pilot programs to foster design of clinical trials that place less burden on patients


Image credits: FDA

Market Authorizations: HIZENTRA, ADCETRIS, ILUMYA, ACUMEN Software


HIZENTRA, Immune Globulin Subcutaneous (Human), 20% Liquid

CSL Behring

SUPPLEMENTAL INDICATION: Treatment of adult patients with chronic inflammatory demyelinating polyneuropathy (CIDP) as maintenance therapy to prevent relapse of neuromuscular disability and impairment.
Limitations of Use: HIZENTRA maintenance therapy in CIDP has been systematically studied for 6 months and for a further 12 months in a follow-up study. Maintenance therapy beyond these periods should be individualized based upon the patient’s response and need for continued therapy


  • Serious nature of CIDP
  • Clinically clinically meaningful benefits in neurologic function


  • Multicenter, double-blind, randomized, placebo-controlled, parallel-group,  2 different weekly doses of HIZENTRA vs. placebo, n=172
  • Main endpoint: % subjects who had CIDP relapse or withdrawn from study
  • Superiority over placebo: 32.8% for 0.4 g/kg HIZENTRA and 38.6% for 0.2 g/kg HIZENTRA, p<0.001 or p=0.007, respectively


  • Compare favorably to the known and observed risks of Hizentra, which include local infusion site reactions, hypersensitivity reactions, aseptic meningitis, headache, etc., and the remote theoretical risk of adventitious infectious agent transmission


  • First approved in 2010 for  primary humoral immunodeficiency (PI)


  • Medicare, Medicaid, and most insurers cover Hizentra for PI
  • Covered as Medicare Part B benefit with claims considered for payment by the four regional Durable Medical Equipment Medicare Administrative Contractors (DME MACs). Medicaid coverage policy varies by state, payer and provider contract
  • Coverage for supplemental indication: TBD



 ADCETRIS (brentuximab vedotin)

Seattle Genetics, Inc.

INDICATION: Treatment of adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with chemotherapy


  • 8,260 people in US diagnosed with Hodgkin lymphoma in 2016; 1,070 patients with non-Hodgkin lymphoma died from disease in 2017
  • Improvement in initial treatment regimens of advanced Hodgkin lymphoma
  • Advancements in treatment that give prescribers and patients different options for care

MECHANISM OF ACTION: Combines antibody and drug, allowing the antibody to direct the drug to a target on lymphoma cells known as CD30.


  • Open label, 2 arm trial, Clinical trial comparing Adcetris plus chemotherapy vs. chemotherapy-only regimen common for cHL treatment, n=1,334 patients
  • Primary endpoint: Modified progression-free survival (mPFS)
  • Patients treated with Acteris + chemotherapy were 23% less likely to experience progression, death, or initiation of new therapy


  • Boxed Warning: Risk of John Cunningham virus infection resulting in progressive multifocal leukoencephalopathy, or PML
  • Serious risks: Perpheral neuropathy; anaphylaxis or infusion-site reactions; hematologic, pulmonary and hepato-toxicities; serious or opportunistic infections; tumor lysis syndrome; serious dermatologic reactions and gastrointestinal complications
  • Common side effects: Neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting and fever (pyrexia)


  • Previously approved in 2011 to treat cHL after relapse, cHL after stem cell transplant when a patient is at a high risk of relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after failure of other treatment, and primary cutaneous ALCL after failure of other treatment
  • This application granted Priority Review and Breakthrough Therapy designations


  • Payor coverage when determined to be medically necessary by meeting predefined medical criteria and guidelines


CaptureILUMYA ( (tildrakizumab-asmn) injection, for subcutaneous use

Merck and Sun Pharma

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

MECHANISM OF ACTION: Humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits release of proinflammatory cytokines and chemokines


  • Two multicenter, randomized, double-blind, placebo-controlled trials, n= 926, ILUMYA vs. placebo. Subjects had Physician Global Assessment (PGA) score of ≥3 moderate) on a 5-point scale of overall disease severity, Psoriasis Area and Severity Index (PASI) score ≥12, and a minimum body surface area (BSA) involvement of 10%
  • Improvement in psoriasis-related parameters


  • May increase the risk of infection
  • Adverse reactions: Upper respiratory infections, injection site reactions, diarrhea


  • Required pediatric assessments
  • Postmarket requirements:  Registry-based observational exposure cohort study on maternal, fetal, and infant outcomes of women,  retrospective cohort study using claims or electronic medical record to assess major congenital malformations,  spontaneous abortions, stillbirths etc, observational study of long-term safety



ACUMEN Hypotension Prediction Index (HPI) Feature Software

Edwards Lifesciences

INDICATION FOR USE: Provides the clinician with physiological insight into a patient’s likelihood of future hypotensive events (defined as mean arterial pressure < 65 mmHg for at least one minute in duration) and the associated hemodynamics.

The Acumen HPI feature is intended for use in operating room (OR) patients receiving advanced hemodynamic monitoring. The Acumen HPI feature is considered to be additional quantitative information regarding the patient’s physiological condition for reference only and no therapeutic decisions should be made based solely on HPI parameter.

GENERIC DEVICE TYPE: Adjunctive predictive cardiovascular indicator

  • Prescription device that uses software algorithms to analyze cardiovascular vital signs and predict future cardiovascular status or events. This device is intended for adjunctive use with other physical vital sign parameters and patient information and is not intended to independently direct therapy.


  • Delayed or incorrect treatment due to erroneous device output resulting from software malfunction or algorithm error : Software verification, validation, and hazard analysis, Non-clinical performance testing, Clinical performance testing,  Labeling
  • Delayed or incorrect treatment due to user misinterpretation or over-reliance on indicator: Usability assessment, Labeling


  • Software description and the results of verification and validation testing based on a comprehensive hazard analysis and risk assessment
  • Scientific justification for the validity of predictive cardiovascular indicator algorithm(s);  verification of algorithm calculations and validation using an independent data set
  • Human factors and usability engineering assessment to evaluate risk of misinterpretation of device output
  • Clinical data assessment
  • Labeling


  • Regulation Number: 21 CFR 870.2210
  • Regulation Name: Adjunctive predictive cardiovascular indicator
  • Regulatory Class: Class II
  • Product Code: QAQ

REIMBURSEMENT: Will initiate a targeted launch of this first-of-its-kind technology


Image credit: CSL Behring, Seattle Genetics, Merck/Sun, Edwards

FDA News: Breast Implants Risk, Prevent Illegal Products entering US, Lead Testing Issues

Capture.JPGFDA updates public information about known risk of lymphoma from breast implants

FDA identified possible association between breast implants and anaplastic large cell lymphoma (ALCL) in 2011

  • Gathering information to better characterize and quantify risk
  • Updating total number of known cases of BIA-ALCL and lifetime risk of developing BIA-ALCL

Reporting 414 total cases of BIA-ALCL

  • Lifetime risk of developing BIA-ALCL for patients with textured breast implants ranges from 1 in 3,817 to 1 in 30,000.

Does not change the agency’s recommendations regarding breast implants

  • Choosing breast implant is personal decision
  • Decision on individual needs and with the most complete information about risks and benefits


Capture.JPGFDA Using Innovative Methods to Prevent Illegal Products with Hidden Drug Ingredients from Entering US 

FDA closely monitor’s products arriving at the nation’s international mail facilities

  • Increasingly challenging task given high volume (>275 million packages/yr)
  • Deploy advanced screening technologies to screen packages more efficiently and reliably

Successful six-month pilot with portable screening device – ion mobility spectrometer

  • Compares chemical signature of unknown substance against chemical signatures of known compounds in less than 30 seconds
  • 65% samples tested positive for undeclared pharmaceutical ingredients – results confirmed in FDA laboratory
  • Developing opioid screening method for the device


Capture.JPG FDA’s findings from ongoing investigation into lead testing issues

Warning in 2017 about inaccurate lead tests by Magellan Diagnostics

  • Aggressively investigated problem
  • Becton Dickinson (BD) & Company, the manufacturer of blood sample collection tubes also investogated

Assessment of accuracy of Magellan’s LeadCare when used with blood collected into BD tubes

  • Significant chance of false results with tubes with rubber stoppers containing  thiuram
  • Can release sulfur-containing gases that dissolve into blood samples and bind tightly to lead particles

BD recalls EDTA Blood Collection Tubes Due to Chemical Interference with Certain Tests


Image credits: FDA, BD



FDA working with manufacturers to withdraw Zinbryta from market

 Zinbryta approved in 2016

  • Relapsing forms of multiple sclerosis

Biogen and partner AbbVie voluntarily withdrawing  marketing application globally

  • Reported cases of encephalitis and meningoencephalitis
  • Nature/complexity of adverse events affects and limited number of patients being treated prevents adequate characterization of evolving benefit/risk profile
  • Withdrawal in the best interest of patients

Working closely with FDA and global regulatory authorities on  withdrawal timelines 

  • European Medicines Agency announced recall following 12 reports of serious inflammatory brain disorders worldwide



Bayer’s voluntary recall of Alka-Seltzer Plus products due to labeling errors

Recall due to labeling errors

  • Ingredients listed on carton front sticker may be different from back AND product in carton
  • May lead consumers to ingest ingredient to which they are allergic to or  ciuld have serious health consequences




Warning Letter: OPTERNATIVE Eye Examination Mobile Medical App 

Product is ‘device’

  • Intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body

Violation of the Federal Food, Drug, and Cosmetic Act 

  • FDA review of website
  • ADULTERATION: No approved application for premarket approval
  • MISBRANDING: No FDA notification of intent to commercialize

2016 FDA meeting on regulatory requirements

  • Meeting with Office of Compliance and Office of Device Evaluation
  • Requirement of premarket submission to evaluate safety and effectiveness

If failure of prompt action to correct violations

  • FDA initiated action without further notice
  • Seizure, injunction, civil money penalties


Image credits: FDA, Biogen, Opternative


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



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

St. Jude’s Medical (Abbott)

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


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


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


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


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


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

Fact Sheet


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



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

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

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

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


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

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

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

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


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


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


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


  • N/A. Non-prescription product


CaptureTROGARZO™ (ibalizumab-uiyk) injection

TaiMed Biologics USA Corp.

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


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

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


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


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


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




Imugen Babesia microtiArrayed Fluorescent Immunoassay (AFIA)

Oxford Immunotec


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

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


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


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

CBER Infectious disease tests


SkinPen Precision System

Bellus Medical, LLC

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

GENERIC DEVICE TYPE: Microneedling device for aesthetic use

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


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


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


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


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

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



 Predicting Stem Cell Activity to Ensure Safe and Effective Therapies

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

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

FDA scientists developing ways to improve predictability

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


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

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

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

FDA Steps

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

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

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

Patient Decision Checklist



 CDER: Regulatory Science

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

Image credit: FDA

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

FDA BRIEF: Week of February 26, 2018

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

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

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

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

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


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

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

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

FDA incentives, approvals, trends

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

Modernization and new initiatives

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

New Website



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

Working to determine the root causes

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

Looking ahead to 2018-2019 flu season

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


Capture.JPGDuodenoscope surveillance sampling and culturing

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

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

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

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


Image credit: FDA, CDC


Market Authorizations: IMFINZI, VERZENIO


 IMFINZI (durvalumab) injection


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


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


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



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


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


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


Capture.JPGVERZENIO (abemaciclib) tablets

Eli Lilly

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

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


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


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



  • No Medicare coverage
  • Obtained through specialty pharmacies


Image credit: AstraZeneca, Eli Lilly 

FDA News: CDER Warning Letters, Information Technology Progress

FDA BRIEF: Week of Feb 19, 2018

CaptureCDER Warning Letters

Provided by CDER Freedom of Information Office (FOI)

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

Types of Letters



PDUFA VI Information Technology Goals and Progress

Goal of improving predictability and consistency of electronic submission process

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

Enhance transprency and accountability of electronic submission and data standards activities

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


Image credit: FDA

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





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

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

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


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


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


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


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

GENERIC DEVICE TYPE:  Radiological computer aided triage and notification software

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


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


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


  • Precedence for CMS qualification of Clinical Decision Support Mechanisms


Capture.JPGERLEADA (apalutamide) tablets


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


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

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


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


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


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


  • Pediatric requirements waived


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


CaptureBANYAN Brain Trauma Indicator

Banyan Biomarkers, Inc.


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

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

The Banyan BTI is for prescription use only.


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

GENERIC DEVICE TYPE: Brain trauma assessment test

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


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


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


  • Performance testing including clinical testing
  • Labeling


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


Capture.JPGAPTIMA HBV Quant Assay

Hologic, Inc


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

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

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

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


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


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


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


  • Product Code: MKT


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


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


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

Week of February 12, 2018

CaptureEfficacy of the 2017-2018 influenza vaccine

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

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

Select strains for next season’s flu vaccines

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



CLIA-Waived Rapid Flu Test Facts

Available Rapid flu tests have demonstrated acceptable clinical performance

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

Performance Levels for antigen-based RIDTs

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

2017-2018 Flu Season

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



Capture.JPGWarfarin INR test meters 

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

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

Updates include

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



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

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

I. Promote Domestic Manufacturing

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

II. Robust and Reliable Source of Compounded Products

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

III. Advance Medical Device Manufacturing and Quality

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

IV. New Medical Data Enterprise

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

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

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

VI. Modern Science-Based Principles for New Drug Development 

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

VII. Medical Products Targeted to Rare Diseases

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

VIII. Modernize Generic Drug Development 

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



Advancing development of novel treatments for neurological conditions

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

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

CDER team-based modern approach

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

Duchenne Muscular Dystrophy and Related Dystrophinopathies

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

Amyotrophic Lateral Sclerosis

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

Early Alzheimer’s Disease

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


  • Innovative approaches to clinical trial design for acute migraine

Partial Onset Seizures

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

External Stakeholder Meeting Request (ESMR) system

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

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

 Image credit: FDA

Market Authorizations: BIKTARVY, ZYTIGA, RADIOGENIX system


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


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

MECHANISM OF ACTION: Fixed dose tablet of antiretroviral drugs:

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


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


  • Required postmarketing studies in pediatrics


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



ZYTIGA (abiraterone acetate) in combination with prednisone


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


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


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


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


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



RADIOGENIX System (technetium Tc-99m generator )

NorthStar Medical

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

Sodium Pertechnetate Tc-99m injection is also indicated:

In Adults for:

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

In Pediatric Patients for:

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


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

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


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


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


 Image credits: Gilead, Janssen, NorthStar Medical


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

FDA BRIEF: Week of February 5, 2018


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

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

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

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

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

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

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



CDER/CBER Data Standards Strategy FY2018-FY2022

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

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

Strategic Goals

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



Generating Antibiotic Incentives Now (GAIN)  FY2012-FY2017

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

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



FDA Helping Generic Industry Submit Complete Applications

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

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

Good ANDA Submission Practices to address

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



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

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

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

Learnings from reports of death associated with kratom

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

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

  • No evidence of safety and effectiveness


Image credit: FDA








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

FDA BRIEF: Week of January 29, 2018


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

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

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

Loperamide packaging limitations and unit-of-dose packaging

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



Opioid REMS Education Blueprint

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

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

Revised FDA Blueprint contains

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


Capture.JPGPayment and Reimbursement to Research Subjects

Updates to the Payment for Research Subjects: Information Sheet

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

Image credit: SAMHSA, FDA

FDA Marketing Authorizations: LUTATHERA, REMODULIN Impant

FDA BRIEF: Week of January 22, 2018


LUTATHERA (lutetium Lu 177 dotatate) injection

 Advanced Accelerator Applications

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


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

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


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


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


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


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


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




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

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

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


Consists of the following components:

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


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


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


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


Image credit:  Advanced Accelerator Applications, Medtronic

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

FDA BRIEF: Week of January 22, 2018

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

  • Considering adjustments to QOS format to improve efficiency

CDER new white paper describes key considerations for QOS preparation:

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


510(k) Third Party Review Metrics

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

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

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

Review Metrics:
Capture.JPG READ

Buying from Online Pharmacies

Rogue online pharmacies

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

Sell dangerous products with compromised safety and effectiveness

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

Shop Safely Online


Capture.JPGPodcast: State of CDER 

Podcast: State of CDER 2018Transcript


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

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

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

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

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


Image credit: FDA







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

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


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

FDA BRIEF: Week of January 15, 2018


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

Achievement of strategic priorities for 2016-2017

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

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

  • Annual number of approved devices has steadily

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

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

2016-2017 Accomplishments

2018-2020 Strategic Priorities

business person

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

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

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

Add identifier number (NCT #) to FDA summaries

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


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

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

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

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


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

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

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

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

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


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

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

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

FDA Actions

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

Looking forward

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


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

FDA to improve recall processes to help ensure product safety

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

FDA Enforcement Report

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


Capture.JPG2018 Compounding Policy Priorities Plan

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

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

2018 Priorities

  • Risk-Based Approach to Manufacturing Standards for Outsourcing Facilities
  • Restricting Compounding of Drugs that are Essentially Copies of FDA-Approved Drugs
  • Regulating Compounding from Bulk Drug Substances
  • Solidifying FDA’s Partnership with State Regulatory Authorities
  • Finalization of Biological Products Guidance and Clarifying Other Policies on Activities that Compounders Undertake
  • Compliance


Capture.JPGLocally-Acting Orally Inhaled and Nasal Drug Products 


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

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

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

  • Orally Inhaled Drug Products
  • Locally Acting Nasal Products


Image credits: FDA, DoD


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


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


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


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

Resources for Sponsors

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

Additional Contacts

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



Formal Meetings Between FDA ad Sponsors or Applicants of PDUFA Products


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


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



Medical Device Accessories – Describing Accessories and Classification Pathways


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


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

Accessory Classification Policy

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

Accessory Classification Process

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




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

Compliance Dates




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

FDA BRIEF: Week of January 8, 2018

Dr. Scott Gottlieb

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

Inspiring year of advances in both medicine and public health

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

pie chart of approvals

Chart of device approvals

2017 generics approvalsREAD


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

Approved new treatments for patients with rare diseases

  • Batten disease
  • Chagas disease
  • Hemophilia A with inhibitors

Novel “Firsts” in treating

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

Other firsts that are not novel drug approvals 

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




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

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

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

Addressing epidemic of opioid addiction

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

List of Prescription Cough and Cold Medicines Containing Codeine

Active Ingredient(s)

Brand Name(s)

codeine, chlorpheniramine

Tuxarin ER, Tuzistra XR

codeine, phenylephrine, promethazine

Only generics available

codeine, promethazine

Only generics available

codeine, pseudoephedrine, tripolidine

Triacin C

List of Prescription Cough and Cold Medicines Containing Hydrocodone

Active Ingredient(s)

Brand Name(s)

hydrocodone, guaifenesin

FlowTuss, Obredon

hydrocodone, pseudoephedrine, guaifenesin

Hycofenix, Rezira

hydrocodone, chlorpheniramine

Tussionex Pennkinetic, Vituz

hydrocodone, chlorpheniramine, pseudoephedrine


hydrocodone, homatropine

Only generics available


Image credits: FDA


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

FDA BRIEF: Week of Jan 1, 2018


CDER Data Standards Program Action Plan

Governing body for drug data standards

  • Provides quarterly updates on  current initiatives

Program Initiatives

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


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

Wrinkle Treatments and Other Anti-aging Products

Cosmetics – if:

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

Drugs or Medical Devices – if:

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

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



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

Continued implementation of the “Drug Competition Action Plan”

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

Releasing 2 documents:

Additional Steps:

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

Potential abuses of the citizen petition process

Restricting access to testing samples of branded drugs

Abuses of the single, shared system REMS negotiation process



FDA-approved smoking cessation products

Nicotine Replacement Therapy (NRT)

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

Over-the-counter NRTs 

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

Prescription nicotine replacement therapy (prescription): Nicotrol

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


Image credit: FDA


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



Sanuwave, Inc.

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

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


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


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


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


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


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



Capture.JPGVERCISE Deep Brain Stimulation (DBS) System

Boston Scientific Corporation

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


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


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


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


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


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


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




Biom’Up SA

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


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


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

REGULATORY PATHWAY: Combination product, PMA

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


  • Pending
  • Precedents for reimbursement for absorbable collagen hemostatic


Image credits: Sanuwave, Boston Scientific, Biom’Up


FDA approved


BOSULIF (bosutinib) tablets


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


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


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


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


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



GIAPREZA (angiotensin II) injection

La Jolla Pharmaceutical Company

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


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

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


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


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


  • Priority Review
  • Required pediatric assessments


  • Available March 2018



CABOMETYX (cabozantinib) tablets


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


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


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



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


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



PERJETA (pertuzumab)


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


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


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


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


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


Image credit: DailyMed, La Jolla

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

FDA BRIEF: Weeks of Dec 22 and 29

FDA Voice

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

Patient Engagement Collaborative (PEC)

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

PEC forum to discuss

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

Nomination ProcessREAD


Case for Quality Pilot Activities

Case for Quality

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

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

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

2. Voluntary Medical Device Manufacturing and Product Quality Pilot Program

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

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

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

4. Digital Health Entrepreneurs-in-Residence Program

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

5. Medical Device Single Audit Program (MDSAP)

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



Medical Device Accessories

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

Accessory Classification Request: Written request for appropriate classification

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

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

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



Voluntary Medical Device and Combination Products Malfunction Summary Reporting

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

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


Image credits: FDA


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


Capture.JPGThe Least Burdensome Provisions: Concept and Principles

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

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

Guiding Principles

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

Applications of Least Burdensome Principles

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


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

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

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

Filing Review and Assessment

Filing issues grouped into two categories:

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

FDA Decision-Making and Notification to the Applicant

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



Drug Products, Including Biological Products, that Contain Nanomaterials


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

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


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


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


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


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




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

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

Boston Scientific Spinal Cord Stimulation System

Boston Scientific 

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

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



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


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


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



ADMELOG (insulin lispro injection), subcutaneous or intravenous use


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


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


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


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


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


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


CaptureIXIFI (infliximab-qbtx) injection


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

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


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

MECHANISM OF ACTION: Tumor necrosis factor (TNF) blocker


Image result for nucala logoNUCALA (mepolizumab) injection


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


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


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


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


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

REIMBURSEMENT: GSK Patient assistance program


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

Spark Therapeutics

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

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


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


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


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


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


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


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


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


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

FDA BRIEF: Week of Dec 18, 2017

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

By: Scott Gottlieb, M.D., Commissioner

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

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

Key priorities

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


Gene Therapy

What Is Gene Therapy? How Does It Work?

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

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


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

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

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

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

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





Image credits: FDA, CDC

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

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


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

Antimicrobial resistance one of  most pressing public health challenges

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

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

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


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

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

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

IDEs submitted for EFS has more than doubled

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

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


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

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

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

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

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

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

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

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

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


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

Certain drug issues need additional evaluation after approval

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

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

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



Advancing Policies to Promote Safe, Effective MedTech Innovation

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

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

Make review process more benefit-risk based

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

New Steps to Reform, Modernize 510(k) Review

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


FDA's Toxicology Roadmap

Predictive Toxicology Roadmap to Enable Advances in Toxicity Testing

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

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

FDA’s Predictive Toxicology Roadmap

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




 Promise and Potential of 3D Printed Pharmaceuticals

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

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

Addressing 3D Printing Questions Through Research

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


Artificial Pancreas Diagram


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

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

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


Image credits: FDA

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

CaptureTechnical Considerations for Additive Manufactured Medical Devices

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

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


Design and Manufacturing Process Considerations

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

Device Testing Considerations

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


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


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

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

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

FDA Interpretation of Medicare Coverage Categories A and B

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

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

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


CaptureClinical and Patient Decision Support Software

FDA’s regulatory oversight of:

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

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

Scope of FDA oversight of CDS/PDS software:

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

FDA Definitions:

CDS: Software functions that are considered as device:

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

Function excluded from the definition of device with additional criterion

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

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

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

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

Examples provided


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

Global regulatory framework and principles for SaMD

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

Clinical Evaluation of SaMD 

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


General Principles and Context of Clinical Evaluation Process 

  • Definition Statement and Category
  • Clinical Evaluation Processes

Clinical Evaluation Process Flow Chart 

  • Considerations for Generating and Assessing Evidence

Importance of Independent Review of Clinical Evaluation 

Continuous Learning Leveraging Real World Performance Data



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

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

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

Level 2 updates to be made to following guidance documents:

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

Withdrawing following guidance document:

  • Submission of Premarket Notifications for Medical Image Management Devices

Interpretation of Cures Act and modifications to existing guidances:

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



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

FDA BRIEF: Week of November 27, 2017

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

Foundation Medicine

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


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


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


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


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

REIMBURSEMENT PATHWAY:  National Coverage Determination (NCD)

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


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

Federal Register: Program for Parallel Review of Medical Devices

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

Teoxane SA



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


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


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


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


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


CaptureTRIVISC (Sodium Hyaluronate ) injection


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



  • Product Code: MOZ


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


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


Image Credits: Foundation Medicine, Teoxane, OrthogenRx