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

FDA BRIEF: Week of October 23, 2017


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

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

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


Biosimilars Education Campaign

Biosimilars are Potentially Cost-Saving Options

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

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

Several approved biosimilars (reference product)

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

FDA has developed educational materials   for health care providers


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

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

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


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

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

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

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

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

MDDT Webpage


Zineh_Issam_Drug_InteractionsCDER Conversation: Evaluating the Risk of Drug-Drug Interactions

What is a drug-drug interaction? 

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

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

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

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

When and how to evaluate drug-drug interactions? 

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

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

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

New draft guidances. Federal Register Notice


Image credits: FDA



Drug and Device Approvals: YESCARTA, IMPELLA RP

Week of October 16, 2017


YESCARTA™ (axicabtagene ciloleucel) suspension for intravenous infusion

Kite Pharma, Inc. (Gilead company)

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

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


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


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

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

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


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


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


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





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

ADDRESSING UNMET NEED: Smallest heart pump for right heart failure


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

DESCRIPTION: Comprised of three components

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


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


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


Image Credits: Kite, Abiomed



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

FDA BRIEF: Week of October 16, 2017


Clinical Trials & Medical Devices

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

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

2016-2017 CDRH Strategic Priority: Partner with patients

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

Culture of Patient Engagement



Patient Engagement Advisory Committee (PEAC) Summary

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

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

The future topics

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

meeting materials



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

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

FDA Final RWE Guidance describes:

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


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

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

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

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

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


Image credits: FDA




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

Flexion Therapeutics, Inc.

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

ADDRESSING UNMET NEED: Non-opioid therapy for pain


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


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


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



SENHANCE Surgical Robotic System

TransEnterix Surgical Inc

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


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


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


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


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


Siemens Medical Solutions Inc.

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


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


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


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

Image credits: Flexion, TransEnterix, Siemens



Guidance: ANDA vs 505b(2) Pathway


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

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

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

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

  • Duplicates
  • Petitioned ANDAs
  • Bundling

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

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



NextGen Collaboration Portal


NextGen Collaboration Portal

New technology platform to allow industry to request FDA pre-ANDA meetings for complex generic drug products

  • initiate requests by uploading meeting request package
  • submit supporting documents e.g. presentation materials, additional information responses, post-meeting comments
  • minimize manual data entry
  • support GDUFA II performance goals.


Image credit: FDA

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

FDA BRIEF: Week of October 9, 2017

Hurricanes Irma and Jose

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

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

  • Facility closings and potential for shortages

FDA maintaining close watch on the most critical medical products

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


FDA Patient Representative Program

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

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

Recruit Patient Representatives on an as-needed basis to 

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

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

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



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

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

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

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

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

Integrate real world evidence into regulatory decision making process

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

Parameters for rigorous, systematically gathered patient preference information

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


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

Opioid formulation with “properties designed to deter abuse”

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

Testing and approval of abuse deterrent formulations (ADF)

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

Challenges associated with ADF evaluation

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

July 2017 workshop

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


Image credits: FDA


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

FDA BRIEF: Week of October 2, 2017

National CyberSecurity Awareness Month

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


Expanded Access: FDA Describes Efforts to Ease Application Process

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

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

Lifting another potential burden for applications

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

Addressing uncertainty about assessment of  adverse event data from expanded access

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

Other activities

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



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


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

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

Grants awarded for

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



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

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

Grants awarded for

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

Photos of Mammography devices

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

Mammography Quality Standards Act (MQSA) established in 1992

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

> 87% of mammography facilities have no MQSA violations

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

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

Priority Review Vouchers 

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

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

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

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

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


 Opioid Policy Steering Committee

Opioid Policy Steering Committee (OPSC) proposed

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

Seeking public input on 3 key areas

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


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

Reducing the Hurdles for Complex Generic Drug Development

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

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

Complex drugs

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

Provide scientific and regulatory clarity with respect to complex generic drugs

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

Other Initiatives

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


Image credits: FDA

Device Approvals: COBAS ZIKA, REMEDE

FDA BRIEF: Week of October 2, 2017



Roche Molecular Systems, Inc.

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

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

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


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


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


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


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


the-remede-system-productRemedē System

Respicardia Inc.

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

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

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


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



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


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

Image credits: Roche, Respicardia


CLIA and Waiver by Application


 CLIA  and Waiver by Application

CLIA: Clinical Laboratory Improvement Amendments

  • Regulate laboratory testing and require clinical laboratories certification prior to in vitro diagnostic (IVD) testing
  • Multiple types of CLIA certificates, based on  complexity of diagnostic tests
  • Responsible federal agencies: FDA, CMC, CDC

CLIA  IVD Categorization:

  • By degree of complexity: waived, moderate complexity, and high complexity

CLIA Waiver by Application:

  • For moderate complexity may test
  • Manufacturer may request categorization of the test as waived
  • Provides evidence to FDA that test meets CLIA statutory criteria for waiver


Image credit: FDA

Compounding Risk Alert

Compounding Risk Alert

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

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

Recent posts

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


Image credit: FDA

FDA Sentinel System

SentinelFDA Sentinel System

Sentinel is used by the FDA-CDER to assess the safety of prescription drugs, including biological therapeutics and generic drugs

  • Managed in CDER’s Office of Surveillance and Epidemiology
  • Important component of CDER’s postmarketing safety system
  • Used to proactively assess drug safety, under real-world conditions, that more closely reflect patient care
  • Sentinel assessments make use of the automated surveillance tools


Image credit: Sentinel/FDA


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

fda guidances


Minutes of Institutional Review Board (IRB) Meetings

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

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

Minutes need to include:

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



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

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

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

Proposed 4-E Framework 

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



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

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

Discussion of Scope and Process




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

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

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

Statutory Definitions

  • Drug
  • Device

Key provisions of Device definition

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



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

MDUFA IV authorizes user fees for De Novo classification requests

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

FDA Actions 

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

De Novo Performance Goals for MDUFA IV

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

Requester Actions 

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





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

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

Overview and General Study Design Considerations

  • Procedure Duration
  • Contamination
  • Transportability

Reperfusion Models

  • Ex Vivo Models
  • In Vivo Models

Sample Panel of Biomarkers in Liver

  • Liver Injury Biomarkers
  • Liver Function Biomarkers


Image credit: FDA



FDA BRIEF: Week of September 25, 2017

PENTAX ED34-i10T Duodenoscope 


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


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


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


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

FreeStyle Libre Flash Glucose Monitoring System

Abbott Diabetes Care Inc.

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

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


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


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


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


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


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


SOFIA 2 Fluorescent Immunoassay Analyzer


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

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



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


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

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

User manual

Capture.JPGVERZENIO (abemaciclib) Tablet

Eli Lilly


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


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


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

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


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


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


Image credit: Pentax, Abbott, Quidel, Lilly