FDA Views: Work @ FDA, CDRH Anniversary

FDA BRIEF: Week of June 20, 2016


FDA: A Great Place for Science…and for Scientists on the New Frontier of Regulatory Science


By: Robert M. Califf, M.D.,  Commissioner

  • FDA  commitment to using best available science to support mission to protect and promote public health
  • Scientific breakthroughs offer unprecedented opportunities  to develop new treatments and cures
  • Deep personal and professional satisfaction gained from working in FDA’s state-of-the-art laboratories on front-line issues

Being Part of a Vibrant Collaborative Scientific Environment

  •  FDA offers  opportunity to be  part of  vibrant, collaborative culture of regulatory science
  • Work is directly tied to regulatory decisions
  • Fellowship, internship, graduate, and faculty programs

Tackling the Most Challenging Scientific Issues

  • Encourages professionals collaborate with FDA on  transformative scientific issues
  • Need the best scientific minds to make science-based decisions on benefit/risk
  • Great  career opportunities at FDA


FDA Celebrates the 40th Anniversary of the Medical Device Amendments

Jeffrey Shuren, M.D., J.D.

by: Jeffrey Shuren, M.D., J.D.,  Director of CDRH

  • FDA’s Celebration of the 40th Anniversary of the Medical Device Amendments
  • Congress gave FDA explicit authority over medical devices in the 1938- but focus only on fraudulent products
  • Safety disaster with ‘Dalkon Shield’ enacted Medical Device Amendments in 1976 for risk based classification and GMP compliance
  • Ushered in a new era for medical technology innovation, patient access, and patient safety – along with political tensions
  • CDRH has adapted expertise and regulatory approaches to meet rapidly evolving innovation
    • Digital Health regulatory framework
    • National Evaluation System (NEST)
    • Patient engagement


FDA on LinkedIn, [email protected] Tutorial


WHAT:  Stay up to date with SBIA by receiving updates directly to your LinkedIn feed

WHY:  Will post items such as:

  • Conferences and workshops
  • Webinars
  • SBIA Chronicles e-newsletters and Podcasts
  • SBIA Education Series
  • Guidance documents
  • New meeting announcements
  • FDA Job Announcements, as applicable
  • and more!



FDA LinkedIn page group.



[email protected]

WHAT: FDA may require a Risk Evaluation and Mitigation Strategy (REMS) to  ensure that the benefits of certain drugs outweigh their risks. FDA has a new  and improved  [email protected] website

WHY: FDA pharmacists show how to navigate FDA’s user-friendly REMS website. The new website makes it easier  what is required to prescribe or dispense a drug with a REMS.




FDA Approvals and Reviews: ASPIREASSIST, VENTANA PDLI Assay, CEREVE Sleep System, WALLFLEX Biliary System

FDA BRIEF: Week of June 13, 2016

FDA approved

Aspire Bariatrics, King of Prussia, PA, USA


INDICATION FOR USE: Intended to assist in weight reduction of obese patients. It is indicated for use in adults aged 22 or older with a Body Mass Index (BMI) of 35.0-55.0 kg/m2 who have failed to achieve and maintain weight loss with non-surgical weight loss therapy. Intended for a long-term duration of use in conjunction with lifestyle therapy and continuous medical monitoring

UNMET NEED: Need for approach for effective control of calorie absorption

REG PATHWAY: PMA, Device Procode: OYF


Designed to facilitate weight loss in obese patients by

  • enabling removal of a portion of stomach contents through a gastrostomy tube
  • requiring thorough chewing in order for stomach contents to enter the 6mm diameter tube

Device consists of

  • ‘A-Tube’ and “Gravity” flow director system through which patients aspirate (drain) gastric contents about 20 to 30 minutes after consumption of a meal directly into toilet
  • Key components: A-tube, Skin Port, Skin Port Installation Toolkit, Connector, Companion, Tubing Set, Reservoir, Lanyard, Emergency Clamp
  • Used after the three (3) major meals each day
  • Takes 5-10 minutes to complete
  • Removes about 30% of the calories consumed
  • Aids in portion control; all food must be thoroughly chewed to fit through the tube


  • PATHWAY Pivotal Trial, prospective, randomized, multi-center, controlled, open-label, 52-week , n=111 vs 60 (control)
  • Co-primary Endpoints:
    • 52-week  comparison of mean percent excess weight loss (%EWL), AspireaAssist (AT) vs Control Group
    • AT responder rate dichotomized at 25% EWL
  •  %EWL: 31.5% vs  9.8%  (p=0.0083)
  • 25% EWL: No met



  • Contraindication: Uncontrolled hypertension, diagnosed bulimia, diagnosed binge eating disorder, night eating syndrome, pregnancy or lactation, inflammatory bowel disease. Also previous history of serious pulmonary or cardiovascular disease, coagulation disorders, chronic abdominal pain
  • Surgical placement risks
  • Risks related to the abdominal opening for the port valve
  • Side effects: Occasional indigestion, nausea, vomiting, constipation and diarrhea.




VENTANA PD-L1 (SP142) Assay

Ventana Medical Systems (Roche), Tucson, AZ, USA


Qualitative immunohistochemical assay using rabbit monoclonal anti-PD-L1 clone SP142 intended for use in the assessment of the PDL1 protein in formalin-fixed, paraffin-embedded (FFPE) urothelial carcinoma tissue stained with OptiView DAB IHC Detection Kit and OptiView Amplifcation Kit on a VENTANA BenchMark ULTRA instrument.

PD-L1 status is determined by the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (% IC) of any intensity. PD-L1 expression in ≥ 5% IC determined by VENTANA PD-L1 (SP142) Assay in urothelial carcinoma tissue is associated with increased objective response rate (ORR) in a non-randomized study of TECENTRIQ™ (atezolizumab).

REG PATHWAY: PMA, Device Procode: PLS


Device Kit Components

  • Optimized reagents to complete immunohistochemical staining procedure
  • Recombinant rabbit monoclonal antibody produced as purified cell culture supernatant and contains sufficient reagent for 50 tests
  • Antibody and detection reagents are provided as ready-to-use dispensers

Device Instrumentation and Software

  • Assay is performed on the BenchMark ULTRA automated staining instrument using the VSS software version 12.2
  • Assay protocol is assay specific
  • Software designed to recognize and group the VENTANA PD-L1 (SP142) Assay, requiring that all system reagents are used together


  • Non-randomized, a multicenter, open-label, trial designed to evaluate the efficacy of TECENTRIQ in patients with locally advanced or metastatic urothelial carcinoma
  • PD-L1 expression in ≥ 5% IC determined by VENTANA PD-L1 (SP142) Assay in urothelial carcinoma tissue associated with increased objective response rate (ORR) from TECENTRIQ
  • Performance of Assay also supported by analytical validation studies


  • Risks based on data collected in clinical study
  • Failure of device may lead to failure to correctly interpret test result
  • Testing on tumor specimens does not present additional significant safety concerns, as these samples are routinely removed for diagnosis


CEREVE Sleep System

Cereve, Pittsburgh, PA, USA

INDICATION FOR USE:  Reduce sleep latency to Stage 1 and Stage 2 sleep in patients with primary insomnia

REG PATHWAY: De Novo, Class II, Product Code: PLU

DEVICE GENERIC DESCRIPTION: Thermal System for Insomnia: Prescription device for use in patients with insomnia that is used to apply a specified temperature to the skin surface

WALL FLEX Biliary Fully Covered Stent System 

Boston Scientific Corporation,  Marlborough, MA, USA

Reconstrainable delivery system

INDICATION FOR USE:  Indicated for indwell up to 12 months in the treatment of benign biliary strictures secondary to chronic pancreatitis

REG PATHWAY: De Novo, Class II, Product Code: PNB

DEVICE GENERIC DESCRIPTION: Metallic Biliary Stent System for Benign Strictures: Prescription device intended for the treatment of benign biliary strictures. The biliary stents are intended to be left indwelling for a limited amount of time and subsequently removed. The device consists of a metallic stent and a delivery system intended to place the stent in the bile duct. This device type is not intended for use in the vasculature.




WHAT:  Office of Prescription Drug Promotion

WHY: To protect the public health by ensuring that prescription drug information is truthful, balanced, and accurately communicated.

HOW: Comprehensive surveillance, enforcement, and education program, and by fostering better communication of labeling and promotional information to both healthcare professionals and consumers


WHAT ELSE: Bad Ad Program –  Truthful Prescription Drug Advertising and Promotion
The Prescriber’s Role – Recognize and Report



Debrief: Patient-Focused Drug Development for Neuropathic Pain Associated with Peripheral Neuropathy


Opening Remarks

Pamela Horn, MD Medical Officer Team Lead, DAAAP, CDER, FDA

  • Meeting addresses an unmet need for treatment that is finding patient-centered endpoints for clinical trials.
  • Hearing from patients will help steer drug development
  • FDA works to ensure safety, effectiveness, and quality of drugs

Overview of FDA’s Patient-Focused Drug Development Initiative

Sara Eggers, PhD OSP, CDER, FDA

  • Goal is to make more systematic way to gether patients inputs and perspectives
  • Originated from PDUFA V
  • This meeting is the 19th of 24 PFDD meetings for FY 2013-2017
  • Active patient involvement and participation encouraged

Background on Pain Neuropathies and Available Treatments

Steven Galati, MD, Medical Officer, DAAAP, CDER, FDA

  • Chronic Pain can be nociceptive (injury/inflammation) or neuropathic (pain without a stimulus)
  • Many different causes of neuropathy including diabetes and medical treatment
  • For the FDA to approve a neuropathy drug, there must be at least two successful trials
  • The FDA wants to know what symptoms bother patients the most so companies can target them in trials
  • Some challenges to drug development are that patients are still not satisfied with the drug and that one medication cannot cover multiple types of neuropathy

The Road from PFDD Meetings to Clinical Trial Endpoints

Nikunj Patel, PharmD Clinical Outcomes Assessments Staff, CDER, FDA

  • Patient recorded outcomes (such as answers to a questionnaire) will help create clinical trial endpoints
  • Stakeholders can listen to patients’ perspectives
  • PFDD meetings ensure that PRO’s accurately describe efficacy and drug safety
  • FDA encourages audience to engage others outside of PFDD meetings for more input
  • 3 pathways to generate outcome assessments
    • Input during investigational new drug submissions
    • Clinical outcome assessments (COA’s) to prove a treatment’s benefit during trials
    • Critical Path Innovation Meetings to advance drug efficacy using input from industry, academia, and patient-related groups

Panel #1 Discussion on Topic 1: Disease Symptoms and Daily Impacts

Adam Halper

    • Symptoms including soreness/muscle heaviness vary in intensity based on how much activity he does
    • Other symptoms including burning sensations are not “activity-dependent”
    • Limited mobility and cannot stand for more than 10-30 minutes
    • On worst days, can walk for only 5 minutes and cannot sleep comfortably
    • On best days, can walk about 3 miles
    • Intensity of symptoms fluctuates (no clear progression)

Susan Waldrop

    • Condition resulted from chemotherapy for colon cancer
    • Experiences burning sensations in limbs, electric shocks, and cannot walk, unpleasant numbness, increased sensitivity to cold
    • She cannot feel feet, causing problems with balance
    • Good days of normal activity are followed by bad nights

David Morrow (VP, Neuropathy Support Network)

    • Also resulted from chemotherapy for colon cancer
    • Slow progression
    • Experiences some foot and hand numbness, stabbing pains in feet, balance problems
    • Symptoms became less noticeable over time

Beth Lannon

    • Began as bilateral pain and slowly progressed
    • Sharp, constant pain (“like a hammer to my feet”), electrical shocks
    • Symptoms worsen with activity
      • Cannot sit for more than 15 minutes

Panel #2 Discussion on Topic #2: Current Approaches to Treatment

Linda Spinella

    • Pain because of multiple herniated disks
    • Was prescribed Lyrica, OTC pain relievers (incl. Tylenol), Prednisolone, opiods
    • Also went to the chiropractor and received epidurals for short-term relief
    • Cannot sleep without medication
    • Usually anxious, jittery, agitated

Cherie Pagett

    • Experiences numbness up to her knees
    • Takes Neurontin, Miradol, Lidocaine, opioids
    • When she took Lyrica, she gained 25 pounds in six weeks
    • Does not feel that her pain is under control because she will have intense flashes of pain

Louis Schmitt

    • 20 months of high dosage of IVIG to repair damaged nerves
    • Believes meditation managed anxiety/depression associated with his neuropathy
    • Prescribed 4000 mg neurontin but it did not work
    • Feels that 450 mg Lyrica is a “life saver” because it gives almost immediate relief
    • Tries to exercise as often as he can
    • Brain feels lagged (“mental fog”),
    • Experiences drowsiness, weight fluctuations, and swelling
    • If he were in a clinical trial, he would like to know of all side effects ahead of time and any estimate of effectiveness

Jackie Evangelista

    • Neuropathy caused by lyme disease
    • Slow progression of disease to the point that she cannot notice the worsening f some symptoms
    • Condition has not improved that much from medication
      • Feels treatment “only takes the edge off… does not stop advance”

Large-Group Facilitated Discussion: Topic 2

  • Trials should measure how much time one can do a specific physical task
  • Some patients feel that just pain relief is not the best indicator for drug effectiveness
  • Patients usually try a treatment for 3-4 weeks before deciding if it works
  • The issue of side effects is the most prevalent causing of switching medications/therapies
  • Some patients feel that support groups, meditation, and other activities to boost emotional well being help diminish the effect of pain


Addressing Statin Intolerance



High LDL-C (low-density lipoprotein – cholesterol or hypercholesterolemia) is a significant risk factor for cardiovascular disease. The CDC (Centers for Disease Control) through NHANES (National Health & Nutrition Examination Survey) estimated that over 81 million U.S. adults have elevated levels of LDL-C. In the U.S., increasing attention has been placed on aggressive LDL-C lowering.

This has led to the combination of statins with other treatments to reach LDL-C goals. Statins which includes such brand names as Lipitor, Zocor, Pravachol, Crestor, Livalo and others have been shown to be effective in reducing LDL-C and consistently have been shown to be associated in reduction in heart and vascular disease risk. The most common side effects of statins include gastrointestinal intolerance such as constipation, nausea, or indigestion, headache and upper respiratory type symptoms.

However, a subset of patients is unable to tolerate statins due to side effects, including muscle pain or weakness (Myalgia), increased glucose levels and increased liver transaminase.  In 2012, the FDA warned that statins can cause hyperglycemia (an increase in blood sugar levels) and increased the risk of worsening of glycemic control and of new onset diabetes.


A new class of cholesterol drug could sharply cut bad LDL cholesterol in people who cannot tolerate the commonly used cholesterol-lowering medications called statins.

Praluent (alirocumab injection) and Repatha (evolocumab injection) are PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. PCSK9 inhibitors work by blocking a protein in the liver that helps regulate LDL. These drugs are for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol. HeFH is an inherited condition that causes high levels of LDL cholesterol.

Kynamro (mipomersen sodium injection) is a first-in-class antisense oligonucleotide (ASO) inhibitor targeted to apolipoprotein B-100 (apoB-100). Mipomersen’s proposed indication is as an adjunct to maximally tolerated lipid-lowering medications and diet to reduce low-density lipoprotein (LDL-C), apoB, total cholesterol, non-high-density-lipoprotein-cholesterol (non-HDL) and lipoprotein (a) in individuals with homozygous familial hypercholesterolemia (HoFH). HoFH is an inherited condition occurs when the body is unable to remove LDL-C from the blood causing abnormally high levels of circulating LDL-C.

Juxtapaid (lomitapide capsule) is a new medication approved for lowering cholesterol. It is approved for use only in patients with familial hypercholesterolemia already on statin mediations. Those are patients with extreme elevations in LDL cholesterol and high risk of early heart disease. It is not a statin, and is the first in a new class of medications called microsomal triglyceride transfer protein (MTP) inhibitors. Juxtapid is an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce LDL-C, total cholesterol (TC), apolipoprotein B (apo B) and non- high-density-lipoprotein cholesterol (non-HDL) in patients with homozygous familial hypercholesterolemia (HoFH).


FDA Approvals and Reviews: VAXCHORA vaccine, LIFESTENT vascular system

FDA BRIEF: Week of  June 6, 2016

FDA approved

VAXCHORA (Cholera Vaccine, Live, Oral) Suspension for Oral Administration

PaxVax Bermuda Ltd., Hamilton, BERMUDA.

INDICATION:  Active immunization against disease caused by Vibrio cholerae serogroup O1 in adults 18 through 64 years of age traveling to cholera-affected areas


  • Cholera, caused by Vibrio cholerae bacteria, acquired by ingesting contaminated water or food;  profuse diarrhea, vomiting, dehydration; potentially life threatening
  • Serogroup O1 is the predominant cause of cholera globally
  • Need for additional cholera-prevention measures beyond preventive strategies recommended by CDC

REG PATHWAY: Fast Track, Tropical Disease Priority Review

MECHANISM OF ACTION: Live attenuated cholera bacteria that replicate in gastrointestinal tract; rises in serum vibriocidal antibody 10 days after vaccination


  • Randomized, double-blind,  V. cholerae challenge study in  US (N=197), no prior history of cholera infection,  VAXCHORA vs. placebo
  • Endpoint: Lack of occurrence of moderate to severe diarrhea
    • With VAXCHORA, 90.3% , 10 days postvaccination,  79.5%  three months postvaccination vs 39% with plabeo
  • Immunogenicity (2 studies):  Vibriocidal antibody assay to measure serum levels of neutralizing antibodies. >90% post vaccination


  • Most common adverse reaction: Tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea



Bard Peripheral Vascular, Inc. Tempe, AZ, USA


INDICATION FOR USE: Improve luminal diameter in the treatment of symptomatic de novo or restenotic lesions up to 240 mm in length in the native superficial femoral artery (SFA) and popliteal artery with reference vessel diameters ranging from 4.0 – 6.5 mm


  • The original PMA approved in 2009 indicated to improve luminal diameter in the treatment of symptomatic de novo or restenotic lesions up to 160 mm in length in the native superficial femoral artery (SFA) and/or proximal popliteal artery with reference vessel diameters ranging from 4.0 – 6.5 mm
  • Supplement to expand indication to include treatment of lesions in mid and distal popliteal artery


  • LifeStent® Vascular Stent (stents 20 – 80 mm)
  • LifeStent® XL Vascular Stent (stents 100 – 170 mm)
  • Bard® LifeStent® Solo™ Vascular Stent System
  • All contain self-expanding, flexible, nitinol stents that expand to a preset diameter upon exposure to body temperature
  • Sents equivalent to one another in design; in addition LifeStent® and LifeStent® Solo™ stents contain 6 tantalum radiopaque markers on both the distal and proximal ends


  •  ETAP trial,  a prospective, randomized, multi-center study (n=246)
  • LifeStent®  vs. percutaneous transluminal angioplasty (PTA) in the treatment of patients with stenosis and occlusion of the popliteal artery .
  • Primary endpoint: Primary patency, defined as freedom from target-lesion restenosis (luminal narrowing of ≥50%) as detected by duplex ultrasound. Lower restenosis rate at 12 months; followup for 24 month with Lifestent
  • Secondary endpoint: Beneficial clinical trend in favor of stent placement with Lifestent

Freedom from Restenosis for Popliteal Segment 1



  • Major adverse events: Death, major amputation and minor amputation, TLR (including need for surgical revascularization), and myocardial infarction similar between two groups
  • No major adverse events attributed to the device or procedure





FDA NEWS: Global Partnerships, Device Patient-Specific Information, Genomic Sampling, Diurnal Pattern Recorder Classification

FDA BRIEF: Week of June 6, 2016


Globalization and FDA’s New Partnerships to Ensure Product Safety

Howard Sklamberg

by: Howard Sklamberg,  Deputy Commissioner for Global Regulatory Operations and Policy

CHALLENGE: Ever-increasing volume and complexity of FDA-regulated products coming to US with has ramifications for our nation’s public health.

  • 34 million shipments
  • 130,000 importers
  • 300,000 foreign manufacturers

SOLUTION: Risk-based approach to oversight by partnering with foreign regulators in verifying safety standards


  • Medical Device Single Audit Program : International approach to auditing and monitoring of DEVICE manufacture and quality management systems. Australia, Brazil, Canada, Japan, and the U. S. in pilot
  • Mutual Recognition Agreements:  Recognize each other’s drug Good Manufacturing Practice (GMP) inspections for DRUG manufacturing US and EU

NEXT: Continued careful reliance on trusted foreign partners and minimization of public health risks globally.



fda guidances

pt gyuidance.JPG


  • Appropriate and responsible dissemination of patient-specific information recorded, stored, processed, retrieved, and/or derived from medical devices
  • From manufacturers to patients


  • Data a healthcare provider inputs to record  status and ongoing treatment
  • Information stored by device to record usage, alarms, or outputs (e.g., pulse oximetry data, heart electrical activity, and rhythms as monitored by a pacemaker)


  • Content:  Paitent specific, interpretable, comprehensive and contemporary. Provide supplementary instructions, materials or references to aid patient understanding – may extend to labeling
  • Context: Include relevant context to avoid misinterpretation; advise patients to contact healthcare providers to discuss




OBJECTIVE: Provide harmonized principles of genomic sampling  and management of genomic data in clinical studies







April 28, 2014:Sensimed AG requested classification of the SENSIMED Triggerfish® device under section 513(f)(2) of the FD&C Act. Recommended class II


March 4, 2016: FDA reviewed and believes special controls, in addition to general controls, will provide reasonable assurance of the safety and effectiveness of the device.Issued  order classifying into class II; codified .21 CFR 886.1925.

GENERIC NAME: Diurnal pattern recorder system

Nonimplantable, prescription device incorporating a telemetric sensor to detect changes in ocular dimension for monitoring diurnal patterns of intraocular pressure (IOP) fluctuations.


  • Ocular Adverse Events (eg Hyperemia, Punctate keratitis, Dry eye, Foreign body sensation, Itching, burning, Swelling of eyelids, Pick eye, Excessive watering): Clinical testing, Biocompatibility, Labeling
  • Infection : Sterilization, Labeling
  • Adverse Tissue Reaction: Biocompatibility, Labeling
  • Software Malfunction: Software Verification & Validation, Hazard Analysis
  • Hardware Malfunction: Nonclinical Testing
  • User Error: Clinical Testing
  • Electromagnetic Interference with Other Devices: Electromagnetic Compatibility & Interference Testing, Labeling
  • Electrical Malfunction: Electrical Safety Testing, Labeling
  • Incorrect Graphical Representation of Variation due to measurement noise: Labeling



FDA BRIEF: Week of May 3o, 3016


FDA approved


Biocartis NV, Mechelen BELGIUM


INDICATION: Presumptive detection of Ebola Zaire virus1 (detected in the West Africa outbreak in 2014) in EDTA venous whole blood specimens from individuals with signs and symptoms of Ebola virus infection in conjunction with epidemiological risk factors

REG PATHWAY:  Emergency Use Authorization (EUA). Test only by laboratories  certified under the Clinical Laboratory Improvement Amendments (CLIA)


  • Automated real-time reverse transcription polymerase chain reaction (rRT-PCR) assay
  • Consisting of instrument,  console, and single-use test-specific cartridge
  • Samples inserted into Cartridge are processed using encrypted software,  Test Type Packages (TTP)
  • System covers entire sample-to-result process: preparation (homogenization, cell lysis and RNA extraction), rRTPCR amplification, target sequence detection, PCR data analysis, result reporting


  • Ebola Zaire viruscan cause Ebola virus disease, a serious or life-threatening disease or condition to humans
  • Based Totality of Scientific Evidence, Virus Triage Test may be effective in diagnosing Ebola Zaire virus and that the known and potential benefits of detection of infection outweigh the known and potential risks
  • No adequate, approved, and available alternative to the emergency use of the Triage Test



OCALIVA (obeticholic acid) tablets

Intercept Pharmaceuticals, New York, New York, USA

INDICATION:  treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA


  • PBC is  chronic, or long lasting, disease that causes inflammation and damage of  small bile ducts in liver
  • Damages liver over time and loses its ability to function.
  • Left untreated, or unresponsive to UDCA, are at risk for liver failure and death

REG PATHWAY: NDA, Fast Track Designation, Orphan Drug Designation, Accelerated Approval

MECHANISM OF ACTION:  Binds to the farnesoid X receptor (FXR), a receptor found in cell nucleus in liver and intestine; increases bile flow from liverm suppresses bile acid production, thus reducing liver  exposure to toxic bile acid levels


  • Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • Trial 1: Randomized, double-blind, placebo-controlled, 12-month trial (n=216), vs. placebo
  • Primary endpoint: Composite Responder analysis, Month 12,:  ALP less than 1.67-times the ULN, total bilirubin less than or equal to ULN, and an ALP decrease of at least 15%. : 48%, 46% on OCALIVA vs 10% for placebo


  • Most common side effects: Severe itching of the skin (pruritus), fatigue, abdominal pain and discomfort, joint pain (arthralgia), pain in the middle part of the throat (oropharyngeal), dizziness and constipation


ZINBRYTA (daclizumab) injection

Biogen Inc., Cambridge, Massachusetts, USA

INDICATION:  Treatment of adult patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of ZINBRYTA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS


  • MS is a chronic, inflammatory, autoimmune CNS disease
  • Most common cause of neurological disability in young adults; more frequently in women
  • Most people experience their first symptoms of MS between the ages of 20 and 40
  • Need for additional choice to patients who may require a new option


MECHANISM OF ACTION: Precise mechanism unknown; presumed to involve modulation of IL-2 mediated activation of lymphocytes through binding to CD25


  • 2 randomized, double-blind, controlled studies (n=1841, 412 respectively) subcutaneous ZINBRYTA taken once every four weeks in patients with relapsing multiple sclerosis (RMS).
  • Study 1: ZINBRYTA vs Avonex. ZINBRYTA had statistically significant effect on annualized relapse rate (ARR) and on the number of new or newly enlarging T2 hyperintense lesions.
  • Study 2:  ZINBRYTA vs. placebo in 412 patients. ZINBRYTA had a statistically significant effect on ARR (week 52), the proportion of patients relapse free, the number of new T1 Gd-enhancing lesions, and the number of new or newly enlarging T2 hyperintense lesions


  • Boxed Warning on severe liver injury, including life-threatening and fatal events; perform routine blood tests
  • Boxed Warning on immune conditions eg non-infectious colitis, skin reactions, lymphadenopathy
  • Warnings on  hypersensitivity reactions (anaphylaxis or angioedema), increased risk of infections, and symptoms of depression and/or suicidal ideation
  • Common adverse reactions:  Cold symptoms, upper respiratory tract infection, rash, influenza, dermatitis, throat pain, eczema, and enlargement of lymph nodes.



Roche Molecular Systems, Pleasanton, California, USA

INDICATION FOR USE: Companion diagnostic test for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the epidermal growth factor recptor (EGFR) gene to identify patients with metastatic non-small cell lung cancer (NSCLC) eligible for treatment with Tarceva® (erlotinib).


  • 221,200 Americans diagnosed with lung cancer; 158,040 will die
  • NSCLC is the most common type of lung cancer.
  • EGFR mutations present in ~10-20 % NSCLC patients
  • Need for blood-based genetic test to detect EGFR gene mutations in NSCLC
  • Highly individualized health care for patients

REG PATHWAY: PMA, Priority Review. Classification: Somatic Gene Mutation Detection System, Pathology Advisory Committee.

Approved prior to MDUFA III goal date

  • Test already approved for NSCLC indication using formalin-fixed paraffin-embedded tissue specimens
  • New use is for detection of  specific mutations in circulating-free tumor DNA  isolated from plasma specimens – liquid biopsy specimens
  • First approved  “liquid biopsy test


  • Phase III TARCEVA vs gemcitabine + cisplatin study, first-line treatment for stage IIIB/IV NSCLC patients (ENSURE study)
  • Cobas EGFR Mutation Test v1 used to test tumor samples positive for EGFR exon 19 deletion or L858R mutations.
  • COBAS EGFR Mutation Test v2 used to test plasma samples for same mutation
  • Positive samples: Agreement 76.7% (70.5%, 81.9%)
  • Negative samples: Agreement 98.2% (95.4%, 99.3%)
  • Tarceva efficacy based on the cobas EGFR Mutation Test v2 in plasma bridged to   efficacy based on the cobas EGFR Mutation Test v1 in tissue


  • To be used to initially screen metastatic NSCLC patients with mEGFR mutations
  • If positive,  EGFR status should be confirmed using tissues specimens

NETSPOT (Somakit-TATE), Kit 

Advanced Accelerator Applications USA, Inc.

INDICATION FOR USE: a kit for the preparation of gallium Ga 68 dotatate injection for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients.


  • Critical to use advanced imaging techniques to detect rare neuroendocrine tumors at an early stage
  • Need for diagnostic tool to determine the location and extent of the tumor
  • Information is important for planning the appropriate course of therapy

REG. PATHWAY: Priority Review, Orphan Drug Designation, Classificaiton: Radioactive diagnostic agent


  • Sterile, single-dose kit for preparation of Ga 68 dotatate injection for intravenous use
  • Uptake of Ga 68 dotatate reflects the level of somatostatin receptor density in NETs
  • Uptake can  be seen in other tumor types, other pathologic conditions, normal variant
  • Uptake of Ga 68 dotatate may need to be confirmed by histopathology


  • Three studies
  • Study 1: Comparison of Ga 68 dotatate images of NETs to images obtained with approved drug, then confirmed with computed tomography (CT) and/ or magnetic resonance imaging (MRI)
  • Study 2: Evaluation of Ga 68 dotatate images using histopathology or clinical follow up as reference standards
  • Study 3: Evaluation of patients with NET recurrence using Ga 68 dotatate images
  • Results confirmed usefulness of Ga 68 dotatate images in finding neuroendocrine tumor location .


  • Contributes to overall long-term cumulative radiation exposure
  • Patients should drink and urinate as often as possible during the first hours following administration to help reduce this risk
  • No serious adverse reactions




FDA Guidance: IDE/CMS Coverage, Data Integrity

FDA BRIEF: Week of May 30, 2016

fda guidances



FDA policy on categorizing investigational device exemption (IDE) devices to assist CMS  in determining coverage (reimbursement)


Category A: Experimental

  • No PMA approval, 510(k) clearance or de novo request has been granted
  • Proposed device has different characteristics compared to a legally marketed device
  • Proposed device is being studied for a new indication or new intended use

Category B: Nonexperimental/Investigational

  • No PMA approval, 510(k) clearance or de novo request has been granted
  • Proposed device has similar characteristics compared to a legally marketed device
  • Proposed device is being studied for a new indication or new intended use






Inspecting for Data Integrity: From Manufacturing Floor to Quality Control Laboratories


  • Backup data are exact and complete, and secure from alteration, inadvertent erasures, or loss
  • Data  stored to prevent deterioration or los
  •  Certain activities documented at the time of performance
  • Laboratory controls be scientifically sound
  • True copies or other accurate reproductions of the original records
  • Complete information, complete data derived from all tests, complete record of all data, and complete records of all tests performed.



  • Responsibilities andapplicable procedures not in writing or fully followed
  • Laboratory controls do not include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures
  • Failure to thoroughly review any unexplained discrepancy or the failure of a batch
  • Procedures designed to prevent microbiological contamination not established
  • No written procedures for identity, strength, quality, and purity
  • Deficient aseptic processing areas
  • Routine calibration, inspection and checking of equipment not performed


FDA Communication: Expanded Access for Drugs and Devices

FDA BRIEF: Week of May 30, 2016


 Release of  Final Individual Patient Expanded Access Form

by: Robert Califf, M.D., FDA Commissioner 


  • FDA has finalized efforts to streamline EXPANDED ACCESS – also called ‘compassionate use’
  • Simplified approach for physicians to request expanded access
  • Individual Patient Expanded Access Investigational New Drug Application – Form FDA 3926.
  • Request expanded access to investigational drugs for individual patients who suffer from serious or immediately life-threatening diseases and for whom no comparable or satisfactory alternative therapy is available


Celebrating a Year of the Expedited Access Pathway Program for Medical Devices

Erin Cutts, B.S., Policy Lead, Office of Device Evaluation, CDRH

Owen Faris, Ph.D., Clinical Trials Director, Office of Device Evaluation, CDRH

Jeffrey Shuren, M.D., J.D.,  Director, CDRH 

Erin Cutts  Owen Faris  Jeffrey Shuren

  • CDRH created the voluntary Expedited Access Pathway (EAP) program to facilitate the development of and access to new technology for these patients who desperately need them
  • EAP Products ultimately undergo either Premarket Approval (PMA) or de novo review
  •  Criteria:
    • Treat or diagnose life threatening or irreversibly debilitating disease
    • Address an  unmet need
    • Data Development Plan outlining scope of future FDA submission





fda guidances

Final guidances related to expanded access.


  • Expanded Access for Individual Patient
  • Emergency Expanded Access for an Individual Patient
  • Considerations and Regulatory requirements including LOA form sponsor or contact FDA directly
  • FDA approval 30 days or sooner



  • Expanded access to an investigational drug under a treatment IND or protocol
  • Expanded access submissions




Revised regulation for charging for an investigational drug:

  • General criteria for authorizing charging
  • Criteria for charging in a clinical trial
  • Criteria for charging for an expanded access
  • Criteria for determining what costs can be recovered when charging





Artificial Pancreas: FDA-Diabetic Community dialogue

artifical panc.JPG




  • FDA is helping advance the development of an artificial pancreas device system (APDS)—an innovative device that automatically monitors blood glucose and provides appropriate insulin doses in people with diabetes who use insulin
  • Forward looking Guidance issued – prior to any approved device – to encourage development
  • Recommendations on appropriate endpoints and evidentiary standards for PMA approval; pediatric development encouraged
  • Manufacturers need to also focus on Quality System: Software (including sensors) and Hardware. Software problems anticipated. Require design features to prevent malfunctioning of system.
  • Cybersecurity concerns need to be addressed.
  • Interoperability issues need to be addressed
  • Regulatory burden for new technology depends on scope
  • Encourage Pre-Submission Meeting to align on required studies and study design to meet Intended Use/Indication for Use. Identify patient population, appropriate software algorithm for dosing for designing trial
  • Medtronic has completed pivotal trial with APDS and FDA submission anticipated










FDA Guidances: COPD, Histopathology for Biomarkers

FDA BRIEF: Week on May 23, 2016

fda guidances


INDICATION: Whole spectrum or defined entities


  • Improving airflow obstruction .
  • Providing symptom relief
  • Modifying or preventing exacerbations
  • Altering disease progression
  •  Modifying lung structure

DOSE SELECTION:  To optimize benefit/risk


  • Objective: Pulmonary function tests,  Exercise capacity,
  • Patient Reported Outcomes: Symptom scores, Activity scales, Health-related quality-of-life instruments
  • Biomarkers, Surrogate Endpoints:: lung function test parameters, such as FEV1,


  • Improving airflow obstruction
  • Providing symptom relief
  • Modifying or preventing exacerbations
  • Altering disease progression.
  • Modifying lung structure.

DURATION: 3 mo. – several years,  dependent on endpoint

DRUGS ADMINISTERED VIA INHALED ROUTE: Assessment of delivery systems on safety/efficacy

COMBINATION DRUGS: Compare product to each of its constituents to demonstrate combination product superior to each constituent





SCOPE: Biomarker qualification using histopathology as reference standard


  • Performance characteristics
  • Sensitivity and Temporal Correlation
  • Specificity
  • Reversibility/Resolution
  • Alternative Testing Models.


  • General Planning
  • Slide examination
  • Timing of Sample Collection
  • Controls
  • Fixation
  • Number of Sections and Sampling Location (at Necropsy)
  • Staining
  • Special methodology

OTHER CONSIDERATIONS: Digital Pathology and Slide Sharing, Lexicons, Filtering

OTHER FACTORS: Diagnostic Drift, Chronological Bias