FDA Brief: Week of February 20, 2017
FDA approved

  Image result for Vidas Brahms PCT AssayVIDAS BRAHMS TEST

bioMérieux Inc. in Marcy l’Etoile, France

INTENDED USE: Automated test for determination of human procalcitonin (PCT) in human serum or plasma (lithium heparin) using the Enzyme-Linked Fluorescent Assay (ELFA) technique. For use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.

INDICATION FOR USE: Help manage antibiotic treatment for lower respiratory tract infections and sepsis. Intended to be used in the hospital or emergency room


  • Unnecessary antibiotic use contribute to antibiotic-resistant infections
  • Need to determine if antibiotic treatment be started/stopped in patients with lower respiratory tract infections
  • This is the first test to use PCT as a biomarker to help make antibiotic management decisions

REG PATHWAY: 510(k) for Expanded Use

  • 21CFR 866.3610, Endotoxin activity
  • Classification: Class II
  • Product code: NTM – Antigen, inflammatory response marker, sepsis


  • Meta-analysis of clinical trial findings from published literature that compared PCT-guided therapy to standard therapy
  • Prospective, randomized studies showed a significant decrease in antibiotic use for patients who had received PCT-guided therapy, without significantly affecting safety.
  • Risks:  False positive results leading to unnecessary treatment with antibiotics, False negative results leading to delay in selection of appropriate therapy.

Image result for Revlimid

REVLIMID (Lenalidomide)

Celgene Corporation Summit, NJ, USA

INDICATION:   Maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT)


  • 2006: Initial approval  for use with dexamethasone in patients with multiple myeloma with one prior therapy
  • 2015: Expanded indication to include newly diagnosed multiple myeloma patients who are not eligible for autologous stem cell transplant


  • 2 randomized controlled studies in patients who had undergone induction therapy followed by auto-HSCT; vs placebo
  • Major efficacy endpoint: Progression Free Survival ( PFS) from randomization to progression/death. Not powered for Overall Survival (OS)
  • PFS: 15-month and 18-month advantage, p<0.001
  • Median OS:  111 and 106 months  vs. 84 and 88 months


  • Similar to previously described in  product label



FDA Approved: SILIQ

 FDA BRIEF: Week of February 13, 2017

SILIQ (brodalumab) injection

Valeant Pharmaceuticals,  Bridgewater, NJ, USA


INDICATION: Treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies.


  • Psoriasis, an autoimmune disorder, causes  plaque psoriasis
  • Moderate-to-severe plaque psoriasis can cause significant skin irritation and discomfort for patients
  • Another treatment option


  • Boxed Warning and Siliq Risk Evaluation and Mitigation Strategy (REMS) due to risk of suicidal ideation and behavior
  • Medication Guide to inform patients of the risk of suicidal ideation and behavior

MECHANISM OF ACTION: Human monoclonal IgG2 antibody that selectively binds to human IL-17RA and inhibits its interactions with cytokines inhibiting release of pro-inflammatory cytokines and chemokines


  • 3 multicenter, randomized, double-blind, controlled trials, n= 4373, SILIQ vs placebo, also vs ustekinumab in 2 studies, 12 weeks duration
  • Change from baseline two co-primary endpoints: 1) At least 75% reduction in Psoriasis Area and Severity Index (PASI) fro baseline  and 2) proportion of subjects with static Physician’s Global Assessment (sPGA) of 0 (clear) or 1 (almost clear), and at least a 2-point improvement from baseline
  • Greater proportion of SILIQ subjects achieved PASI score 0 or 1


  • Suicidal ideation and behavior, including completed suicides
  • Most common adverse reactions: Arthralgia, headache, fatigue, diarrhea, throat pain (oropharyngeal pain), nausea, muscle pain (myalgia), injection site reactions, influenza, low white blood cell count (neutropenia) and fungal (tinea) infections



FDA Brief: Drug Snapshot, POCA, Heart Devices, Drug Data Standards

FDA BRIEF: Week of Feb 13, 2017

Drug Trials Snapshots Summary Report Thumbnail

FDA Drug Trials Snapshots and Diversity When Testing New Drugs

by: John J. Whyte, M.D., M.P.H., Director of Professional Affairs and Stakeholder Engagement, CDER

John Whyte

CDER piloted Drug Trials Snapshots program

  • who participated in the studies
  • information by sex, race, and age subgroups
  • any reported differences in drug efficacy/safety by subgroup

Release of  Drug Trials Snapshots Summary Report

  •  diversity of participants
  • extent of efficacy/safety based on demographic factors
  • will help facilitate discussion on clinical trial demographics.
  • Now, anyone can go to the site and see the numbers for themselves in a quick snapshot.


FDA Website


POCA program is a software tool

  • uses advanced algorithm to determine orthographic & phonetic similarity between two drug names
  • can compare a drug name against multiple drug names in different “data sources”
  • datasources: [email protected], RxNorm

POCA is web-based application that was originally developed for the Microsoft .Net Framework 1.1 and the Oracle 9i Database. It has now been upgraded to include the following:


EKG and human heart illustration (600x350)

FDA-Approved Devices That Keep the Heart Beating

FDA-approved devices are used to treat various cardiovascular issues

  • Automated external defibrillators (AEDs)
  • Cardiac ablation catheters
  • Cardiovascular angioplasty devices
  • Cardiac pacemakers
  • Implantable cardioverter defibrillators (ICDs)
  • Prosthetic (artificial) heart valves
  • Stents
  • Ventricular assist devices (VADs)

Reporting problems with devices:



Data Standards in the Drug Lifecycle

Need for standard & uniform study data

  • enables combining data from multiple studies
  • help receive, process, review, archive submissions more efficiently and effectively
  • modernize and streamline the FDA review processClick through the interactive “Data Standards in the Drug Lifecycle” Infographic


Biomarkers Used as Outcomes


Biomarkers In Development of FDA-Approved Therapeutics

October 2007- December 2015


  • used as clinical trial outcome
  • accepted as basis for drug and biologic approvals
  • consult with FDA review division as early as possible in drug development regarding the use of a particular biomarker in clinical trials
  • examples of approved biomarkers below


Anesthesiology T1*; magnitude of T4/T1* ratio by acceleromyography
Cardiology Blood pressure
Serum low-density lipoprotein (LDL-C)
Hematology Hemoglobin
Platelet count
Ecarin clotting time; activated partial thromboplastin time; thrombin time; activated clotting time; plasma diluted thrombin time
Serum ferritin
Infectious Disease Hepatitis C virus (HCV) RNA*
Human immunodeficiency virus (HIV)-1 RNA
Sputum culture conversion to negative
Parasite count resolution
Inborn Errors of Metabolism White blood cell count; neutrophil count; red blood cell count; mean corpuscular volume
Growth in height or weight
Serum LDL-C
Blood phenylalanine
Forced vital capacity (FVC)
Plasma ammonia; plasma glutamine; and plasma citrulline
Splenic volume by magnetic resonance imaging (MRI)
Metabolism and Endocrinology Body weight
Bone mineral density by DEXA* scan
Hemoglobin A1c*
Serum calcium; oral calcium supplements; oral vitamin D supplements
Serum LDL-C
Urinary free cortisol (UFC)
Vertebral fractures by X-ray
Visceral adipose tissue (VAT) by computed tomography (CT) scan
Nephrology Hemoglobin
Serum sodium
Oncology CD34 positive cell count
Complete blood count (e.g., absolute neutrophil count)
Tumor burden by Bcr-Abl* (Philadelphia chromosome)
Tumor burden by Philadelphia chromosome positive cells
Plasma methotrexate
Splenic volume
Serum asparaginase
Serum testosterone
Tumor burden by imaging (using criteria such as RECIST* or EBMT*)
Ophthalmology Anterior chamber cells
Intraocular pressure (IOP)
Vitreomacular adhesion (VMA) by optical coherency tomography
Pulmonology Forced expiratory volume in one second (FEV1)
Respiratory distress syndrome (RDS) by chest X-ray and fraction of inspired oxygen (FiO2)
Rheumatology Joint angle
Uric acid
Transplant Biopsy-proven acute rejection (BPAR)

Medical Imaging Qualitative assessment of cerebral distribution of radioactive signal
Qualitative assessment of radioactive uptake (such as lymph node or tumor detection)
Qualitative regional assessment of localized radiographic signal intensity
Quantitation of arterial narrowing
Radioactive uptake in myocardial segments
Semi-quantitative lesion characteristics (such as internal morphology; contrast enhancement; border delineation)
Ultrasonographic signal intensity


FDA Brief: EMFLAZA approval, Dear HCP Guidance

FDA BRIEF, Week of February 6, 2017

FDA approved

EMFLAZA (deflazacort) tablets, oral suspension

Marathon Pharmaceuticals, Northbrook, IL, USA

Image result for emflaza

INDICATION: Treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older.


  • DMD occurs in about 1/3,600 male infants worldwide
  • Caused by absence of dystrophin; symptoms between 3 -5 trs of age
  • Lose ability to perform activities independently; life-threatening heart and respiratory conditions can occur


  • Fast Track designation, Priority Review, Orphan Drug Designation, Rare Pediatric Disease Priority Review Voucher
  • marketed outside US

MECHANISM OF ACTION:  Corticosteroid prodrug, acts through glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects; precise mechanism unknown


  • Multicenter, randomized, double-blind, placebo-controlled, 52-week study, n=196 male pediatric patients, documented dystrophin gene mutation, EMFLAZA vs placebo at 12 weeks; vs active comparator at additional 40 weeks
  • Primary Endpoint: Change in Baseline and Week 12 in average strength of 18 muscle groups using MRC 11-point scale
  • Significantly greater vs placebo (p=0.017) at week 12
  • Persistence of the treatment effect at week 52
  • Additional randomized, double-blind, placebo-controlled, 104-week vs placebo, n=29 (6-12 yr)
  • Average muscle strength score at 2 years not statistically significant; patients on EMFLAZA appeared lose the walking ability later than placebo


  • Side effects similar to other corticosteroids
  • Most common : Facial puffiness (Cushingoid appearance), weight gain, increased appetite, upper respiratory tract infection, cough, extraordinary daytime urinary frequency (pollakiuria), unwanted hair growth (hirsutism) and excessive fat around the stomach (central obesity)


GUIDANCE: Dear Healthcare provider Letters



Dear Health Care Provider (DHCP) letters intended to alert physicians and other health care providers about important new or updated information on  human drug or biologic

  • Often in the form of a mass mailing from the manufacturer
  • Need to improve effectiveness in communicating drug information


  • FDA consultation on development
  • When to use and which type to use
  • Important Drug Warning Letters
  • Important Prescribing Information Letters
  • Important Correction of Drug Information Letters
  • Content and Format
  • Assessment of impact




FDA BRIEF: Week of January 30, 2017

FDA approved

ASPIRE Cristalle Digital Breast Tomosynthesis Option

Fujifilm Medical Systems, Stamford, CT, USA

ASPIRE Cristalle by FUJIFILM Medical Systems U.S.A., Inc

INDICATION FOR USE: Acquires and generates full-field digital mammograph (FFDM) and Digital Breast Tomosynthesis (DBT() images, and is intended for use in the screening and diagnosis of breast cancer.


  • Device Generic Name: Digital Breast Tomosynthesis Mammography System Device
  • Product Code: OTE


  • 2 main subsystems & 3 operating modes
  • Main subsystems 1) The FDR-3500DRLH X-ray Stand (Exposure Unit) integrated x-ray delivery system   and 2) The FDR-3000AWS Acquisition Workstation (AWS) controls the exposure unit to acquire and process mammographic images.
  • Operation modes to capture 2D and 3D images


  • Multiple-reader multiple-case (MRMC) study:  Reader performance on average increases 0.053 AUC ROC units with two-sided 95% CI: 0.028, 0.078; p < 0.01.
  • Combined with physical laboratory test results and sample image evaluation, ASPIRE Cristalle DBT option used as an adjunct is superior to FFDM alone
  • Device Risks: Patient direct harm is minimal. Risk posed similar to other screening and diagnostic mammography devices.

Approval Order

GORE® VIABAHN® VBX Balloon Expandable Endoprosthesis

W. L. Gore & Associates, Flagstaff, AZ, USA


INDICATION FOR USE:  Treatment of de novo or restenotic lesions found in iliac arteries with reference vessel diameters ranging from 5 mm – 13 mm and lesion lengths up to 110 mm, including lesions at the aortic bifurcation


  • Generic name: Stent, Iliac
  • Product Code: NIO


  •  Surgical grade stainless steel balloon expandable stent and fluoropolymer graft
  • The CBAS® Heparin Surface consists of stable, covalent, end-point attached heparin of porcine origin
  • Endoprosthesis premounted on delivery system equipped with balloon
  • Delivery system can be used for initial stent placement and post stent dilatation


  • Single prospective, multicenter, single-arm clinical study e in patients with de novo or restenotic lesions in the common and / or external iliac arteries (n=132)
  • Primary endpoint:   device- or procedure-related death within 30 d, myocardial infarction (MI) within 30 d; amputation above the metatarsals in the treated leg, resulting from a vascular event or target lesion revascularization (TLR) within 9 mo
  • No device- or procedure- related deaths and no MIs within 30d, no major amputations within 9 mo, TLR in 3 subjects



FDA Approvals and Device Classification Orders: OPDIVO, PARSABIV,SEEKER

FDA BRIEF: Week of January 30, 2017

FDA approved

OPDIVO (nivolumab ) injection

Bristol-Myers Squibb, Princeton, NJ, USA


Image result for opdivo

INDICATION: Treatment of patients with locally advanced or metastatic urothelial carcinoma who:

  • have disease progression during or following platinum-containing chemotherapy
  • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

REG PATHWAY: Supplemental BLA

  • Accelerated Approval: Based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

MECHANISM OF ACTION: Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells


  • Single study (n=270), locally advanced or metastatic urothelial carcinoma with disease progression, OPDIVO every 2 weeks until unacceptable toxicity/progression
  • Objective response rate (ORR): Assessed by independent committee using RECIST criteria
  • Duration of response (DOR)
  • Complete Resposne=7, Partial Response= 46
  • DOR= 10.3 months


  • Most common adverse reactions: Fatigue, musculoskeletal pain, nausea, and decreased appetite
  • Fourteen patients died from causes other than disease progression, including pneumonitis or cardiovascular failure attributed to nivolumab

PARSABIV™ (etelcalcetide) injection

Amgen, Thousand Oaks, CA, USA

Image result for parsabiv image

INDICATION:  Treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on hemodialysis.

  • Has not been studied in adult patients with parathyroid carcinoma, primary hyperparathyroidism, or with chronic kidney disease who are not on hemodialysis and is not recommended for use in these populations


MECHANISM OF ACTION: Calcimimetic agent that allosterically modulates calcium-sensing receptor (CaSR) and decreases PTH secretion


  • Two 26-week, randomized, double-blind, placebo-controlled studies
  • Primary outcome measure: Proportion of patients with > 30% reduction in PTH levels from baseline –  weeks 20 through 27
  • Significantly higher proportion of patients treated with PARSABIV achieved a greater than 30% reduction in PTH levels from baseline
  • Reduction in mean PTH, corrected serum calcium, and serum phosphate levels from baseline to the end of study were observed in  PARSABIV arm; statistically significant different from placebo


  • Most common adverse reactions: Blood calcium decreased, muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, and paresthesia
  • Warnings and Precautions: Hypocalcemia,  Worsening Heart Failure,  Upper Gastrointestinal (GI) Bleeding, Adynamic Bone


classSEEKER System

Baebies Inc, Durham, NC, USA



INDICATION FOR USE: Quantitative measurement of the activity of α-L-iduronidase, α-D-glucosidase, β- glucocerebrosidase and α-D-galactosidase A from newborn dried blood spot specimens as an aid in screening newborns for Mucopolysaccharidosis Type I, Pompe, Gaucher and Fabry diseases. Reduced activity of these enzymes may be indicative of these lysosomal storage diseases. The enzymes measured using the SEEKER LSD Reagent KitIDUA|GAA|GBA|GLA and their associated lysosomal storage diseases are listed below.

  • α-L-iduronidase (IDUA)  – Mucopolysaccharidosis Type I (MPS I)
  • α-D-glucosidase (GAA)- Pompe
  • β-glucocerebrosidase (GBA)- Gaucher
  • α-D-galactosidase A (GLA)- Fabry

REG PATHWAY: De Novo Request

  • Regulation Number: 21 CFR 862.1488
  • Regulation Name: Lysosomal storage disorder newborn screening test system
  • Regulatory Classification: Class II
  • Product Code: PQW, PQT, PQU, PQV


  • Inaccurate test results that provide false negative test results could lead to a newborn to not be detected as a possible lysosomal storage disorder case and to be delayed from timely therapy – Special Controls
  • Inaccurate test results that provide false positive test results could lead a newborn to have unnecessary additional confirmatory testing and to add emotional burden to the family of the newborn – Special Controls
  • Special Controls:  Premarket notification submissions with  device performance characteristics of the device, Labeling



FDA News: ICH GCP Renovation, Medical Device Safety, Drug Development by Small Companies, Call for Advisory Committee Nominations

FDA BRIEF: Week of January 30, 2017

Image result for ICH logo

ICH Reflection on “GCP Renovation”: Modernization of ICH E8 and Subsequent Renovation of ICH E6

The International Council for Harmonisation (ICH) Reflection Paper

  • FDA helped with draft
  • Focus on modernizing clinical trial design, planning, management and conduct
  • Addresses increasing diversity of study types and data sources used to support regulatory and health policy decisions
  • Underlying principles of human subject protection and data quality would remain

Revisions to:

  • ICH E6: Guideline for Good Clinical Practice
  • ICH E8 : General Considerations for Clinical Trials


 Registry-Based Prospective, Active Surveillance Of Medical-Device Safety

FDA funded study

PROBLEM: Medical Device Safety Assurance based constrained by reliance on voluntary reporting of adverse events

STUDY: Prospective, active surveillance of national clinical registry to monitor post-marketing safety of Mynx (Cardinal Health) implantable vascular-closure device

  • Had  suspected association with increased AE after percutaneous coronary intervention

METHOD: Used active clinical-data surveillance system –  DELTA (Data Extraction and Longitudinal Trend Analysis)

  • Integrated software components linking open-source database management and statistical analysis tools
  • Prospectively monitored clinical registries, detailed clinical-data sources


  • Rapidly identified potential safety signals among recipients
  • Initial safety alerts occurred within the first 12 months



Drug-Development Challenges for Small Biopharmaceutical Companies

Article co-authored by FDA and Sanofi Genzyme

Majority of drugs currently in development are  by small biopharmaceutical companies

  •  Virtual Companies (no products/revenue)  to  Small Companies (few commercial programs)

May have lower rate of success than that of large companies

  • Limited : Clinical development experience, infrastructure, manufacturing, resources and funding

Creative Approaches to Regulatory Success


Comments open through March 1, 2017


Collection of Nominations for Candidates To Serve on the FDA’s Advisory Committees

Nominee should provide:

(1) CV

(2) Written confirmation that the nominee is aware of nomination (unless self-nominated)

(3) Letters of Recommendation

Nominee should review:

  • Vacancies, Qualifications, and Experience
  • Potential Conflicts of Interest: Financial holdings, employment, research grants and/or contracts

Previous Metrics:

  • 2011: 638 submissions
  • 2012: 603 submissions
  • 2013: 622 submissions
  • 2014: 545 submissions
  • 2015: 357 submissions



Office of Manufacturing Quality Presentations



FDA Approvals: TRULANCE, VIOGUARD Keyboard, Tear Duct Occluder

FDA BRIEF: Week of January 23, 2017

FDA approved

TRULANCE (plecanatide) tablets

Synergy Pharmaceuticals, New York, NY, USA 

Image result for trulance
Source: Google

INDICATION:  Adults for the treatment of chronic idiopathic constipation (CIC).


  • ~ 42 million people affected by constipation
  • CIC causes persistent constipation with no structural or biochemical explanation
  • Need for new therapies for appropriate treatment


MECHANISM OF ACTION: Plecanatide and active metabolite act locally on luminal surface of intestinal epithelium resulting in increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation stimulates secretion of chloride and bicarbonate into the intestinal lumen, resulting in increased intestinal fluid and accelerated transit.


  • Two 12-week, double-blind, randomized, multicenter clinical studies (n=905, 820), TRULANCE vs. placebo
  • Primary Endpoint: Responder analysis and change-from-baseline in complete spontaneous bowel movements (CSBM) and SBM endpoints
  • Assessed using daily patient input in electronic diary
  • Frequency of CSBMs/week seen as early as week 1; maintained through week 12
  • Also improvements in stool frequency, stool consistency, straining with bowel movements

SAFETY: Most common and serious side effects  was diarrhea



VIOGUARD Self-Sanitizing Keyboard 
Vioguard, Kirkland, WA, USA
Source: Vioguard

INDICATION FOR USE: For use in a healthcare environment to reduce microbial populations typically found on a computer keyboard.

Device Effectiveness: In laboratory testing, the Vioguard Self-Sanitizing Keyboard (Model UVKB50) has been shown to be effective at reducing populations of the following microorganisms when operated at its factory power setting of 240 mW-s/cm2:

Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia

REG PATHWAY: De Novo Request
  • Regulation Number: 880.6600
  • Regulation Name: Ultraviolet Radiation (UV) Chamber Disinfection Device
  • Regulatory Classification: Class II
  • Product Code: OSZ


An ultraviolet radiation (UV) chamber disinfection device intended for the low-level surface disinfection of non-porous equipment surfaces by dose-controlled UV irradiation. This classification does not include self-contained open chamber UV disinfection devices intended for whole room disinfection in a healthcare environment.

  • Inadequate Equipment Disinfection: Performance Testing,  Labeling
  • UV Radiation Exposure: Performance Testing, Labeling
  • Electrical Shock: Electrical Safety Testing
  • Electromagnetic Interference:Electromagnetic Compatibility (EMC) Testing,  Labeling
  • Ozone Exposure: Ozone Generation Limits, Labeling
  • Processed Equipment Incompatibility: Performance Testing, Labeling
  • Contamination of Device: Cleaning and Disinfection Validation, Labeling
  • Software Malfunction: Hazard Analysis, Verification and Validation
  • Special Controls: Performance testing, Software verification, validation, and hazard analysis,  Electrical, Mechanical safety, Electromagnetic Compatibility, Labeling
Innovatex, Weston, MA, USA
Source: Innovatex
INDICATION FOR USE:  Temporarily occlude the nasolacrimal ducts in adult patients to reduce outflow through the nasolacrimal ducts.
REG PATHWAY: De Novo Request
  • Regulation Number: 21 CFR 886.5838
  • Regulation Name: Nasolacrimal Compression Device
  • Regulatory Classification: Class I Exempt
  • Product Code: PLX


Nasolacrimal compression device is a prescription device that is fitted to apply mechanical pressure to the nasal aspect of the orbital rim to reduce outflow through the nasolacrimal ducts.