FDA Guidances: Medication Errors, Digital Pathology, Data Integrity & CGMP

FDA BRIEF: Week of April 25, 2016

fda guidances


  • Best practices on how to improve the drug product and container closure design
  • Examples that have resulted in postmarketing medication errors
  • Minimize errors by proactive risk assessments and addressing risks before marketing


PROACTIVE RISK ASSESSMENTS: Failure Mode and Effects Analysis, Simulated Use Testing


technical perf

  • For regulatory evaluation of a digital whole slide imaging (WSI) system
  • Several recent technological advances in digital microscopy
  • Need understanding of technical performance of WSI system and components to design appropriate non-technical analytical and clinical studies
  • Guidance provides recommendations for assessment of WSI technical characteristics

-Description and Test Methods for Each Component

-System-level Assessment

-User Interface


-Quality Control




  • Increased observation of  CGMP violations involving data integrity- compromising industry’s responsibility to ensure safety, efficacy, quality of drugs
  • Guidance provides Agency’s current thinking on creation and handling of data in accordance CGMP
  • Allows for flexible, risk-based strategies to prevent and detect data integrity issues
  • Guidance outlines scope and application of21CFRpart 11 pending FDA’s reexamination of part 11
  • Clarification provided on : “data integrity”,  “metadata”, “audit trail”,  “static” and “dynamic”  record formats, “backup”
  • Several other Q&As provided


MDUFA IV Stakeholder Meeting Minutes

FDA BRIEF: Week of April 25 2016



STAKEHOLDERS : Duke University, National Center for Health Research, Alliance for Aging Research, Epilepsy Foundation, National Coalition for Cancer Survivorship, National Health Council, American College of Cardiology, American Academy of Neurosurgery,  FasterCures, Society for Women’s Health Research, Pew Charitable Trusts, National Organization for Rare Disorders, Research!America, Avalere Health

  • FDA discussed the current status of proposals

-Cost of additional enhancements to program as identified by Industry

-Industry vs FDA areas of interest and priority

-Additional discussions needed to close gap in priority assessments

  • FDA presentation: Inter-center consultation review process for combination products

-History and Challenges

-Recommendations: Increased collaboration, review consistency, improved IT access, expedited data access, standardized processes and guidances


DEFITELIO Clinical Pharmacology Card

DEFITELIO (defibrotide sodium) Injection

Mechanism of Action

In vitro, defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Defibrotide sodium also increases tissue plasminogen activator and thrombomodulin expression and decreases von Willebrand factor and plasminogen activator inhibitor 1 expression, thereby reducing endothelial cell (EC) activation and increasing EC-mediated fibrinolysis. 

Pharmacodynamics (PD)

At a dose 2.4 times the maximum recommended dose, DEFITELIO does not prolong the QTc interval to any clinically relevant extent.

 There were no statistically significant differences in mean plasminogen activator inhibitor1 (PAI-1)  levels by treatment or outcome.

Pharmacokinetics (PK)

In healthy volunteers, the defibrotide sodium area-under-the-curve (AUC) increases in a dose-proportional manner over the range of 6.25 to 15 mg/kg (1 to 2.4 times the approved recommended dosage); however, the increase in Cmax is more than dose-proportional.

 Human plasma protein binding is 93%

 Terminal half-life: less than 2 hours in Veno-occlusive Disease patients.

Defibrotide sodium is mainly eliminated by metabolism followed by renal excretion (approximately 5 to 15% unchanged in the urine).

PK-PD Analysis

Not reported

Population PK

Not reported

Special Populations

No dose adjustment is needed for age (range <1 to 72 years), renal impairment, or hepatic impairment.

Drug Interactions

Co-administration of systemic anticoagulant or fibrinolytic therapy such as heparin or alteplase is contraindicated because of an increased risk of hemorrhage.

Source : http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208114lbl.pdf



ANTHIM Clinical Pharmacology Card

ANTHIM (obiltoxaximab) injection

Mechanism of Action

Obiltoxaximab is a deimmunized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds the protective antigen (PA) of B. anthracis, thereby preventing its association with the anthrax toxin receptor on host cells.

Pharmacodynamics (PD)

Because the effectiveness of ANTHIM cannot be evaluated in humans, a comparison of ANTHIM exposures achieved in healthy human subjects to those observed in animal models of inhalational anthrax in therapeutic efficacy studies. Based on observed and simulated data, healthy subjects and humans infected with B. anthracis achieve similar obiltoxaximab median Cmax and 2-fold greater median AUCinf following a single 16 mg/kg IV dose compared to exposures associated with efficacy in rabbits and monkeys in inhalational anthrax efficacy studies.

Pharmacokinetics (PK)

The PK of obiltoxaximab are linear over the dose range of 4 mg/kg (0.25 times the lowest recommended dose) to 16 mg/kg following single IV administration in healthy subjects.

 Mean Cmax and AUCinf were 400 mcg/mL and 5170 mcg•day/mL, respectively, following a single 16 mg/kg IV dosing to healthy male and female subjects.

 Mean obiltoxaximab steady-state volume of distribution was greater than plasma volume, suggesting some tissue distribution.

 Terminal half-life is approximately 15 to 23 days in healthy 75 subjects.

Obiltoxaximab clearance was much smaller than the glomerular filtration rate indicating that there is virtually no renal clearance.

PK-PD Analysis

Not reported

Population PK

Population pharmacokinetic analysis indicated that gender (female versus male), race (non-Caucasian versus Caucasian), or age (elderly versus young) had no meaningful effects on the PK parameters for ANTHIM. 

Special Populations

ANTHIM PK have not been evaluated in children

Drug Interactions

Co-administration of 16 mg/kg ANTHIM intravenously with intravenous or oral ciprofloxacin in human subjects did not alter the PK of either ciprofloxacin or obiltoxaximab

Source: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=39ad8799-00a4-4fc8-9852-c0536350c474

TALTZ Clinical Pharmacology Card

TALTZ (ixekizumab) injection, for subcutaneous use 

Mechanism of Action

Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.

Pharmacodynamics (PD)

No formal pharmacodynamic studies have been conducted.

Pharmacokinetics (PK)

Ixekizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over a dose range from 5 mg to 160 mg following subcutaneous administration.

 Iixekizumab bioavailability ranged from 60% to 81% following subcutaneous injection in subjects with plaque psoriasis. Administration of ixekizumab via injection in the thigh achieved a higher bioavailability relative to that achieved using other injection sites including the arm and abdomen.

 Mean systemic clearance was 0.39 L/day and the mean half-life was 13 days in subjects with plaque psoriasis.

 Mean volume of distribution at steady-state was 7.11 L  in subjects with plaque psoriasis. Clearance and volume of distribution increase as body weight increases.

PK-PD Analysis

Not reported

Population PK

Age did not significantly influence the clearance of ixekizumab in adult subjects with plaque psoriasis. 

Special Populations

No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of ixekizumab was conducted..

Drug Interactions

Drug interaction studies have not been conducted with TALTZ.

Source : http://pi.lilly.com/us/taltz-uspi.pdf


Pacemaker reclassification, Electrical Stimulators ban

FDA BRIEF: Week of April 18, 2016



 External Pacemaker Pulse Generator Devices

Reclassified from Class III to Class II

Based on:

  • Review of the MAUDE safety database and recall data
  • Review of current scientific literature
  • 2013  Circulatory System Devices Panel  deliberations
  • Special controls, in conjunction with general controls, will provide reasonable assurance of the safety and effectiveness




Electrical stimulation devices intended to treat self-injurious or aggressive behavior

Proposal to BAN 

Based on:

  • Review of clinical and scientific data, input from experts, treated individuals and their parents, disability rights groups, 2014 FDA advisory panel
  • Unreasonable and substantial risk to public health
  • Risk cannot be corrected or eliminated through labeling
  • Alternative approaches available – Positive behavioral support, medications

FDA will work with health care providers to facilitate safe transition to alternate care




FDA Views: EvGen, Expedited Reviews, Continuous Manufacturing, FDA-China partnership

FDA BRIEF: Week of April 18, 2016

FDA Voice


What We Mean When We Talk About EvGen

Part I: Laying the Foundation for a National System for Evidence Generation

shermanRachel E. Sherman, M.D., M.P.H., Associate Deputy Commissioner for Medical Products and Tobacco


califfRobert M. Califf, M.D.,  Commissioner 

  • High-quality evidence derived from appropriately designed randomized controlled trials result in better outcomes for patients
  • However, most clinical practice guideline recommendations are not based on this standard
  • Therefore, FDA considering a national system for evidence generation (EvGen)
  • Foundational concepts—interoperability and connectivity
  • Interoperability : For use by patients, consumers, professional groups, payers, the medical products industry, and health systems by creating standardized approaches
  • Connectivity: Enable collaboration among patients, clinicians, hospital systems, health insurance organizations by leveraging all available data to provide answers to important public health questions.



FDA’s Breakthrough Therapy Designation and Expedited Review Programs



Richard Moscicki, M.D., Deputy Director for Science Operations, CDER, FDA 


  • Drug candidates in early development that have the potential to be breakthroughs
  • Intended to treat a serious condition and has preliminary clinical evidence
  • Receive enhanced communication and input from CDER
  • By March 2016: 342 requests; 111 granted


  • Drug candidate for serious condition and advantageous over available therapies
  • Use of surrogate endpoint- change indicators likely to predict clinical benefit
  • Require post-approval to confirm clinical clinical benefit

FAST TRACK designation

  • Drug candidates for serious condition
  • Non-clinical demonstration of potential to address an unmet medical need.
  • Obtained very early in drug development

All can lead to:


  • For very serious condition, trials have been completed, significant improvement in safety, effectiveness or both
  • Reduced FDA review time – but review standards not compromised

Areas of overlap:

Breakthrough Therapy drug would also receive a Priority Review and could receive an Accelerated Approval as part of its path to patients


Continuous Manufacturing Has a Strong Impact on Drug Quality



By: Lawrence Yu, Ph.D. Deputy Director, Office of Pharmaceutical Quality, CDER



  • Little change in pharmaceutical production over the last 50 years
  • Traditional  “batch” technology — many stops and starts in a series of steps
  • New technology — continuous manufacturing — faster production, reliable products
  • Decreases manufacturing costs with possible lower drug prices

Some manufacturers building continuous manufacturing into their processes

  • VERTEX: Orkambi (lumacaftor/ivacaftor) – cystic fibrosis drug
  • JANSSEN: Prezista (darunavir)- HIV-1 infection

Draft Guidance by Emerging Technology Team – ETT

ETT.JPG Reviewed in this blog


Strengthening Partnerships: FDA’s China Office Engages in Key Outreach with Chinese Provincial FDA, Academia, and Industry

chinaBy: Leigh Verbois, Ph.D., Director of FDA’s China Office in the Office of International Programs

独木不成林,单弦不成音  ‘A single tree makes no forest, one string makes no music.’


  • China – home to a significant number of FDA-regulated medical product manufacturers
  • Mission to collaborate with Chinese regulators, industry and academia to ensure medical products manufactured for the U.S. market are safe and effective
  • FDA China office met with key leaders and experts across the Yangtze river delta

SHANGHAI: Students and faculty at East China University of Science and Technology’s School of Pharmacy and China Pharmaceutical University, .U.S. Embassy Consul General on  FDA priorities in the region.

NANJING: Jiangsu FDA, regional regulator, to share information on  U.S. safety standards

SUZHOU: Town hall meeting with  China’s Association for Medical Device Industry

HANGZHOU: Provincial FDA officials on collaboration on future medical device and drugs

ZHEJIANG: Industry roundtable on pharmaceuticals and Zhejiang FDA




FDA Device Approval Summaries: HEARTLIGHT Ablation Catheter,CHEATHAM Stent System

FDA BRIEF: Week of April 11, 2016

FDA approved



HeartLight® Catheter

HeartLight® Endoscope

HeartLight® Balloon Fill Media

CardioFocus Inc., Marlborough, MA, USA

INDICATION: Endoscopic Ablation System for the treatment of drug refractory recurrent symptomatic paroxysmal atrial fibrillation (AF)


  • Approved catheter ablation tools: ThermoCool (J&J), TactiCath (St. Jude Medical)
  • Need for device to allow electrophysiologists  use direct visual guidance while in the pulmonary veins (PV)



  • System consists of  Catheter, Endoscope and Balloon Fill Media, and a console
  • Multi-lumen Catheter with inflatable, compliant Balloon at the distal end, Lesion Generator that delivers light energy,  Optical fibers for illuminating  tissue to permit visualization by  Endoscope


  • Single prospective, randomized, controlled, open-label, multicenter U.S. investigation, n=366, HeartLight System vs. ThermoCool ablation catheter
  • Primary Endpoint: Freedom from documented symptomatic AF occurrence of at least 60 seconds occurring after the 90-day blanking period –  61.1% vs. 61.7%, p=0.003,  met prespecified non-inferiority  margin of 15% for effectiveness and 8% for safety
  • Favorable outcome for Secondary endpoints: Success in isolating all attempted PVs acutely, Chronic Durable PV Isolation , Recurrence of Asymptomatic AF
  • Upon completion of the ablation procedure, electrical PV isolation was achieved in the vast majority of the clinically relevant PVs (97.3%)
  • No gender discrepancy in primary effectiveness success
  • Operator Learning Curve  with the use of the system for PV isolation

KM Curve


  • Phrenic nerve injury resulting in diaphragmatic paralysis was more frequent
  • PV stenosis (> 50% narrowing) less frequent
  • Complication rates greater female subjects; post approval study in female subjects warranted to further evaluate safety profile




Cheatham Platinum (CP) Stent System 

Covered CP Stent
Mounted CP Stent 
Covered Mounted CP Stent 
BiB Stent Placement Catheter 

NuMed Inc., Hopkinton, New York, USA

INDICATION: Treatment of native and/or recurrent coarctation of the aorta involving the aortic isthmus or first segment of the descending aorta where there is adequate size and patency of at least one femoral artery



  • System includes  bare or covered CP Stent and a delivery catheter (BIB)
  • Each stent is balloon expandable and intended for permanent implant


  • COAST: Did not meet performance goal of eduction in the systolic blood pressure gradient, length of hospital stay;  however,patients  achieved complete obliteration of the pre-procedural blood pressure gradient
  • COAST  II: Improvement in aortic wall injury and/or aortic arch obstruction based on level of severity as well as evaluation of aortic wall injury and/or aortic arch obstruction at Grade 4 or above at 12 months with no clinical worsening.
  •  All patients derived initial benefit; by 24 months 93% had shown either no change or improvement in  Severity of Illness grade vs. baseline


  • Suitable for long-term implant
  • Reduces the proportion of patients with serious and somewhat serious adverse events when compared to surgical intervention.
  • No uncontained aortic tears,large aneurysms or pseudo-aneurysms
  • All new aortic wall injuries successfully repaired by covered stent implantation

FDA Biomarker Qualification Program

Biomarker qual


WHAT:  To facilitate drug development process by  supporting  regulatory qualification of  biomarker for a particular context of use


  • Provide framework for development and regulatory acceptance
  • Facilitate integration into regulatory review
  • Encourage identification of new and emerging biomarkers
  • Support outreach to stakeholders

HOW: Submit biomarker for qualification


FDA Drug Withdrawals due to Lack of Efficacy: LUVERIS, ADVICOR, SIMCOR

FDA BRIEF: Week of April 11, 2016


  • FDA approved LUVERIS in 2004, under the Accelerated Approval regulations
  • Indication: Stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound luteinizing hormone deficiency
  • EMD Serono requested wiithdrawal of  NDA approval as it was not feasible to complete a trial that the company had agreed to at the time of approval



  • FDA approved ADVICOR in 2001 and SIMCOR in 2008
  • Indication: Treatment of hypercholesterolemia
  • Collective evidence from several large cardiovascular outcome trials no longer support efficacy conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDLcholesterol levels results in reduction in the risk of cardiovascular events
  • Benefits of ADVICOR and SIMCOR no longer outweigh the risks



FDA BRIEF: Week of April 11, 2016

FDA approved

VENCLEXTA™ (venetoclax) tablets

Vysis CLL FISH probe kit

AbbVie Inc., North Chicago, Illinois, USA

Genentech, South San Francisco, California, USA  

Abbott Molecular, Des Plaines, Illinois, USA

INDICATION: Treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy ( approval based on overall response rate; continued approval contingent upon verification in confirmatory trial)


  •  15,000 new CLL cases diagnosed each year
  • 17p deletion lchromosomal abnormality ~ 10%
  • Need for new targeted therapy

REG PATHWAY:  Breakthrough Therapy Designation, Priority Review, Accelerated Approival, Orphan Drug

MECHANISM OF ACTION: Inhibitor of BCL-2, an antiapoptotic protein


  • Open-label, single-arm, multicenter trial (n=106); patients with CLL with 17p deletion who had received at least one prior therapy
  • 17p deletion was confirmed using Vysis CLL FISH Probe Kit
  • Primary Endpoint: Overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia guidelines : 80.2%
  • Median time to first response: 0.8 months
  • Median duration of response:  2.9 to 19.0+ months


  • Serious complications: Pneumonia, neutropenia with fever, fever, autoimmune hemolytic anemia, anemia and metabolic abnormalities known as tumor lysis syndrome
  • Most common side effects: Low white blood cell count (neutropenia), diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count (thrombocytopenia) and fatigue






Clinical Pharmacology Card: ZEPATIER

ZEPATIER™ (elbasvir and grazoprevir) tablets

Mechanism of Action A fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus.
Pharmacodynamics (PD) At therapeutic concentration both elbasvir and grazoprevir do not prolong QTc to any clinically relevant extent.
Pharmacokinetics (PK) Elbasvir pharmacokinetics were similar in both healthy and HCV-infected subjects and were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects.

Elbasvir median Tmax is at 3 hours (range of 3 to 6 hours); grazoprevir median Tmax is at 2 hours (range of 30 minutes to 3 hours) in HCV-infected subjects. Steady-state Cmax for elbasvir and grazoprevir are 121 ng/mL and 165 ng/mL, respectively. Corresponding values for AUC24 are 1920 ng.hr/mL and 1420 ng.hr/mL, respectively.

Elbasvir AUC0-inf and Cmax decreases by approximately 11% and 15%, respectively with high fat food in healthy subjects, whereas AUC0-inf and Cmax of grazoprevir increases by approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, ZEPATIER may be taken without regard to food.

Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively.

The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects.

The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine. Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma.

PK-PD Analysis Not reported.
Population PK Elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age.

Elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males.

Elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans.


Special Populations Exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant.

Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. Elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.

Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. Grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCV infected, non-cirrhotic subjects.

Drug Interactions Elbasvir and grazoprevir are substrates of CYP3A. Co-administration of moderate and strong CYP3A inducers with ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER. Co-administration of strong CYP3A4 inhibitors with ZEPATIER may increase elbasvir and grazoprevir plasma concentrations. 17 Grazoprevir is a substrate of OATP1B1/3. Co-administration of ZEPATIER with drugs that inhibit OATP1B1/3 transporters may result in a clinically relevant increase in grazoprevir plasma concentrations.

Source : https://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf

BRIVIACT Clinical Pharmacology Card

 BRIVIACT® (brivaracetam) tablets, oral solution and injection

Mechanism of Action Brivaracetam has a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.
Pharmacodynamics (PD) BRIVIACT did not prolong the QT interval to a clinically relevant extent.

Co-administration of BRIVIACT and ethanol caused a larger decrease from baseline in saccadic peak velocity, smooth pursuit, adaptive tracking performance, and Visual Analog Scale alertness, and a larger increase from baseline in body sway and in saccadic reaction time. The immediate word recall scores were generally lower.

Pharmacokinetics (PK) The median Tmax for tablets taken without food is 1 hour (range 0.25 to 3 hours). Effect of food is on Cmax (decreased by 37%) and Tmax (delayed by 3 hours), and not on AUC.

 Brivaracetam is weakly bound to plasma proteins (≤20%). The volume of distribution is 0.5 L/kg, a value close to that of the total body water.

 Brivaracetam metabolism involves CYP2C19. Variations in CYP2C19, production of the hydroxy metabolite is decreased 2-fold or 10-fold, while the blood level of brivaracetam is increased by 22% or 42%, respectively.

 Brivaracetam is eliminated primarily by metabolism and by excretion in the urine. More than 95% of the dose, including metabolites and is excreted in the urine within 72 hours after intake.

 The terminal half-life is approximately 9 hours.

PK-PD Analysis      Co-administration of Phenobarbital, Phenytoin or Carbamazepine  with Brivaracetam (25 mg twice daily to 100 mg twice daily) decreases plasma concentrations of Brivaracetam by 19%, 21% or 26%, respectively. Conversely, Brivaracetam increases the plasma concentrations of Phenytoin or epoxy metabolite of Carbamazepine. Interactions with carbamazepine and phenytoin can be clinically important.
Population PK There was no significant different in PK in Caucasian and non-Caucasian patients.
Special Populations Steady-state plasma clearance of brivaracetam was slightly lower (0.76 mL/min/kg) in elderly subjects (65 to 79 years old) than in young healthy controls (0.83 mL/min/kg).

 AUC of brivaracetam was increased (21%) in subjects with severe renal impairment, while the AUCs of the acid, hydroxy, and hydroxyacid metabolites were increased 3-fold, 4-fold, and 21-fold, respectively. The renal clearance of these inactive metabolites was decreased 10-fold. Hepatic Impairment

Brivaracetam exposure increased by 50%, 57%, and 59% in subjects with hepatic cirrhosis, Child-Pugh grades A, B, and C, respectively.

Drug Interactions CYP inhibitors or transporter inhibitors has no significant effect on brivaracetam exposure. Rifampin decreases brivaracetam plasma concentrations by 45%, an effect that is probably the result of CYP2C19 induction.

Source : http://www.briviact.com/briviact-PI.pdf



FDA Device Approvals: MICRA Transcatheter Pacemaker, PNEUMOLINER Tissue Containment System


FDA approved



MICRA Transcatheter Pacemaker System

Medtronic, Minneapolis, Minnesota, USA

INDICATION: Patients with a heart arrhythmia called atrial fibrillation or those who have other dangerous arrhythmias, such as bradycardia-tachycardia syndrome.


  • First pacemaker that does not require wired leads to provide an electrical connection between the pulse-generating device and the heart
  • Avoids lead malfunction, infections, pocket- and lead-related complications, dislodgements



  • World’s smallest pacemaker
  • One inch-long, self-contained pacemaker implanted directly in right ventricle
  • Integrated delivery system : Micra Delivery Catheter, Micra Introducer


  • Single clinical trial, n=719
  • Pacing capture threshold : 98%, 6 mo. after implantation


  • Complications (<7%):  Prolonged hospitalizations, deep vein thrombosis, pulmonary embolism, heart injury, device dislocation, heart attacks
  • Contraindications: Patients with implanted devices that would interfere, severely obese, intolerance to device materials, heparin


PNEUMOLINER Tissue Containment System

Advanced Surgical Concepts, Bray, Ireland

INDICATION:  Use in women without uterine fibroids undergoing hysterectomy, pre-menopausal women with fibroids- laparoscopic power morcellation appropriate therapeutic option compared to more invasive surgery. PneumoLiner device has not been proven to reduce the spread of potentially cancerous tissue during power morcellation.


  • 1 in 350 women undergoing hysterectomy/myomectomy have uterine sarcoma
  • Morcellation risks  spread of the cancerous tissue; lowers survival
  • Need for system to contain morcellated tissue



  • Containment bag and a tube-like plunger to deliver the device into the abdominal cavity
  • Bag is sealed and inflated – creation of working space around tissue and visualization during morcellation


  • Tested in laboratory settings to simulate actual use and worst-case scenario
  • Containment bag impermeable to substances similar in molecular size to tissues, cells, body fluids
  • Inflated bag provided adequate space to perform morcellation with good visualization
  • Stress testing demonstrated device could withstand forces in excess of clinical use


  • Contraindications: Limited patient population
  • Risks : Dissemination of morcellated tissue, injury to surrounding tissues or organs, infections, prolongation of surgical procedure
  • Required physician training

FDA continues to warn against use of laparoscopic power morcellators for removal of uterus or uterine fibroids in the vast majority of women





FDA approved



infliximab-dyyb for Injection

Celltrion, Inc, Yeonsu-gu, Incheon, Republic of Korea

For : Hospira, Lake Forest, Illinois, USA


  • Moderately to severely active Crohn’s disease
  • Severely active ulcerative colitis
  • Moderately to severely active rheumatoid arthritis
  • Active ankylosing spondylitis
  • Psoriatic arthritis
  • Chronic severe plaque psoriasis


  • Biosimilars provide access to important treatment options
  • Second FDA approved biosimilar
  • Biosimilar to Janssen Biotech’s Remicade (infliximab), originally licensed in 1998
  • Not an interchangeable product

REG. PATHWAY: Approval based on showing high similarity to Remicade – no clinically meaningful differences in safety and effectiveness


  • Structural and functional characterization
  • Animal study data
  • Human pharmacokinetic and pharmacodynamics
  • Clinical immunogenicity
  • Clinical safety and effectiveness data demonstrating biosimilarity


  • Boxed Warning: Increased risk of serious infections leading to hospitalization/death
  • Serious side effects: Liver injury, blood problems, lupus-like syndrome, psoriasis, and in rare cases nervous system disorders
  • Most common expected side effects: Respiratory infections, headache, coughing and stomach pain





Emtricitabine (FTC) and Tenofovir Alafenamide (TAF) combination tablet 

Gilead Sciences, Foster City, California, USA

INDICATION:  Treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. Not a complete regimen for HIV-1 treatment; must be combined with other antiretroviral agents

REG PATHWAY:  Demonstration of relative bioavailability of FTC and TAF exposures vs  GENVOYA (elvitegravir/cobicistat/FTC/TAF)



CDRH National Evaluation System, Mobile Health Apps Interactive Tool



WHAT:  To generate evidence across total product lifecycle by leveraging real-world evidence for medical device evaluation and regulatory decision-making

WHY:  Quality real-world evidence for health care providers and patients to make informed treatment decisions and balance safety vs device innovation and patient access

WHEN: Initial report in 2012. Included in CDRH 2016-2017 priorities





WHAT: Web-based tool for developers of health-related mobile apps

WHO: Federal Trade Commission (FTC), Dept of  Health and Human Services, FDA

WHY: Help developers understand what federal laws and regulations  might apply to their apps – FTC Act, HIPAA, FD&C Act




FDA BRIEF: Week of Mar 28, 20116

FDA approved


DEFITELIO (defibrotide sodium) injection

Jazz Pharmaceuticals, Palo Alto, California, USA.

INDICATION: Treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT)


  • Hepatic VOD can occur in patients who receive chemotherapy and HSCT
  • Swelling and decrease in liver blood flow, liver damage
  • In most severe form, failure of kidneys, lungs
  • 80% severe hepatic VOD patients do not survive
  • Need in transplantation community to treat this rare fatal complication

REG PATHWAY: NDA, Priority Review, Orphan Drug Designation

MECHANISM OF ACTION: Not fully elucidated. Enhances the enzymatic activity of plasmin to hydrolyze fibrin, clots. Protect from damage caused by chemotherapy, tumor necrosis factor-α, serum starvation, and perfusion


  • Three studies: 2 prospective clinical trials (n=102, 75) 1 expanded access (n=351)
  • Survival at Day + 100 after HSCT : 38%,  44%, 45%  (vs. published reports of 21%-31% with no drug)


  • Serious potential side effects: Bleeding (hemorrhage) and allergic reactions
  • Should not be used in patients with bleeding complications, taking blood thinners
  • Common side effects: Abnormally low blood pressure (hypotension), diarrhea, vomiting, nausea and nosebleeds (epistaxis)











FDA Blogs: Teamwork, Biosimilar Product Labeling

FDA Brief: Week of Mar 28, 2016

FDA Voice




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



  • Regulates 20% nation’s economy
  • Mission to protect and promote public health
  • Makes decisions vital to the well-being of all Americans
  • High-quality and impartial judgments—although many may disappoint


  • Workforce Initiative to build professional environment
  • Evidence Generation Systems to meet technological advances
  • Specific Critical Issues:

Pain: Opioid action plan

Tobacco product deeming: Oversight  over all tobacco products

Food Safety Modernization Act: Implementation

Antimicrobial resistance: Appropriate use and novel antimicrobials

Interagency effectiveness: With NIH, CDC, CMS

Precision Medicine: Future for biomedicine and agriculture

Cross-Cutting Issues: Combination products, improving product labeling








Leah Christl, PhD,  Associate Director, Therapeutic Biologics, FDA CDER



  • Communicates the product’s safety and effectiveness information
  • Summarizes key scientific information on risk-benefit profile and appropriate use
  • Physician Labeling Rule (PLR) provides format and content


  • Similar to reference therapeutic biologic e.g. monoclonal antibodies, cell signaling proteins
  • Comparative data on structural/functional characterization, animal, clinical studies


  • Issued  GUIDANCE
  • Addition of “Biosimilarity Statement”
  • Incorporate relevant reference information; may differ from reference
  • Do not recommend  comparative data