Clinical Pharmacology Card


ALECENSA® (alectinib) capsule

Mechanism of Action Tyrosine kinase inhibitor targeting anaplastic lymphoma kinase & rearranged during transfection
Dosage 600 mg twice daily
Pharmacodynamics (PD) QT interval prologation assessed at 600 243 mg twice daily
Pharmacokinetics (PK) Major active metabolite M4 by CYP3A4

Dose-proportional increases over the dose range of 460 mg to 900 mg (daily

Mean accumulation ~6-fold for both at steady-state

Tmax  4 hour

T1/2  33 hr (alectinib), 31 hr ( M4)

Absolute bioavailability 37%

High-fat, high-calorie meal increased the combined exposure by 3.1-fold

Plasma protein binding 99% for both

Excretion in feces 84% as alectinib, 6% as M4.

PK-PD Analysis Have not been reported
Population PK Have not been reported.



Special Populations No dose adjustment mild and moderate renal impairment, mild hepatic impairment.

Age, body weight, mild hepatic impairment, mild to moderate renal impairment,  race, and sex no clinically meaningful effect on systemic exposures of alectinib and M4.

Drug Interactions Strong CYP3A inhibitor or a strong CYP3A inducer or an acid-reducing agent (esomeprazole) no clinically meaningful effect


FDA Brief, Week of December 14th, 2015

Issues to consider when it comes to keeping your pet safe from holiday hazards. Youtube

FDA Voice

precisionFDA Launches precisionFDA to Harness the Power of Scientific Collaboration

By: Taha A. Kass-Hout, M.D., M.S. and Elaine Johanson


  • Collaboration between industry, academia, government
  • Online, cloud-based portal on  “reading” DNA  – next-generation sequencing (or NGS)
  • Look for meaningful DNA differences for disease risk, treatment response, tailor personalized treatment
  • Leverages experience with establishing openFDA – easy access to public datasets



2016 CDER PRIORITIES:  Janet Woodcock M.D., Director, CDER, FDA


Front Burner



PDUFA 6 agreements

Advertising /Promotion  regulations

Prescription Opioid Epidemic

Sentinel Network  and Drug Safety

Drug Supply Chain, Imports

Drug Label Improvement, Pregnancy & Lactation Rule

Biomarkers, Accelerated Approval, Qualification

Personalized Medicine

Breakthrough Therapies

Qualitative Benefit/Risk assessment

Electronic  Health Data, Clinical Evidence

Patient-focused Drug Development

CV safety studies for Diabetes and Obesity

Pediatric Evaluation for non- PREA/BPCA drugs

Bayesian Statistics, Adaptive Designs, Modeling

PFUFA and meeting goals

FOI and reducing backlog

 Advisors and Consultants and AC meetings

IT assessment

  • Supporting Regulatory Operations and strengthening Electronic Submissions Gateway (ESG)
  • Electronic Regulatory Submissions
  • Data Standards
  • Metrics and Measures
  • Communications and Technical Interactions

Objectives, 2015 Milestones and Accomplishments, Future Milestones


Safety reporting

  • Timely and Effective (with causality assessment) reporting
  • Key elements of a systematic approach to safety surveillance
    • Safety Assessment Committee
    • Safety Surveillance Plan describing policies and procedures
  • Recommendations for :
    • Committee Organization
    • Safety Assessment practices
    • Prospective development of Safety Surveillance Plans

Draft Guidance

 FDA approved

merck   Bridion (sugammadex)


Indication :  Reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery.

Unmet need:

  • Neuromuscular blocking drugs (e.g. rocuronium bromide, vecuronium bromide) cause temporary paralysis by interfering with nerve impulse transmission to muscle
  • Used to paralyze vocal cords for tracheal intubation, used as general anesthesia during surgery, used to prevent automatic breathing when a patient is on a ventilator
  • Need for treatment option to help patients recover sooner from intubations and ventilations during surgery

Reg Pathway: NDA submitted in 2007, Complete Response Letter, Approval of responses to Action Letter

Mechanism of Action: As a modified gamma cyclodextrin, forms a complex with the neuromuscular blocking agents rocuronium and vecuronium and reduces availability to bind to receptors in  neuromuscular junction.


  • 3 Multicenter, randomized, parallel-group studies vs neostigmine or succinylcholine (n=456), post-surgical patients with moderate and deep blockage
  • Primary Endpoint : Time from start of administration to recovery of twitch responses to train-of-four (TOF)  ratio of 0.9 (correlates with  recovery from neuromuscular blockade)
  • Study 1 Moderate Blockade (vs neostigmine) :  Faster recovery,  1.4 min  vs  21.5 min
  • Study 2 Deep Blockade (vs neostigmine) : Wider range of recovery; median times comparable
  • Study 3 (blockade by succinylcholine vs blockade by rocuronium followed by Bridion) : Faster Recovery, 4.4 min vs 7.2 min


  • Possibility of a hypersensitivity reaction or anaphylaxis – intervene as appropriate.
  • Marked bradycardia some leading to cardiac arrest – monitor closely and treat appropriately
  • Most common adverse reactions: Vomiting, low blood pressure (hypotension), pain, headache and nausea.
  • May reduce effect of hormonal contraceptives

lilly Basaglar (insulin glargine )


Indication:  Improve glycemic control in adult and pediatric patients with type 1 diabetes mellitus  and in adults with type 2 diabetes mellitus.

Unmet need:

  • 21 million people in US diagnosed with diabetes; increases risk of heart disease, blindness, nerve and kidney damage
  • Need to expand availability of treatment options for long-acting insulin products

Reg Pathway:  FIRST “follow-on” insulin glargine product . 505(b)(2) application : Comprised of reference to FDA’s approval of Lantus (insulin glargine injection)  and additional clinical studies. Tentative approval in 2014.

Mechanism of Action:  Lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production.


  • Comparability to other insulin glargine products: 2,327 adults and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus. Basaglar similar to other products.
  • The Basaglar-specific data : 2 clinical trials enrolling 534 and 744 patients with type 1 and 2 diabetes mellitus, respectively.


  • Insulin Class effect : Severe, life-threatening, generalized allergic reactions, including anaphylaxis, or generalized skin reactions, angioedema, bronchospasm, hypotension and shock
  • Common adverse reactions: Hypoglycemia, allergic reactions, injection site reactions, pitting at the injection site (lipodystrophy), itching, rash, edema (fluid retention) and weight gain.


LifevestLifeVest Wearable Cardioverter Defibrillator

Zoll Lifecor Corporation, Pittsburgh, Pennsylvania. 

Intended Use : Wearable cardioverter defibrillator to monitor and treat cardiac arrhythmias in children (restrictions must have a chest circumference of 26 inches and weigh at least 18.75kg). Has been previously approved for use in adults (> 18 years of age).

Unmet need :

  • A life-threatening abnormal heart rhythm- ventricular fibrillation (V-fib) or ventricular tachycardia (V-tach), most common cause of sudden cardiac arrest and death
  • Rapid treatment with a defibrillator can save lives
  • For children – Need for defibrillator worn by patients with constant monitoring of arrhythmias and provision of appropriate response

Reg Pathway: PMA supplement, based on published studies and Registry of 248 patients

Description :

  • 2 main components: (i) electrode belt and garment surrounding chest,(ii) monitor around waist
  • Responds automatically if it senses the need to deliver a shock, restoring a life-sustaining heartbeat.


checkme proCheckme Pro portable health monitor

Viatom Technology, Taiwan, 510K

  • One-lead ECG recording, pulse oximetry, temperature measurement, and movement sensing
  • Provides QRS duration, ST segment, and rhythm analysis for basic cardiac monitoring
  • Track SpO2 up to 10 hours during sleep
  • Records can be reviewed by Physician

gruveGRUVE anterior cervical plate system

Lifespine, Huntley, IL, 510K

  • Surgical treatment of spine disorders
  • Allows extreme bone screw angulation, large graft windows, in addition to a tactile and visual confirmation of the locking mechanism during final screw placement


NxTAG NxTag Respiratory Pathogen Panel

Luminex, Austin TX, 510K

  •  Simultaneous detection of 20 respiratory pathogens in a single closed-tube system, including atypical bacteriaChlamydophila pneumoniae and Mycoplasma pneumonia
  • Minimal hands-on time with no upstream reagent preparation, simplified workflow
  • Synct software for data analysis and reporting






Advisory Committee Meeting – Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting Announcement

What: Discuss/Recommend clinical trial, postapproval study design, and physician training requirements for leadless cardiac pacemaker device technology.

When: February 18, 2016

Where: Hilton Washington DC

Who : [email protected]


Public Workshop – Point of Care Prothrombin Time/International Normalized Ratio Devices for Monitoring Warfarin Therapy

What: Analytical and clinical validation of point of care (POC) Prothrombin Time/International Normalized Ratio (PT/INR) in vitro diagnostic devices for improved clinical management of warfarin therapy

When:  January 25, 2016

Where:  FDA White Oak Campus

Who : Registration


Psychopharmacologic Drugs Advisory Committee Meeting (Jan 12)

NDA 204442, PROBUPHINE (buprenorphine hydrochloride and ethylene vinyl acetate) subdermal implant for proposed indication of maintenance treatment of opioid dependence  More information

Vaccines and Related Biological Products Advisory Committee Meeting (Jan 14)

Research  updates from Division of Viral Products, CBER, FDA.  More information

Public Workshop – Moving Forward: Collaborative Approaches to Medical Device Cybersecurity (Jan 21-22)

Details posted previously. Medical device cybersecurity  More information

Public Workshop – Point of Care Prothrombin Time/International Normalized Ratio Devices for Monitoring Warfarin Therapy (Jan 25)

Posted above

The Twentieth FDA CASSS Symposium on the Interface of Regulatory and Analytical Sciences for Biotechnology Health Products  (Jan 26)

Latest bio-analytical methods and practical applications. More information


2015 REVIEWS : Good Reads

FDA Blog Archive

FDA Basics Webinar

Physiologically based Pharmacokinetic Modeling approach in Pediatric Drug Development



Pharmacokinetic (PK) parameters for pediatric patients have traditionally been scaled using a linear per kilogram model.  This paradigm has resulted in under- and overdosing, depending on the specific age group.

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can bridge pediatric and adult pharmacology. Assuming that the PD is similar in pediatrics and adults, creating a comparable PK profile requires a more logical approach based on the development of pediatric PBPK models.

The general concept of PBPK modeling is to mathematically describe relevant physiological, physicochemical, and biochemical processes that determine the pharmacokinetics of a compound in as much detail as is appropriate or needed. PBPK models map the complex mechanistic drug movements in the body to a physiologically realistic structure. It needs to incorporate information about developmental physiology and ontogeny of cytochrome P450 and their use to extrapolate drug pharmacokinetics from adults to children and to explore age-related changes.

In recent years, the implementation of PBPK models in pediatric drug development has become more attractive, encouraged by an increased awareness of interest in pediatric research, especially after the new regulations on medicinal products for pediatrics. However, lack of good in vitro and in vivo data could cause PBPK model to under or over predict the pediatric PK.

PK studies in children have limitation of sampling times; therefore appropriate methods such as the population PK (PPK) approach, are necessary for analysis of the PK data. PPK allows the estimation of population and individual parameters as well as intra- and intersubject variability and also the effects of predefined covariates. The PPK approach has a number of attractions for studying PKPD in children: it is less invasive and can thus be considered as more ethical in this age group, and PK sampling times are flexible and can be taken without causing the inconvenience to the patient. However, the choice of the PK sampling design has an important impact on the precision of population parameter estimates.

Several commercial software packages are available in developing PBPK models. Simcyp software (, allows simulation of complex absorption, distribution, metabolism, and excretion outcomes involving multiple drug interactions and parent drug and metabolite profiles. Software also allows the simulation of virtual patient populations such as obese/morbidly obese individuals and patients with renal impairment or liver cirrhosis, and include a clearance prediction model that incorporates knowledge about growth, maturation of various organs and tissues involved in drug metabolism and elimination across pediatric age groups to predict clearance in children using adult values.






Clinical Pharmacology Card

TAGRISSO® (osimertinib)


Mechanism of Action Kinase inhibitor of the epidermal growth factor receptor (EGFR)
Pharmacodynamics (PD) QTc interval prolongation potential :  Maximum mean change from baseline = 16.2
Pharmacokinetics (PK) Dose-proportional increases in systemic exposure : 20 – 240 mg dose(i.e., 0.25 to 3 times the approved recommended dosage).

 Accumulation 3-fold following qd dosing.

 Plasma protein binding likely to be high based on  physiochemical properties

 Mean Terminal half-life  48 hours

 Primarily metabolized by CYP3A.          

Excretion : 68%  (feces), 14% (urine), 2% (unchanged)

High-fat, high-calorie meal enhanced the Cmax and AUC of osimertinib by 14% and 19% resp. vs. fasting

PK-PD Analysis Concentration-dependent QTc interval prolongation of 14 msec at 80 mg dose
Population PK No dose adjustment is recommended in patients with mild or moderate renal impairment  and mild hepatic impairment.
Special Populations No clinically significant differences in the PK based on age, sex, ethnicity, body weight, smoking status, mild or moderate renal impairment, or mild hepatic impairment

Effect of severe renal impairment, hemodialysis, or moderate to severe hepatic impairment on exposure unknown

Drug Interactions Avoid concomitant administration with strong CYP3A inhibitors or inducer





FDA Brief, Week of Dec 7th, 2015

FDA Voice

What We Mean When We Talk About Data

By: Robert M. Califf, M.D. and Rachel Sherman, M.D., M.P.H.

Tackling Terminology


Data : Raw measurements of some thing or process

Information : With critical context about what is being measured

EvidenceWith analysis to guide decision-making


  • “real-world data” or “real-world evidence”
  • depict what patients and care providers will experience
  • help to fundamentally better understand states of disease and health
  • however; issues with quality and interpretability of data for regulatory decision making

FDA POSITION:   Recognizes challenges and developing effective ways to adapt “real-world data” into processes for creating scientific evidence 


MDUFA IV Reauthorization Meeting  (DEVICE)

FDA and Industry presented their respective initial proposal packages

Commonality : Around the themes of consistency and predictability in the medical device review program, as well as process improvements that include pre-submission consultations and de novo submissions.

Apparent Differences : In the approaches taken to address the common themes. FDA and Industry anticipate productive discussions on the details of and assumptions underlying the proposal packages.

Overview of FDA Proposals

  • Ensuring Consistent, Predictable, and Efficient Review Experience: (i) Quality Management System, (ii) Recruitment, Retention, and Development of Managers and Staff, (iii)Program Reliability, Resiliency, and Transparency,
  • Innovative Review Process for Innovative Products : (i) patient preference information in benefit/risk assessment, (ii) link data from health care claims, electronic health records, and registries, (iii) digital health device regulation and smart policy on areas of interoperability, clinical decision support, software modifications, telemedicine, and cybersecurity (iv) device specific guidnaces

PDUFA V  Metrics:  Programs for Supporting Expedited Development and Enhanced Reviews (DRUG) 

Oct 2014 – Sept 2015

fast track


Expedited Drug Development and Review, intended to Treat Serious or Life-Threatening Conditions, Potential to address Unmet Need



Approval based on Surrogate Endpoints reasonably likely to Predict Clinical Benefit




Treatment of Rare Diseases/Disorders < 200,000 U.S. patients.


breakthroughEarlier FDA Attention and Guidance (Cross-Disciplinary Team w/Senior Mgrs) to Expedite Drugs Development for Serious/Life-Threatening Condition

Independent Assessment of PDUFA V metrics (thus far):

  • Enhanced review transparency and communication
  • Enhanced predictability of reviews and resolve approvability issues promptly
  • Enhanced opportunities for FDA and Sponsor to address issues to increase first cycle approval
  • Label Review Good Practics : Providing explanations/rationales for proposed label
  • However, Inconsistent availability/communication of information about inspections

Full 2015 metrics anticipated in 2016. Stay Tuned.


FDA approved



VISTOGUARD (uridine triacetate)


Indication:  Emergency treatment of adult and pediatric patients:

  • Following a fluorouracil or capecitabine overdose
  •  Who exhibit early-onset, severe or life-threatening toxicity within 96 hours following the end of fluorouracil or capecitabine administration.

Unmet Need:

  • Fluorouracil (taken by infusion) and capecitabine (taken orally)  used for decades to treat several types of cancer
  • While rare, unintentional overdose can occur
  • Need for therapy to potentially save lives following overdose or life-threatening toxicity

Reg Pathway : NDA  orphan drug designation,  priority review and fast track

Mechanism of Action :  After oral administration, uridine triacetate is deacetylated to uridine that competitively inhibits cell damage and cell death caused by fluorouracil.


  • 2  open-label trials, Study 1 (n=60) and Study 2 (n=75)
  • Primary measure: Survival at 30 days or  chemotherapy resumption
  • Overdose : 97% still alive at 30 days
  • Toxicity onset : 89%  alive at 30 days
  •  33 % resumed chemotherapy in less than 30 days.

Safety: Diarrhea, vomiting and nausea.

alexionKANUMA (sebelipase alfa) 


Indication :  Treatment of Lysosomal Acid Lipase (LAL) deficiency.

Unmet Need: 

  • LAL deficiency is a rare inherited genetic disorder that can lead to serious and life-threatening organ damage, especially when onset begins in infancy
  • Need for treatment that may improve their lives and chances of survival

Reg Pathway:   BLA, Orphan Drug Designation, Breakthrough Therapy Designation, Priority Review and Rare Pediatric Disease Priority Review Voucher

  • Reviews by 2 FDA centers:
    1. Center for Veterinary Medicine (CVM)  for a recombinant DNA (rDNA) construct in chickens genetically engineered to produce recombinant form of human lysosomal acid lipase (rhLAL) protein in egg whites
    2. The Center for Drug Evaluation and Research (CDER) for  efficacy and safety of human therapeutic biologic (Kanuma)

Mechanism of Action: Deficient LAL enzyme activity results in progressive complications due to the lysosomal accumulation of cholesteryl esters and triglycerides in multiple organs. Kanuma binds to cell surface receptors and catalyzes lysosomal hydrolysis of cholesteryl esters and triglycerides


  • Multicenter, open-label, single-arm study (n=9 infants)
  • Primary Endpoint: Survival vs  untreated historical cohort (n=21)
  • Survival beyond 12 mo. of age : 6 vs 0
  • Median age of surviving patients: 18.1 mo. (range 12 – 42.2 mo.)

Safety :  Diarrhea, vomiting, fever, rhinitis, anemia, cough, headache, constipation, and nausea.

baxaltaVONVENDI [von Willebrand factor (Recombinant)]

INTRAVENOUS INJECTION (Lyophilized Powder for Solution)

Indication:  On-demand treatment and control of bleeding episodes in adults (age 18 and older) diagnosed with von Willebrand disease (VWD)

Unmet need:

  • VWD is most common inherited bleeding disorder, affecting approximately 1 percent of U.S. population
  • Severe bleeding from the nose, gums, intestines, muscles and joints. heavy menstrual periods, excessive bleeding after childbirth
  • Need for additional therapeutic option for treatment of bleeding episodes

Reg Pathway: BLA,  Orphan product designation

Mechanism of Action: Promote hemostasis by mediating platelet adhesion and as a carrier protein for factor VIII, protecting it from rapid proteolysis.


  • Multicenter, open label trial  (n=69), with vs. without recombinant factor VIII for on-demand treatment and control of bleeding episode
  • Primary Endpoint : Number of subjects with treatment success based on pre-specified 4 point rating scale
  • Rating of excellent (96.9%) or good (3.1%)
  • Control of bleeding episodes was consistent across all degrees of severity.

Safety: Most common adverse reaction observed was generalized pruritus

genentechALECENSA® (alectinib)


Indication: Treatment of anaplastic lymphoma kinase (ALK)-positive,
metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

Unmet Need:

  • Lung cancer leading cause of cancer death in US
  • Estimated 221,200 new diagnoses and 158,040 deaths in 2015
  • ALK gene mutations are present in about 5 percent of patients
  • Brain is a common place for the disease to spread
  • Need for  new therapy for patients who no longer respond to  Xalkori

Reg Pathway: NDA, accelerated approval breakthrough therapy designation and priority review status. Also received orphan drug designation,

Mechanism of Action: Tyrosine kinase inhibitor that targets ALK and RET.

Efficacy: Approval based on tumor response rate and duration of response.  Confirmatory trial required 

  • 2 single-arm, multicenter clinical trials (n=87 and 132)
  • Major efficacy outcome : Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) by Independent Review Committee (IRC)
  • Additional outcome measures  : Duration of response (DOR), CNS ORR, and CNS DOR.

Efficacy in Study 1 and 2


CNS Efficacy



  • Most common side effects : Fatigue, constipation, swelling (edema) and muscle pain (myalgia).
  • Serious side effects: Liver problems, severe or life-threatening inflammation of the lungs, very slow heartbeats and severe muscle problems
  • May cause sunburn when patients are exposed to sunlight





Dignitana DigniCap Cooling System

Dignitana Inc., Lund, Sweden


Indication for Use : Reduce the likelihood of chemotherapy-induced alopecia in women with breast cancer.

Unmet Need:

  • Hair loss is a common side effect of certain types of chemotherapy, commonly associated with the treatment of breast cancer
  • Minimizing or relieving hair loss contributes to improving quality of life and overall health and recovery

Reg Pathway: 

  • De Novo evaluation
  • Regulation Name: Scalp Cooling System to Reduce the Likelihood of
    Chemotherapy-Induced Alopecia
  • Regulatory Classification: Class II

Device Description:  Computer-controlled system that circulates cooled liquid to a head-worn cooling cap during chemotherapy treatment. The cooling cap is covered by a second cap made from neoprene, which holds the cooling cap in place and acts as an insulation cover to prevent loss of cooling.


  • Stage I and Stage II breast cancer undergoing chemotherapy (n=122)
  • Primary endpoint: Self-assessment of hair loss using standardized photographs
  • 66 percent of patients reported losing less than half their hair

Safety: Cold-induced headaches and neck and shoulder discomfort, chills, and pain




XSTAT 30 wound dressing

RevMedX, Inc., Wilsonville, Ore.

Indication for Use:  Patients at high risk for immediate, life-threatening, and severe hemorrhagic shock and non-compressible junctional wounds, when definitive care at an emergency care facility cannot be achieved within minutes.

Unmet Need:

  • Early control of severe bleeding may prevent shock and may be life-saving.
  •  30 to 40 percent of civilian deaths by traumatic injury are the result of hemorrhaging – 33 to 56 percent occur before the patient reaches a hospital.
  • Need for dressing to control severe, life-threatening bleeding from wounds in battlefield and civilian trauma settings

Reg Pathway: 510 K, Class II, substantially equivalent to the XSTAT

Device Description:

  • Syringe-style applicators containing 92 compressed, cellulose sponges that have an absorbent coating.
  • Sponges expand and swell to fill the wound cavity, creating a temporary physical barrier to blood flow.


Best Practices for IND Sponsor-FDA Meetings

FDA best practicesSummarizes FDA’s Philosophy

  • Timely & interactive
  • Scope
  • Types
  • Expectations
  • Best practices

Ideally, IND sponsors and FDA work collaboratively during the drug development process, having a shared public health goal of early availability of safe, effective, and high-quality drugs to the American public.



FDA – Industry – Academia Fellowships


Interested ?

Purple Book

purple book

WHAT : To see if particular biological product has been determined by to be biosimilar to or interchangeable with a reference biological product

WHY : User friendly resource for Biologics & Biosimilars (similar to The Orange Book for drugs & generics)



Model based pediatric dose selection



Current  Approaches and Challenges 

Pediatric clinical trials are becoming more prevalent and are now typically mandatory within clinical development plans. The important challenge in pediatric studies is in selecting a safe and effective dose or dose range.

System Pharmacology and Pharmacometrics  (PK) provide for development of model-based approaches to describe and understand important age-related factors influencing drug disposition and response in pediatric patients.

The application of Modeling and Simulation provide for better estimates of pediatric doses.

The Extrapolation of Efficacy findings from adults to the pediatric population has streamlined the development process especially for studies in older children.

According to the literature, the weight-corrected doses for drugs eliminated by renal excretion or metabolism involving CYP2C19, CYP2D6, N-acetyltransferase 2, or uridine diphosphate glucuronosyltransferases are similar in children and adults.

Unmet Need:  Focus on developmental changes in infants as well as further developing a paradigm for conducting PK/efficacy studies in infants, and children remain important unmet needs. PK of drugs in children may differ from adults for several reasons: variability due to age, gender, body composition, functionality of liver and kidneys and maturation of enzymatic systems throughout the life span from neonates to adults are all potential sources of pharmacokinetic differences.

There are other challenges that arise during pediatric clinical trials which may not be apparent during clinical trials in adults such as recruitment difficulties, lower limits on blood collection volumes, the lack of surrogate markers which predict clinical outcome and the difficulty of dose selection in a rapidly changing population.

Additional Considerations

Children’s growth can be investigated using readily observable demographic factors such as weight and age.

Size is the primary covariate and can be referenced to a 70-kg person with allometry using a scale to the ¾ power coefficient for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Lean body mass might be expected to do better than total body weight when there are wide variations in fat affecting body composition.

Sigmoid Emax model best describes the gradual maturation of clearance in early life leading to a mature adult clearance. Assuming similar exposure–response relationships between adult and children, efficacy in children is warranted if the same exposure can be achieved in either population.

Case Studies

  1. Small molecule (desloratadine; Gupta et al. Br J Clin Pharmacol, 64, 174-184, 2007
  2. Large molecule (peginterferon alfa-2b; Xu, Gupta, et al. Eur J Clin Pharmacol, 69, 2045-2054, 2013

Desloratadine Dose Selection:

We combined data from the pediatric study with adult data for population pharmacokinetic analysis to determine doses of desloratadine suitable for administration to children aged ≥ 6 months-≤ 2 years in clinical and efficacy studies.

Single doses of 0.625 mg (1.25 ml) and 1.25 mg (2.5 ml) desloratadinesyrup were well tolerated in this age group. Because the study was designed to collect only a minimal number of blood samples, a population pharmacokinetic modelling approach was used.

Results of the pharmacokinetic analysis indicate :

  • desloratadine apparent clearance rates were slower in the pediatric group studied than in adults, and that the 0.625 mg dose appeared to be suboptimal for both children aged ≥ 6 months-<1 year and for those aged ≥ 1 year- ≤ 2 years, particularly with respect to Cmax.
  • Variability between subjects in the model parameters was moderate, but was consistent with estimates of pharmacokinetic variables obtained with noncompartmental analysis. No systematic bias was observed in parameter estimation.
  • On the basis of the results of this analysis, to ensure similar desloratadine exposure to that seen in adults, the age appropriate doses for children aged ≥ 6 months-<1 year and for those aged ≥ 1 year- ≤2 years were established as 1.0 mg and 1.25 mg, respectively.
  • Desloratadine is extensively metabolized in the liver to its active metabolite, 3-OH-desloratadine. It is known that some individuals, termed poor metabolizers, have a reduced ability to form the active metabolite. Exposure to desloratadine has previously been shown to be approximately six-fold greater in poor metabolizers than in the rest of the population, with a similar magnitude of reduction in the formation of 3-OH-desloratadine in adults and children given age-appropriate doses. Based on the observed AUC ratio of 3-OH-desloratadine relative to desloratadine, the proportion of poor metabolizers in this study population was approximately 7%. The poor metabolizers are African American. This is consistent with the findings of a large clinical study in older children and adults, which found an age-independent prevalence of this phenotype of 6%.
  • Despite the difference in exposure to desloratadine in poor metabolizers, data from studies in patients as young as 2 years have shown it to be well tolerated. This was also the case in this study, with no differences in the safety profile of desloratadine between poor metabolizers and other subjects. These pediatric dose concentrations yielded systemic desloratadine exposures similar to those seen in adults.

Peginterferon alfa-2b dose selection:

The final population pharmacokinetic model of PEG-IFN alfa-2b was a one-compartment model with first-order absorption, first-order elimination, exponential inter-individual variability on apparent clearance, and with a combination additive and proportional residual error model. The body surface area normalized apparent clearance of PEG-IFN alfa-2b was similar across all age groups (3-17 years) and the mean estimated CL/F at age 19 was 1.38 L/hr, which is similar to the CL/F in adults of 1.29 L/hr to 1.54 L/hr. Populations in pediatric studies frequently cover a much wider relative range in body size than comparable studies in adults; the current pediatric data set confirms that size parameters—including body weight, height, BMI, and body surface area are highly correlated with other developmental or maturation-related parameters. Previous clinical trials have shown PEG-IFN alfa plus ribavirin to be an effective treatment option in children and adolescents. These studies have revealed that many of the predictors of sustained viral response (SVR) in adults are also applicable when treating children. Rates of SVR are lower among children with genotype 1 infection compared to genotype 2 or 3 (53% vs 93%, P = .0005), and within the genotype 1 population, baseline viral load <600,000 IU/mL is associated with increased rates of SVR compared to high baseline viral load. (72% vs 29%, P = 0.0006). Furthermore, rapid- and early virologic response are also strong predictors of SVR in the pediatric population with positive predictive values of 89% and 84%, respectively.

As with all studies of this type, several factors may limit interpretation of the data. The concentrations from sparse pharmacokinetic sampling may not contain enough information to estimate Ka accurately for each individual, and the estimated standard error of inter-individual variability for Ka was greater than for CL/F and V/F. In addition, there were 5 outliers with low CL/F whose observed concentration of PEG-IFN alfa-2b tended to increase after week 8, leading to lower CL/F values compared with other patients. To assess this further, an additional population pharmacokinetic analysis was performed, which included week 1-8 concentration data for all 107 patients. The final population pharmacokinetic one-compartment model suggests age-dependent increases in clearance and volume of distribution of PEG-IFN alfa-2b in pediatric patients with chronic hepatitis C. The body surface area normalized apparent clearance was similar across pediatric age groups, validating the use of a body size–adjusted dosing schedule in pediatric subjects.




FDA Brief, Weeks of Nov. 23 and 30, 2015

FDA approved

BMSEMPLICITI (elotuzumab) for injection

Indication:  In combination with lenalidomide (Revlimid)  and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies

Unmet need:

  • Multiple myeloma form of blood cancer in  bone marrow
  • 26,850 new cases and 11,240 related deaths in the US in 2015
  • Need to therapies to provide additional benefit vs currently approved

Reg Pathway:  BLA, Breakthrough Designation, Priority Review, Orphan Drug Designation

Mechanism of Action:  Humanized IgG1 monoclonal antibody targeting  SLAMF7 (Signaling Lymphocytic Activation Molecule Family member 7)  expressed on myeloma cells and Natural Killer cells to mediate the killing of myeloma cells


  • Randomized open label (n=646); Empliciti + lenalidomide and  dexamethasone vs . lenalidomide and  dexamethasone
  • Progression-Free Survival : Hazard Ratio (95% CI) :0.70 [0.57, 0.85], p = 0.0004
  • Overall Response Rate : 252 vs.213, p = 0.0002
  • 1-and 2-year PFS rates :  68% and 41% vs. 57% and 27%, respectively



  • Most common side effects: Fatigue, diarrhea, fever (pyrexia), constipation, cough, nerve damage resulting in weakness or numbness in the hands and feet (peripheral neuropathy), infection of the nose and throat (nasopharyngitis), upper respiratory tract infection, decreased appetite and pneumonia


 Fluad (inactivated influenza vaccine containing adjuvant)

 Indication:   Aactive immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine; approved for use in persons 65 years of age and older

Unmet Need:

  • 80 – 90 %  of seasonal influenza-related deaths & 50 – 70 %  of seasonal influenza-related hospitalizations occur in 65  years of age and older.
  • Need for immunizing in this age group; to decrease disease burden as well as  influenza-related hospitalizations and deaths

Reg Pathway: BLA, Accelerated Approval

Mechanism of Action:  Inactivated trivalent influenza vaccine,  containing hemagglutinin of influenza virus strains (two subtypes A and one type B), representing the  viruses likely to be circulating in the US  in  winter

Efficacy: Approval is based on the immune response; data demonstrating a decrease in influenza disease after vaccination  not available

  • Single study (n= 7,082) Fluad vs Agriflu (unadjuvanted vaccine)
  • Primary  immunogenicity analyses:Non-inferiority for all three vaccine strains for antibody levels


  • No safety concerns
  • Most common adverse events : Injection site pain and tenderness, muscle aches, headache and fatigue


lilly  Portrazza (necitumumab injection)

Indication: In combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer

Unmet need:

  • Lung cancer leading cause of cancer death in US
  • 221,200 new diagnoses and 158,040 deaths in 2015
  • Lung cancer tumors  varied, so need tailored treatment options to extend survival

Reg Pathway:   BLA, Standard Review

Mechanism of Action : Recombinant human lgG1 monoclonal antibody that binds to human epidermal growth factor receptor (EGFR) commonly found in lung cancer and blocks  malignant progression, induction of angiogenesis, and inhibition of apoptosis.


  • Multicenter, randomized, open-label (n= 1,093(, Portrazza + chemotherapy (gem + cis) vs chemotherapy alone
  • Overall Survival (median) : 11.5 mo. vs 9.9 mo. (p = 0.01)
  • Progression Free Survival (median) : 5.7 mo. vs 5.5 mo. (p=0.02_
  • No difference in Overall Response Rate


  • Most common side effects: Skin rash and magnesium deficiency (hypomagnesemia), which can cause muscular weakness, seizure, irregular heartbeats and can be fatal
  • Boxed Warning: Serious risks of  cardiac arrest and sudden death, as well as hypomagnesemia.


BMSOpdivo (nivolumab injection)

Indication : Treat advanced (metastatic) renal cell carcinoma  who have received prior anti-angiogenic therapy

Unmet need: 

  • Renal cell carcinoma is the most common form of kidney cancer
  • 61,560 new cases and 14,080 deaths from kidney and renal pelvis cancer in the US in 2015 .
  • Need for therapy to extend  survival ( Torisel, approve din 2007, only agent to extend survival)

Reg Pathway : Supplemental BLA, Breakthrough Therapy Designation, Fast Track Designation, Priority Review

Mechanism of Action: Human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor,releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.


  • Single open-label  randomized (n=821), Opdivo vs  everolimus
  • Overall Survival (median) : Median 25.0 mo. vs 19.6 mo. (p = 0.0018)
  • Complete or partial tumor shrinkage : 21.5 % (for 23 mo.) vs 3.9 % (for 13.7 mo)



  • Most common side effects : Abnormal weakness or lack of energy (asthenic conditions), cough, nausea, rash, difficulty breathing (dyspnea), diarrhea, constipation, decreased appetite, back pain and joint pain (arthralgia).
  • Serious  side effects :  “immune-mediated side effects” involve healthy organs, including the lung, colon, liver, kidneys, hormone-producing glands and the brain.


emergentBioThrax (Anthrax Vaccine Adsorbed)

Indication : Active immunization for the prevention of disease caused by Bacillus anthracis in persons 18 through 65 years of age.

Unmet Need: 

  • Anthrax disease, esp.inhalation form, is often fatal
  • Need for vaccine to prevent disease after exposure to anthrax spores (Post Exposure prophylaxis – PEP)

Reg Pathway:Supplemental BLA, FIRST  Approval  based on  Animal Rule.;  allows animal efficacy data to be used as a basis for approval when human efficacy studies are not ethical or feasible.

 10-year collaborative effort between Emergent, Biomedical Advanced Research and Development Authority (BARDA),  National Institute of Allergy and Infectious Diseases. A  2010 pre-Phase 3 Vaccines and Related Biological Products Advisory Committee meeting confirmed the regulatory pathway  

Mechanism of Action : Induces antibodies for  neutralizing the activities of the cytotoxic lethal toxin and edema toxin of Bacillus anthracis

Efficacy :

Animal Models : To derive protective antibody thresholds to bridge animal efficacy and human immunogenicity data and predict efficacy in humans.

  • Pivotal efficacy animal studies  in rabbits and nonhuman primates: Model developed for  70% probability of survival
  • 70-100% survival in animals receiving both  antimicrobial treatment and vaccination vs  antimicrobial treatment only

Human Studies : Safety and antibody responses

  • 200 healthy adults in three doses at zero, two, and four weeks;  antibody responses  correlated to a 70 percent probability of survival  observed in animal models.

Safety : Localized adverse events reported as tenderness, pain, swelling, and redness at the injection site, as well as limited movement of the injected arm. The most common systemic adverse reactions were muscle aches, headache, and fatigue


AngioJet™ ZelanteDVT™ Thrombectomy Catheter

510K Clearance, Boston Scientific

  • Use with the AngioJet Ultra Console to break apart and remove thrombus, including deep vein thrombus (DVT), from:
    • Iliofemoral and lower extremity veins ≥ 6.0 mm in diameter
    • Upper extremity peripheral veins ≥ 6.0 mm in diameter.
  • Infusion of physician specified fluids, including thrombolytic agents, into the peripheral vascular system.
  • NOT been evaluated for pulmonary embolism (PE)

algovitaAlgovita Spinal Cord Stimulation (SCS) System

510K Clearance, Nuvectra

  • Aid in the management of chronic intractable pain of the trunk and/or limbs, including unilateral or bilateral pain associated with failed back surgery syndrome, intractable low back pain, and leg pain.
  • 24-channel implantable pulse generators (IPGs)
  • Wireless clinician programmer with  computer-assisted stimulation programming to assist with effective and efficient localization, targeting and fine-tuning of pain coverage.




SilverCoat Silicone Foley Catheter

510K Clearance, Covalon Technology

  • Greater bacterial kill than two of the leading antimicrobial catheters
  • Minimizes biofilm formation and bacterial adherence
  • Kills pathogens most associated with CAUTI (Catheter Associated Urinary Tract Infections)




IQQA-Guide, an intra-operative 3D navigation system for thoracic, abdominal, and pelvic surgery

510K Clearance, EDDA Technology

  • Patient-specific anatomic models  extracted from multi-modality images for  3D navigation during surgery
  •  Surgeon can “see through” organ surfaces; may reduce use of intra-operative CT scans during imaging-guided surgical procedures

FDA Drug Safety Communication:

WARNING:  SGLT2 inhibitors for diabetes can cause too much acid in the blood and serious urinary tract infections

SGLT2 inhibitors


  • March 2013 – May 2015: 73 cases of ketoacidosis with hospitalization, 19 cases of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis)
  • May 2015 : Drug Safety Communication alert; continue to evaluate
  • Now :  Patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they have any symptoms of ketoacidosis. Health care professionals should assess for ketoacidosis and urinary tract infections in patients.  Label updated to include WARNING





ASH/FDA Joint Symposium on Late-Breaking Drug Approvals


WHAT: Discuss safety and efficacy issues, clinicians perspectives on use in real world.

WHERE : American Society of Hematology (ASH) 57Th Annual meeting and Symposium, Orlando, Florida

WHEN:  December 7, 2015: 4:30 PM-6:00 PM

WHO: Panelists- FDA, Mayo Clinic, Harvard Medical School

Orange Book : Approved Drug Products with Therapeutic Equivalence Evaluations

  • Identifies FDA approved drug products on the basis of safety and effectiveness
  • 1980 : Print publication in October 1980.
  • 1997 : Orange Book Search on FDA website
  • NOW : Download App


orange book

Public Workshop – Moving Forward: Collaborative Approaches to Medical Device Cybersecurity

WHAT: To discuss complex challenges in medical device cybersecurity that impact the medical device ecosystem.

WHEN, WHERE:  Jan 20-21, 2016, FDA White Oak Campus , MD

WHO: FDA, National Health Information Sharing Analysis Center, Department of Health and Human Services, Department of Homeland Security

HOW: Open to Pubic.